A History of Vaccines and their Opponents 0443134340, 9780443134340

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A History of Vaccines and their Opponents

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A History of Vaccines and their Opponents

Ian R. Tizard University Distinguished Professor of Immunology, Department of Veterinary Pathobiology, The Texas Veterinary Medical Center, Texas A & M University, College Station, Texas, USA

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright Ó 2023 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-443-13434-0 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Stacy Masucci Acquisitions Editor: Elizabeth A. Brown Editorial Project Manager: Lira Faurillo Production Project Manager: Swapna Srinivasan Cover Designer: Matthew Limbert Typeset by TNQ Technologies

Dedication To Claire

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Contents Preface

1.

xv

How vaccines work The microbial world The immune system The defenders Innate immunity Adaptive immunity Antibody-mediated immunity Cell-mediated immunity The adaptive immune response Step 1: Antigen capture and processing Step 2: Helper T cell activation Step 3: B or T cell responses Antigen processing Step 4: Memory cell generation References Further reading

2.

Medical science at the beginning of the 18th century Hippocratic medicine The humoral theory The status of physicians Witchcraft Seventeenth century Variolation References Further reading

3.

1 4 4 5 6 8 11 11 13 14 14 15 16 17 18

19 20 24 25 26 27 28 28

Variolation: the early years in Britain and Europe Immunity Variolation in Asia Emanuel Timoni’s letter Lady Mary Montagu Inoculation progress

30 30 32 33 36

vii

viii Contents Early resistance to inoculation Edmund Massey Endorsement of inoculation Persistent opposition Resistance and acceptance in Europe France Germany References

4.

Variolation in New England Cotton Mather Smallpox in Boston Zabdiel Boylston Responses William Douglass Subsequent reconsideration Medical arguments Religious arguments Arguments for variolation Actual results More Boston epidemics References

5.

53 54 56 57 59 60 60 61 63 63 64 66

Variolation and American independence Boylston’ legacy Legislation and inoculation Washington’s dilemma Smallpox and the revolutionary war The first immunization mandate Major influencers Benjamin Franklin and his son Abigail Adams and her children The state of medicine References

6.

37 38 40 47 48 48 50 50

70 70 72 72 73 76 76 78 79 80

The introduction of vaccination in Britain and Europe Vaccination Edward Jenner Subsequent studies Rapid adoption Methodology Horsepox Initial responses Hostility Dr William Rowley

83 83 87 87 89 90 90 90 91

Contents

Dr Benjamin Moseley Charles Creighton Positive responses Vaccination in Europe References Further reading

7.

103 103 105 108 108 109 110 112 113 113 113

Making vaccination compulsory in Britain and Europe Compulsory vaccination laws The 1840 Act The 1853 Act The 1867 Act The 1871 Act The 1898 Vaccine Act Benefits of mandates Ireland Mandates in Europe Typhoid vaccines References

9.

92 94 95 98 100 101

The introduction of vaccination to America First deliveries John Clinch Benjamin Waterhouse Supply problems Early opposition and exploitation The first federal vaccination legislation Vaccine farms The Camden incident The Biologics Control Act of 1902 Triumph References

8.

ix

117 117 117 118 119 120 121 122 122 123 126

Vaccine mandates in the United States State-mandated vaccination Phase 1: 1810e1920. Mandatory smallpox vaccination Mandatory smallpox vaccination Mandate enforcement Phase 2: 1910 to 1940e60: Voluntary vaccination Phase 3: 1960epresent: New vaccine mandates Polio vaccine mandates Measles vaccine mandates Current state mandates Covid vaccine mandates Canada

127 128 130 130 132 134 136 137 137 138 138

x Contents Exceptions Military mandates References Further reading

10.

Anti-inoculation and anti-vaccination riots Anti-inoculation riots The 1730 Marblehead riot 1774dMarblehead again! 1768e1769: The Norfolk riots Anti-vaccination riots The Montreal vaccine riots of 1885 The Milwaukee riots of 1894 The Laredo smallpox riots, 1899 Some British riots The Seven Wise Men of Keighley The Charlbury anti-vaccination riots The vaccine rebellion, Brazil, 1904 Coronavirus vaccine protests References

11.

145 145 146 146 148 148 150 150 151 151 152 153 153 154

The Supreme Court weighs in Smallpox in Boston Anti-vaccination sentiment The Pfeiffer affair Jacobson v Massachusetts Zucht v King Prince v Massachusetts O’brien v Cunard Maricopa County v Harmon Vaccine compulsion References

12.

139 140 142 144

157 158 159 160 163 163 164 164 165 165

The rise of anti-vaccine societies in Britain The Anti-Vaccination League of 1853 The Anti-Compulsory Vaccination League of 1867 The London Society for the Abolition of compulsory Vaccination The National Anti-Vaccination League of 1896 George Bernard Shaw Alfred Russel Wallace Leicester William Tebb References

168 169 171 172 172 173 174 177 178

Contents

13.

Anti-vaccination movements in the United States and Canada The Anti-Vaccination League of America William Tebb The Anti-Vaccination Society of America The Anti-Vaccination League of America Lora Little State anti-vaccination efforts New England Minnesota Louisiana Pennsylvania California Meanwhile in Canada The arguments Freedom Safety Other issues References

14.

182 183 183 185 187 189 189 189 190 190 190 191 193 193 193 194 195

Medical liberty and vaccination Diverse medical theories Homeopaths Eclectics Hydropathy Chiropractors Osteopaths Physiomedicalism Patent medicines Medical associations The American Medical Association The National League for Medical Freedom The American Medical Liberty League The Flexner Report of 1910 References

15.

xi

198 198 200 200 200 202 202 203 203 203 204 204 205 207

Developments and dead ends in immunology Horsepox and vaccination Syphilization Syringes and needles Vaccination Louis Pasteur Anthrax and rabies

209 213 214 215 215 216

xii Contents Dead vaccines Antiviral vaccines References Further reading

16.

Antibacterial vaccines and their opponents Diphtheria The Ididarod The Balto debate The St Louis incident of 1901 Active immunization Tetanus Pertussis Combination vaccines Opposition USA Analysis References

17.

224 227 229 230 231 234 234 236 238 240 242 242

Polio vaccines and their opponents The disease Jonas Salk Albert Sabin Opposition Chiropractors The Cutter incident Global eradication Nigeria Vaccine-induced polio Pakistan Afghanistan The endgame References

18.

218 218 221 222

246 248 249 251 252 254 255 256 257 258 260 261 262

Measles, mumps, and rubella: three contentious virus diseases Adverse effect principles Measles Current status Measles vaccines Mumps Mumps vaccines Rubella Rubella vaccines Dr. Andrew Wakefield

266 266 267 267 271 271 272 272 273

Contents

Conflicts of interest Methodological problems Retraction Autism spectrum disorder The response The consequences Thiomerosal Foreign intervention References

19.

282 282 284 284 285 286 288 288 289 290 291

COVID-19: politics and disinformation The origins of COVID-19 COVID-19 vaccines RNA vaccines Vaccination mandates Political partisanship Reasons for hesitancy Social media Antivaccine strategies Lack of trust Conspiracy theories Medical misinformation Consequences References

21.

274 274 275 275 276 276 277 278 279

Safety and sexual promiscuity: hepatitis B, human papilloma virus, and influenza vaccines Hepatitis B Multiple sclerosis SIDS and HBV vaccine Human papilloma virus Initial problems Current problems Encouragement of immorality Heavy marketing/mistrust Trypanophobia Influenza vaccine hesitancy References

20.

xiii

294 295 296 297 300 301 302 303 303 307 310 311 313

Religious objections to vaccination Early religious objections Christian attitudes Non-objecting denominations Objecting denominations The problem of “sorcery”

316 317 318 320 324

xiv Contents Issues and moral responsibility Jewish attitudes Islamic attitudes Hindu attitudes Buddhist attitudes References

22.

324 325 325 326 328 328

Rational hesitancy: situations where hesitancy is and was appropriate Medical exemptions The swine flu scared1976 The smallpox scared2002 Anthrax vaccination References

Glossary Index

332 332 335 338 338

341 345

Preface This is not a book about good versus bad people. This not about smart versus stupid people. It is not a book about differing opinions. It is a book about opinions versus scientific evidence. It is a book about a 300-year war. The first shots were fired in Constantinople in March 1718 when Lady Mary Montagu had her son inoculated in Constantinople despite the objections of her chaplain. The fight reignited in June 1721 when the Boston physician Zabdiel Boylston first inoculated his son against smallpox. At the same time, Lady Mary Montagu in London was promoting smallpox inoculation to the British Royal Family. The conflict continues to this day. It is a battle between facts and opinion. Those who oppose vaccination, the losers, like the diseases they support, have suffered defeat after defeat. Yet they continue to battle the inconvenient fact that vaccines have been among the greatest medical achievements ever. Even today, they fight against COVID-19 vaccination. As in real battles, there are real casualties. People die as a result of anti-vaccination beliefs and misinformation. Unvaccinated children die. Not just in the developed West but around the world. The war has pitted prejudice, selfishness, opinion, superstition, and anecdote against hard data and scientific reality. The outcome has been clear; vaccines have won these battles based on the principles of evidence-based medicine and saved untold millions of lives. Vaccines continue to improve. Efficacy improves as well as safety. Safety is paramount despite the efforts of vaccine deniers. Long may that continue and the efforts of anti-vaxxers, and their viral allies continue to be thwarted by proven results and lives saved. Vaccination has been one of the most significant life-saving achievements of medicine across the past two centuries. Vaccines do not treat a disease, they prevent it. They train the immune system to recognize and destroy invaders such as viruses and bacteria. The fact that they prevent infectious diseases is a problem since recipients do not always see immediate results. Drugs treat disease and patients often see a rapid improvement. That is not the case with vaccines. Positive results with vaccines are not immediately obvious and are measured by what does NOT happen. Vaccines not only protect individuals but society as a whole by preventing disease transmission. They reduce the number of susceptible individuals and protect those who are vaccinated as well as those who are not through establishing herd immunity. Consider smallpox and the efforts made by anti-vaxxers over more than 100 years to prevent vaccination. Their efforts

xv

xvi Preface

were totally wasted since as a result of vaccination, and vaccination alone, the smallpox virus has been eradicated from the globe. One consistent feature of the conflict has been that each side accuses the other of falsifying data. Even at the present time such claims continue to be made. However, facts will out. Anecdotes, however lurid, do not change facts. Anecdotes are not the plural of data. The events recorded in this book also remind us that science, while not infallible, is self-correcting and objective. Thus, it acknowledges and corrects past failures and inaccurate or misleading claims. That does not permit its opponents to claim that science is never accurate, or scientists are lying as a matter of principle. That is how science works. Results must be reproducible. It is inherently objective. Selfishness, misinformation, and disinformation have continued to maintain the anti-vaccine fight using all the tools of modern communications. But facts are stubborn things and vaccines will continue to triumph over infectious diseases despite the opinions of their opponents. Notwithstanding this, inoculation was first promoted by Cotton Mather a believer in witchcraft. It is currently opposed by politicians who consider it to be sorcery. Some things never change. Mark Twain may well have said. “History does not repeat itself, but it often rhymes.” This is certainly the case with the opponents of vaccination. From the very beginning they have followed a standard playbook. Exaggerate safety concerns and minimize benefits. It is certainly true that when first introduced, vaccination, and variolation were indeed hazardous procedures, but the risks involved were significantly less than those incurred in developing smallpox. This risk/benefit ratio accompanies the use of all medications including both drugs and vaccines. Vaccines however differ from drugs in that they are normally administered to healthy individuals and any adverse effects are both obvious and unwanted. Despite the emphasis in this book on the role of anti-vaccinators in history, it must always be remembered that they have usually represented a small, but loud, minority of the population, although degrees of opposition vary greatly. The great majority of thinking individuals recognize the life-saving benefits of vaccination and are prepared to put up with the discomfort and inconvenience of getting vaccinated for the sake of themselves and their children. To those who do not believe that vaccines are effective, consider the use of vaccines in veterinary medicine, especially in the livestock industries. Vaccination use in cattle, pigs, or poultry is not driven by sentiment. The use of vaccines is a hard economic decision. Not one vaccine would be used by these industries if they could be avoided. Vaccines cost money to purchase and more significantly, cost money to administer. Animals must be gathered, handled, held, and given the vaccine. All this costs money. Nevertheless, these livestock industries would not consider not vaccinating. Vaccines keep animals alive and healthy. They make a difference between profit and loss. Vaccines work.

Preface xvii

For 200 years anti-vaxxers fought smallpox vaccination. Their interventions cost many lives, but they cannot argue that smallpox has not been globally eradicated. Had they not fought how many more lives would have been saved? Antivaxxers in Pakistan and Afghanistan are currently preventing the final eradication of polio. As a result, children suffer and die unnecessarily. Even in developed Western countries, they still are. COVID-19 has become a disease of the unvaccinated. Reliable data shows that in the United States, there has been significantly greater mortality from COVID-19 among the adherents of one political party than the other. The American patriot Patrick Henry once proclaimed, “Give me Liberty or give me Death.” By that he presumably meant that he was prepared to die to promote the cause of liberty. Many anti-vaxxers believe that they are making the same choice in refusing to vaccinate. However, any consequent deaths do not benefit mankind, nor the cause of freedom. The only thing that benefits is the virus! Likewise, those politicians who have banned vaccine mandates promote not the cause of liberty, but the spread of viruses. Much of this current reluctance to vaccinate and the consequent deaths in the United States are a result of political anti-vaccine activism focusing on “medical freedom.” Much reluctance also reflects a total lack of “vaccine literacy” and a resulting susceptibility to assorted conspiracy theories. Either way, when politicians from states that have discouraged vaccination and yet claimed “victory” over the disease despite an enormous mortality rate among their supporters, it reflects a level of hubris not previously seen through history. The battle will no doubt continue to rage, but the lessons of history are inescapabledvaccines work. Infectious agents and their anti-vaccination allies are the inevitable losers. Ian R. Tizard

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Chapter 1

How vaccines work Recently, a Texas lawmaker characterized the research undertaken by a prominent immunologist in that state as “sorcery.” It is obvious that this legislator had never had the privilege of taking a course on immunologydthe science of the defense of the bodydthe science that is the basis for vaccination. Indeed, it is apparent that much opposition to vaccination results from a complete lack of understanding as to how vaccines work. In effect, the immune system is to many, a mysterious “black box.” Thus, before discussing the history of opposition to vaccines, it is important to have a sense of the complex mechanisms behind them and the sound scientific foundations upon which they stand. Put quite simply, the immune system encompasses the body’s defenses and is needed if we are to survive in a microbial world.

The microbial world We live in a world dominated by microbes, both bacteria and viruses. They are everywheredin the air we breathe, in the water we drink, in our soil, in our homes, even within our own bodies, and on our skin. Some of these microbes may invade our bodies and multiply, seeking to exploit our resources, and in so doing can cause tissue and cell damage leading to sickness and death. In the absence of strong immune defenses, we would simply be eaten alive by these microorganisms. Effective defenses are an absolute requirement if animals are to survive in a microbial world and efficiently repel such microbial invasions. Given however the great diversity of these disease-causing microbes, our defenses have to be flexible and able to defend us against any threat irrespective of the nature of the causal microbe. They have to be prepared for any eventuality. The animal body contains all the components necessary to sustain life. It is warm, moist, and rich in nutrients. As a result, animal tissues are extremely attractive to microorganisms that try to invade the body and exploit these resources for themselves. The magnitude of this microbial attack can be readily seen when you die. Within a few hours, especially when warm, a dead body decomposes as bacteria invade its tissues. On the other hand, the tissues of living, healthy animals are highly resistant to invasion since their survival depends on preventing this microbial attack.

A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00017-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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2 A History of Vaccines and their Opponents

Historically, our experiences regarding infectious diseases have caused us to think of all microbes as potential enemies. Dangerous microbial invaders include not just bacteria and viruses but also diverse fungi, protozoa, and parasitic worms. Nevertheless, the real situation is much more complex than simply antimicrobial warfare. Bacteria (and some viruses) find animals, including us humans, to be a rich source of nutrients and a great place to shelter. As a result, enormous numbers live on our body, especially within our intestines, in our airways, and on our skin. Most of these bacteriadour normal microbiotaddo not even try to invade the body and do not normally cause any damage. They share resources with us and so are regarded as commensal organisms. The presence of this commensal microbiota on our surfaces must either be tolerated or ignored if an animal is to remain healthy. We cannot afford to act aggressively toward our own microbiota. Our defensive immune responses must be carefully regulated and must not be triggered unless necessary for the defense of the body. For example, our immune system is well aware of the intestinal microbiota. Molecules from these bacteria can cross the intestinal wall, enter the body, and influence our immune system. These molecules do not however automatically trigger strong defensive responses unless tissue damage also occurs. Any defensive response is therefore measured, proportional, and carefully controlled. The immune system has to watch the microbiota warily, but they rarely cause trouble in healthy individuals. In fact, they are needed for the proper digestion of our food as well as serving as a stimulus that keeps our defenses in peak operating condition. A small number of other more aggressive bacteria and viruses try to invade human tissues where they can multiply and so cause damage and disease. This is normally prevented, or at least controlled, by our immune system. If these organisms succeed in invading the body and overcoming our immune defenses, they may be able to cause sufficient damage to result in disease or death. On the other hand, some microorganisms such as the viruses, are intracellular parasites that can survive for only a limited time outside the human body. Viruses can only survive if they can avoid the host’s defenses for sufficient time to replicate and transmit their progeny to a new human host. While it is essential for animals to control invading organisms (or at least minimize the damage they cause), viruses are under even more potent selective pressure. They must find a host or die. Viruses that cannot evade or overcome the immune defenses will not survive and will be eliminated. As a result, viruses have evolved many methods of evading our immune defenses. For example, influenza and coronaviruses are constantly changing their coat proteins. They try to stay one jump ahead of our defenses. Fungi, like bacteria, are opportunistic invaders that can take advantage of local circumstance to invade the host. They commonly exploit situations where the host’s immune system is defective or suppressed in some way. Parasitic worms and protozoan parasites

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must also be able to survive within a host or be eliminated. They have also evolved numerous and complex strategies to evade immune destruction. An organism that can cause sufficient damage to result in disease is said to be a pathogen. Remember, however, that only a small proportion of the world’s microorganisms are associated with humans and very few of these can overcome the body’s defenses and become pathogens. Pathogenic microorganisms also vary greatly in their ability to invade the body and cause damage. This ability is measured in terms of virulence. Thus, a highly virulent organism has a greater ability to cause damage than an organism with low virulence. If an organism can cause significant damage almost every time it invades a healthy individual, even in low numbers, then it is considered to be a primary pathogen. Examples of primary pathogens include coronaviruses, smallpox virus, the diphtheria bacillus, and malaria parasites. Other pathogens may be of such low virulence that they will only cause disease if administered in very high doses or if the immune defenses of the body are impaired first. These are considered opportunistic pathogens. An example of an opportunistic pathogen is the fungus, Pneumocystis jirovecii, the cause of lung disease in AIDS patients. Pneumocystis rarely causes disease in healthy humans. For many years, it was believed that the role of the immune system was simply to ensure the complete exclusion of all invading microbes by distinguishing between “self” and “not-self” and eliminating anything identified as foreign. We now know however that this is an oversimplification. The immune system must also be able to determine the threat level posed by any microbes it encounters and adjust its responses accordingly. It must be relatively unresponsive to the normal microbiota while, at the same time, be highly responsive to invading pathogens. As a result, when making a vaccine, scientists must produce a product that stimulates the strongest possible protective response while, at the same time, not causing any significant injury to the patient. Because effective resistance to microbial invasion is critical for survival, our bodies dare not rely on a single defense mechanism alone. To ensure reliability and flexibility, multiple different defense pathways must be available and on-call. Some are effective against many different invaders. Others can only destroy specific organisms. Some act on body surfaces to exclude invaders. Others act deep within the body to destroy organisms that have breached the outer defenses. Some defend against bacterial invaders, some against viruses that live inside cells, and some against large invaders such as fungi, or parasitic worms. The protection of the body therefore depends upon a complex system of overlapping and interlinked defense pathways that form networks using cells and molecules and that, when activated, can collectively destroy or control almost all invaders. Any failure in these defenses that permits invading organisms to overcome or evade them will result in disease and possibly death. An effective immune system is therefore not simply a useful system to have around. It is essential to life itself.

4 A History of Vaccines and their Opponents

The immune system can be thought of as a set of cellular and molecular networks where the presence of foreign invaders triggers changes in cellular activities and generates an expanding set of defensive responses that eventually results in elimination of the invaders and increased resistance to infection. Most of the complexity of the immune system stems from the fact that it has to be able to respond to thousands of diverse bacteria, viruses, and parasites. To do this, the networks must interact and intersect. Microbial invasion therefore triggers multiple responses involving many different cell types producing many different molecules. Collectively, these pathways and their responses constitute our immune system. Under normal circumstances, the major component of protective immunity, the adaptive immune system, may take several days to respond to an invader that it has never encountered previously. During that time, we can get very sick indeed and may die. Vaccination is a method of activating the immune system in advance of microbial invasion. The immune system of vaccinated individuals is forewarned and ready to go. The system develops and stores large populations of “memory” cells that can respond immediately and rapidly to any microbial invaders that they have encountered previously, so preventing the development of sickness. As a result, a vaccinated individual remains healthy and, in many cases, totally unaware of how their immune system saved them from disease and death (Iwasaki and Omer, 2020).

The immune system The immune system consists of two major subsystems that differ in their speed of response. One is a rapidly responding innate system while the other is a much slower, but more effective adaptive system. Both of these subsystems, namely innate immunity, and adaptive immunity, are required to generate a strong, effective protective response to invading microbes or to vaccines. The rapidly responding innate immune responses also promote the initial stages of adaptive immunity. We take advantage of this by adding substances called adjuvants to some vaccines in order to trigger these innate responses and so enhance their effectiveness. Innate immune responses are also essential in providing the rapid protective immunity that develops when we use vaccines containing live organisms such as oral polio vaccine.

The defenders Resistance to infection relies on many different cells and molecules. Together, these cells and molecules possess redundancies, regulatory mechanisms, and the ability for multiple simultaneous responses working together to ensure microbial destruction. In addition, their responses need to be adaptable and able to adjust their strategies depending upon the nature and severity of the threat. This of course maximizes their efficiency and minimizes the chances of

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any individual microbe successfully evading those defenses. It is also important to point out that because the successful defense of the body is critical, the body does not rely on a single pathway for its defense. As a result, invading organisms are confronted with multiple defensive barriers that together are usually sufficient to block, kill, and then eliminate most invaders.

Innate immunity Animals need to detect the presence of microbial invaders as fast and as effectively as possible. The functioning of this rapid alarm system and its immediate response is the task of the innate immune system. Many different innate defense mechanisms have evolved over time and the innate immune system therefore consists of multiple subsystems that work through many different pathways. Collectively, they all respond rapidly to block microbial invasion, kill any invaders they detect, minimize tissue damage, and start any repairs needed. These responses are generic. That is, they can detect invading microbes such as bacteria and viruses because these organisms differ structurally and biochemically from normal animal tissues. Once the presence of the invaders has set off the alarms, multiple defensive responses are activated. These induced defenses are a response to the presence of bacteria, viruses, or even just cell and tissue damage (Fig. 1.1). The body’s alarm system consists of populations of sentinel cells that are located throughout the body. These cells possess receptors that can detect molecules characteristically associated with invading bacteria and viruses in addition to molecules released by dead and broken cells, collectively called “alarmins”. The activated sentinel cells then emit molecular signals that attract white blood cells, called leukocytes. Huge numbers of leukocytes, leave the bloodstream where they normally circulate, enter the tissues, and converge on the invaders. When they encounter any invader, they catch, eat, and kill it. This process is called inflammation. Inflammation is central to the innate defenses of the human body. Once all the invading microbes are eliminated, some of these leukocytes may also stay behind to help repair damaged tissues. It is this combination of microbial-induced tissue damage as well as inflammation and the release of signaling molecules into the bloodstream that results in the set of behaviors that we call sickness. These include fevers, malaise, loss of appetite, and fatiguedan occasional complication of some vaccines. In many of the following chapters, we discuss vaccination against the virus disease, smallpox. The earliest smallpox vaccines consisted of pus taken from the inflammatory lesions caused by the smallpox virus. Pus is a thick whitish-yellow fluid containing enormous numbers of leukocytes. It reflects the intensity of the body’s innate response to the virus. The innate immune system lacks any form of memory and as a result, each episode of infection tends to be treated identically. The intensity and duration of innate responses such as inflammation therefore remain unchanged no

6 A History of Vaccines and their Opponents

Invading microbes Pattern-recognition receptors on sentinel cells

BACTERIA

VIRUSES

Interleukin 1 Tumor necrosis factor

Interferons Block viral growth

Attract swarms of white cells Local effects

Systemic effects

Pain Redness Swelling

Fever Fatigue Malaise

FIGURE 1.1 The basic features of the innate immune system. It rapidly detects invaders using specialized receptors on sentinel cells. These cells then release proteins such as interleukin 1, tumor necrosis factor, and interferons. The interferons block viral growth. The other proteins attract white blood cells that kill and eat bacteria. This process is the cause of uncomfortable inflammation and even sickness behaviors. Some vaccines may trigger strong innate immune responses.

matter how often a specific invader is encountered. Innate immunity cannot be boosted by repeated doses of vaccine. These innate responses also come at a pricedthe pain of local inflammation or the mild toxic effects of vaccines largely result from the activation of innate immune processes. More importantly, however, the innate immune responses serve to stimulate the adaptive immune responses and so eventually result in strong long-term protection. Mild innate immune responses to injected vaccines, such as soreness at the injection site, are therefore normal and to be expected.

Adaptive immunity Innate immune responses, while critically important, cannot offer the ultimate solution to the defense of the body. What is really needed is a defense system that can recognize and destroy specific invaders, and then learn from the process so that if invaded a second time, the invaders will be destroyed even

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more effectively. In this system, the more often an individual encounters an invading bacterium or virus, the more effective will be its defenses against that organism. This type of “smart” response is the function of the adaptive immune system, so-called because it adapts itself to ongoing threats. Although resistance develops slowly, when a human eventually develops adaptive immunity, the chances of successful invasion by that organism decline precipitously and the individual is said to be immune. The adaptive immune system provides the ultimate defense of the body. Its essential nature is readily seen when its loss (called immunodeficiency) leads to uncontrolled microbial infections and death (Fig. 1.2). A key difference between the innate and adaptive immune systems lies in their use of cell surface receptors to recognize foreign invaders. The sentinel cells of the innate system have a limited number of preformed receptors that can recognize a limited number of common molecules expressed by many different microbes and their response is therefore generic in nature. In contrast, the cells of the adaptive immune system randomly generate enormous numbers of completely new, structurally unique, receptors. As a result, some of these will be able to bind specifically to foreign molecules that an individual has never encountered previously. Because the binding repertoire of these receptors is generated randomly, they are enormously diverse and as a result are assured of recognizing at least some of the molecules expressed by almost every possible invading microorganism. The generic term we use for a foreign molecule that can trigger a specific adaptive immune response is “antigen.” Microbes are complex and express

MICROBIAL INVASION

INNATE IMMUNITY

ADAPTIVE IMMUNITY

Recognition of pathogens (PAMPs) and tissue damage (DAMPs)

INFLAMMATION

PATHOGEN ELIMINATION

Antigen capture and processing T or B cell activation

IMMUNOLOGIC MEMORY

PATHOGEN ELIMINATION

FIGURE 1.2 The different properties of innate and adaptive immunity. Adaptive immunity generates memory cells. Innate immune responses do not. Adaptive immunity can therefore be boosted, innate immunity cannot.

8 A History of Vaccines and their Opponents

many different antigens both inside them and on their surface. Some antigens are more effective than others in triggering protective immune responses. Thus, when we make a vaccine, we seek to identify the most important antigens and incorporate them into the vaccine. Some vaccines may contain many diverse antigens, sometimes combined from different organisms such as diphtheria, pertussis, and tetanus (DPT). Other vaccines may consist of a single selected antigen from a single organism such as the purified spike protein of the COVID-19 virus. The cells of the adaptive immune system not only bind the antigens in invading microbes, but they then respond by destroying them, and retaining the memory of the encounter. If an individual encounters these same antigens a second time, the adaptive immune system can respond more rapidly and very much more effectively. Such a sophisticated system must, of necessity, be complex. Another reason for the complexity of the adaptive immune system is the great diversity of potential invaders including bacteria, viruses, fungi, protozoa, and helminths (worms) that an individual is liable to encounter. These invaders may be classified into two broad categories. One category consists of those organisms that normally live outside cellsdextracellular invaders. These include most bacteria and fungi, as well as many protozoa and invading helminths. The second category consists of organisms that originate or live within the body’s own cellsdthe intracellular invaders. These include viruses and intracellular bacteria or protozoa. Each category of invader requires a different type of adaptive immune response if they are to be efficiently eliminated. The adaptive immune system therefore consists of two major branches. One branch is directed against the antigens of the extracellular invaders. The other is directed against the antigens from intracellular invaders. Both branches depend upon the use of specialized antigen-responsive cells called lymphocytes. There are two major lymphocyte populations that respond to antigens: B lymphocytes (B cells) and T lymphocytes (T cells). (B cells are so called since they originate in the Bone marrow; T cells in contrast develop within the Thymus). Defense against extracellular invaders such as bacteria is mainly the function of B cells while T cells are critical for the defense against intracellular invaders such as viruses (and some bacteria) (Fig. 1.3).

Antibody-mediated immunity Soon after Louis Pasteur discovered that animals could be made immune to specific infectious agents by vaccination, it was recognized that the substances that provided this immunity could be found in blood serum. For example, if blood is taken from a horse that has been previously vaccinated against tetanus toxin (or has recovered from tetanus), and its serum, the clear fluid separated from the blood cells, is then injected into a human, the recipient will become temporarily resistant to tetanus (Graham and Ambrosino, 2015).

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CELL-MEDIATED IMMUNITY T CELL

EFFECTOR T CELL

MEMORY T CELLS

VIRUSES

BACTERIA

B CELL

MEMORY B CELLS

Y

Y

Y Y Y Y Y

DENDRITIC CELL

ANTIBODYMEDIATED IMMUNITY FIGURE 1.3 Adaptive immunity takes two different forms. In responding to extracellular bacteria, the body uses B cells that make protective antibodies. In responding to intracellular viruses, the body uses T cells that can kill the virus-infected cells. Both processes generate large numbers of memory cells.

These protective molecules found in the serum of immune animals are proteins called antibodies. Antibodies against tetanus toxin (the antigen) are not found in the blood of normal individuals but are produced following vaccination with the toxin. Tetanus toxin is an example of an antigen that stimulates an adaptive immune response. When an antigen enters a human, their B cells are stimulated to produce antibodies that circulate in the blood, bind to that antigen, neutralize its toxic effects, and ensure its destruction. Antibodies are highly specific and bind only to the antigen that stimulates their production. For example, the antibodies produced in response to tetanus toxin bind only tetanus toxin. When these antibodies bind, they “neutralize” the toxin so that it is no longer toxic. In this way antibodies protect humans against lethal tetanus. This B-cell-mediated immune response is sometimes called a “humoral immune response” since antibodies are found in body fluids (or “humors”). The time-course of the antibody response to tetanus toxin can be determined by taking blood samples from an individual at intervals after injection of a low dose of the toxin (or preferably detoxified toxoid). Their blood is allowed to clot, and the clear serum that contains the antibodies separated. The amount of antibody in the serum may be estimated by measuring its ability to neutralize a standard amount of toxin. Following a single injection of toxoid into an unexposed person, no antibody is detectable for several days. This “lag period” lasts for about 1 week as responding B cell populations grow and begin to produce antibodies. Once detectable antibodies eventually appear,

10 A History of Vaccines and their Opponents

their levels climb to reach a peak by 10e20 days before declining and disappearing within a few weeks. The amount of antibody formed, and therefore the amount of protection conferred, during this first (or primary response) is relatively small since there are few antibody-producing B cells. However, long-lived, memory B cells are also produced in large numbers (Fig. 1.4). If sometime later, a second dose of toxin is injected into the same individual, it is recognized by this large population of memory B cells. As a result, the lag period lasts for no more than 2 or 3 days. The amount of antibody in serum then rises rapidly to a high level before declining slowly. Antibodies to tetanus may be detected for many months or years after this injection. A third dose of the antigen given to the same individual results in an immune response characterized by an even shorter lag period and a still higher and more prolonged antibody response. It has also been found that antibodies produced after repeated injections are better able to bind and neutralize the toxin than those produced early in the immune response. This progressive improvement of adaptive immune responses to infectious agents by repeated injections of antigen (vaccination, in other words), effectively generates long lived memory cells and forms the basis of prolonged resistance to the disease. This stepwise increase in the number of memory T cells in the body is the reason why some vaccines require multiple doses to induce strong, effective immunity. However, even a single dose will prime an individual and increase their resistance to that infection.

Antibody response Amount of antibody in serum (titer)

Innate Immunity (inflammation 0

7 14 Primary immune response

Vaccine injected

7

14

Secondary immune response Booster Booster shot shot

7

14 Days

FIGURE 1.4 The time course of an adaptive immune response. The initial response may be weak and slow to develop. Depending upon the vaccine, it may be necessary to give one or more booster shots in order to ensure protection. Note however that innate immunity does not increase over time.

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The response of a human to a second dose of antigen is very different from the first in that it occurs much more quickly, antibodies reach much higher levels, and it lasts for much longer. This secondary B cell response is specific in that it can be provoked only by a second dose of the same antigen. A secondary response may be provoked many months or years after the first injection of antigen. These features of the secondary response indicate that memory B cells possess the ability to “remember” previous exposure to an antigen. A similar situation is seen when using antiviral vaccines such as those directed against the coronavirus that causes COVID-19 in humans. The antigen in this case is the viral spike protein. On injection it stimulates B cells to produce antibodies against the spike protein. These antibodies bind the spike protein and as a result coat the virus and prevent it from invading and killing the person’s cells. Two doses of the vaccine are required to induce sufficient memory cells in order to provide prolonged strong immunity.

Cell-mediated immunity Not all invaders are found outside cells. As pointed out above, all viruses and some bacteria grow inside cells at sites where antibodies cannot go. Antibodies are therefore of limited use in defending the body against such invaders. These intracellular organisms must be eliminated by cell-mediated processes. The most important cell-mediated process results when virus-infected cells are simply killed by specific, cytotoxic, T cells. The T cells attach themselves to their target and inject them with lethal enzymes triggering cell suicide. When the infected cell dies, so too do any viruses inside it.

The adaptive immune response When foreign invaders enter the body, they must first be trapped and processed so that their antigens can be recognized by the immune system. Once recognized, this information must be conveyed to the antibody-forming B cells or T cells of the cell-mediated immune system. These B or T cells must then respond by producing specific antibodies and/or cytotoxic T cells that can eliminate the invader. At the same time, the adaptive immune system also generates long-lived B or T memory cells that can remember their encounter with these specific antigens so that the next time a person is exposed to the same antigen, these cells will respond faster and with greater efficiency. The process of adaptive immunity proceeds by a series of steps (Fig. 1.5). The first step is mediated by specialized cells that capture and process the invading organisms and so isolate its antigens. The most important of these cells are called dendritic cells. In the second step, the dendritic cells then present the processed microbial antigens to either the T or B cells of the immune system. In the third step, the T and B cells recognize and respond to these processed antigens. B and T cells possess specific antigen receptors on

12 A History of Vaccines and their Opponents ENDOGENOUS ANTIGENS

EXOGENOUS ANTIGENS

1 2

DENDRITIC CELL

VIRUS -INFECTED CELL

Th2 CELL

Th1 CELL

Y B CELL

EFFECTOR T CELL

Y

3

Y Y Y Y Y

CELL-MEDIATED IMMUNITY

ANTIBODY PRODUCTION

4

MEMORY B CELLS

MEMORY T CELLS

FIGURE 1.5 The major steps required for the body to mount adaptive immune responses and so develop protective immunity. While complex, these steps have been analyzed in detail by immunologists thus ensuring that modern vaccines are highly effective in generating protection and immunological memory.

their surface. The B cells, once activated, will divide rapidly, greatly increasing their numbers while at the same time producing large quantities of antibodies. If the T cells are activated, they also divide rapidly, increase greatly in numbers and attack virus-infected cells. As these cells divide, they also differentiate. Long-lived B and T memory cell populations are generated at the same time. These memory B and T cells settle throughout the body and may survive for years. They can react very rapidly to each specific antigen if it is ever encountered again. They are thus responsible for the enhanced immunity and long-term memory that develops in vaccinated individuals. Finally, helper and regulatory T cells control these responses and ensure that they function at an appropriate level. The persistence of vaccine-mediated protection is determined by the survival of memory cells that can respond very rapidly to subsequent microbial invasion. Note that antibodies and T cells have quite different functions. Thus, antibodies are optimized to deal with the organism itself, such as free virus

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particles and extracellular bacteria. T cells on the other hand attack and destroy abnormal cells such as those that develop in virus infections or mutated cancer cells. T cells do not recognize free viruses or bacteria. Antibodies produced by B cells constitute the primary immune mechanism against extracellular organisms. On the other hand, viruses, bacteria and protozoa that can live inside cells can only be controlled by T cells. The T cells can either kill the virus-infected cells or produce proteins called interferons that inhibit viral growth. Vaccine usage must take this major divide between antibodies and T cells into account. It is often necessary to design a vaccine that specifically stimulates an antibody or a cell-mediated immune response, depending on the nature of the infectious agent. Antibody-mediated immune responses are preferentially induced by vaccines containing nonliving antigens. Vaccines can also activate the cell-mediated responses required to eliminate intracellular invaders such as viruses and some specialized bacteria. These cell-mediated responses are preferentially induced by vaccines containing live organisms, especially viruses.

Step 1: Antigen capture and processing Antigens are foreign molecules, mainly proteins that can trigger immune responses. They can be proteins made by bacteria or proteins that form the structural components of viruses. In any given microorganism, some antigens trigger a stronger immune response than others. Part of the art of making a successful vaccine is to identify and purify these “protective antigens.” Older crude vaccines used to contain all the proteins and other components found in the whole organism. This was the case, for example, with the first-generation pertussis (whooping cough) vaccines. Many of these other bacterial components, in addition to being nonprotective, also stimulated a strong innate response. As a result, these “whole cell vaccines” often caused soreness at the injection site. Modern “acellular” pertussis vaccines use only purified components and cause much less severe reactions. The triggering of an adaptive immune response requires the activation of antigen-presenting cells, called dendritic cells (DCs) and macrophages. These activated cells capture invaders by phagocytosis. If they ingest bacteria, they can usually kill them. However, the ingested microbial antigens are not totally degraded but fragments are preserved. These fragments are used to stimulate B or T cell responses. Only a few DCs or macrophages are needed to trigger a strong T cell response and one dendritic cell may activate as many as 3000 T cells. The function of T cellemediated immune responses is the detection and destruction of cells producing abnormal or foreign proteins. Examples of such cells are those infected by viruses. When they invade, viruses take over the machinery of infected cells and use it to make new viral proteins. To control virus infections therefore, cytotoxic T cells must recognize a virus-infected

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cell by detecting these viral proteins on its surface. T cells can detect these antigens but only after they have been processed and presented in the correct manner. Living cells continually break up and recycle the proteins they produce. Some of these protein fragments are rescued from further destruction and transported to the cell surface and displayed to any passing T cells.

Step 2: Helper T cell activation The immune system must be very flexible in that it has to respond to a great variety of diverse invasive bacteria and viruses. This flexibility is conferred by different T cell populations, each with specific functional roles. When microbial invasion occurs, the immune system effectively chooses the most appropriate T cell population for the task in hand. These T cell populations include helper and regulatory T cells that control immune responses and cytotoxic T cells that destroy abnormal cells. Each of these T cell types will respond to any vaccine antigens that can bind to their receptors. When DCs and macrophages present their antigen load to helper T cells, they generate three signals. The first signal activates the cell. The second signal determines the degree and intensity of this activation. The third signal determines the direction in which naı¨ve helper T cells will develop. For example, some microbial antigens trigger DCs to promote antibody-mediated responses. Other microbial antigens can cause DCs to trigger cell-mediated responses. It may also be that the same dendritic cell can promote either type of response, depending on the dose and type of antigen it encounters. The response may also depend on its location. For example, DCs in the intestine or airways seem to preferentially promote antibody responses. This is the basis of Sabin’s oral polio vaccine.

Step 3: B or T cell responses In general, B cell responses are affected by the dose of antigen administered. Thus, increased doses of antigen, within limits, promote greater B cell responses. Adjuvants, by providing the required “danger” signals reduce the dose of antigen needed to induce a strong protective response. Modified live vaccines that cause local inflammation are “naturally adjuvanted” and are thus more immunogenic than killed/inactivated vaccines. Very few killed vaccines can induce high, sustained antibody responses after only a single dose. B cells reside within the lymph nodes that drain the vaccine injection site. When a B cell encounters an exogenous antigen that binds its receptors, it will, with appropriate co-stimulation, respond by secreting these receptors into body fluids, where they are called antibodies. Each B cell is covered with about 200,000e500,000 identical antigen receptors (BCRs). Unlike the TCRs, however, BCRs can bind soluble antigens. Antibodies are simply BCRs released into body fluids.

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When appropriately stimulated and co-stimulated, B cells divide. This division is asymmetric so that one daughter cell gets lot of antigen while the other daughter cell gets very little or none. The cell that gets lots of antigen then differentiates into an antibody-producing celldcalled a plasma cell. The cell that gets much less antigenic stimulus continues the cycle of dividing and mutating and eventually becomes a memory cell. The cells destined to become plasma cells increase their rate of synthesis and secrete large amounts of antibody. Antibodies alone can confer protection against many infections. These include diseases due to microbial intoxication such as tetanus and diphtheria where antibodies neutralize toxins. Antibodies can also inhibit virus binding to susceptible cells and so limit viral spread. Antibodies can kill bacteria by activating killing systems or promoting their ingestion and destruction by leukocytes and so reduce bacterial colonization. Oral or intranasal vaccines such as those used for influenza or polio can induce antibodies in the mucus that blocks viral colonization and inhibits virus shedding in the intestine or respiratory tracts. Once activated, T cells undergo multiple rounds of division to generate large numbers of cytotoxic effector cells. Some calculations have suggested that they probably divide every 4e6 h and undergo as many as 19 cell divisions in the week following vaccination. These activated cells migrate to lymphoid organs where they differentiate into cytotoxic and memory cells. Short-lived cytotoxic cells form the bulk of the population, and these will mostly die once any antigen has been eliminated. Cells that received less stimulation survive and become long-lived memory cells. The differentiation into these two cell populations is probably due to asymmetric cell division. Once fully activated, cytotoxic T cells leave lymphoid organs, circulate in the bloodstream, and seek out virus-infected cells by themselves. When they recognize a foreign antigen expressed on another cell, the T cells will bind and kill their target. Thus, T cell recognition of a single antigen-receptor complex may be sufficient to trigger killing of the infected target. Cytotoxic T cells need to be highly sensitive to viral antigens so that they can kill all the virusinfected cells as soon as possible. Within seconds after contacting a T cell, the target cell begins to die and is dead in less than 10 min. Cytotoxic T cells can disengage and then move on to kill other target cells within minutes. In addition, several cytotoxic cells can join in killing a single target. Within a few minutes of binding to a target cell, the T cell fuses with the target cell in such a way that their toxic granule contents are injected into the target.

Antigen processing As described above, cell-mediated immune responses are primarily directed against abnormal cells such as those infected with viruses. Cytotoxic T cells recognize antigen fragments bound to receptor molecules expressed on

16 A History of Vaccines and their Opponents

infected cells. In order to stimulate these cytotoxic responses, the foreign invader must grow inside the cells. These endogenous antigens are therefore the key to stimulating cell-mediated responses. Vaccines containing killed organisms or purified antigens cannot do this and therefore stimulate predominantly antibody-mediated responses. Only live organisms capable of inducing intracellular protein synthesis can trigger cell-mediated responses. Thus, live vaccines have an immunogenic ability lacking in inactivated vaccines. That is why, for example, Sabin’s live polio vaccine is more effective than Salk’s injectable killed vaccine.

Step 4: Memory cell generation The key to a successful vaccine is the production of populations of memory cells that persist in the body for years, ready to respond in an instant to an invading microbe. In effect, vaccines work through memory cells. Immunological memory is the ability of the immune system to respond in a faster and stronger manner when it reencounters the same antigen. This is the scientific basis for adaptive immunity and of vaccination. In addition to mounting an immediate defensive response when encountering antigen, both B cells and T cells set aside a new population of memory cells. These memory cells are able to respond more rapidly and effectively to antigens they reencounter. The memory cells confer immediate protection and generate immune responses that are much more rapid and effective than primary responses.

Memory B cells One reason that the primary antibody response ends is that the responding B cells and plasma cells are short-lived and thus simply die. If all these cells died, however, immunological memory could not develop. Clearly some B cells must survive as memory cells. These cells persist under the influence of survival and rescue signals. Memory cells thus form a reserve of long-lived antigen-specific stem cells to be called on next time they encounter an antigen. If a second dose of antigen is given to a primed individual, it will encounter large numbers of memory B cells, which respond in the manner described previously. As a result, a secondary immune response is much greater than a primary immune response. The lag period is shorter since more antibodies are produced, and they can be detected earlier. In addition, memory B cells characteristically display and secrete antibodies with a much higher antigen affinity than primary cells. Memory T cells Memory T cells are long-lived cells that continuously recirculate between tissues, the bloodstream and lymphoid organs. Once they encounter an invader a second time, they multiply rapidly in an effort to keep pace with the growth

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of invading pathogens. The number of responding cells may increase more than 1000-fold within a few days. Memory T cells persist for a very long-time lurking in the tissues and lymphoid organs and remaining in effect, functionally silent until they reencounter antigen. When that happens, they respond very rapidly indeed. Memory T cells accumulate over an animal’s life and can be the most abundant T cell population in older persons. Compared to naı¨ve T cells, memory T cells are easier to activate, live longer, and have enhanced cytotoxic activity. As a result, they mount a strong rapid response when they next encounter the antigen and can provide prolonged protection against pathogens. Again, it is important to point out that memory cells do not live forever. They too eventually die, so booster doses of some vaccines may be required to maintain a high level of immunity. Over a person’s lifetime, immunological memories accumulate. Older individuals have more memory cells than young people and are thus much better prepared to respond to antigens than children. Repeated vaccination generates new memory cells. However, the size of the memory cell compartment expands to accommodate them. Previously generated memory cells are not removed to make space for the newcomers.

A word of caution Immunologic memory is real in the sense that most people only develop many infectious diseases once, perhaps when young, and their subsequent resistance may persist for the rest of their life. This has been attributed to long-lived memory cells. There is however a second reason for prolonged immunityd inadvertent boosting. Thus, for many common infections, an individual may indeed develop immunological memory, but they may then be boosted by exposure to that agent in the course of daily life. A good example was measles where a single infection appeared to confer life-long immunity. When measles was a common infection, individuals would encounter the virus repeatedly and be boosted without realizing it. Now that measles is rare, it is clear that human immune memory is by no means as prolonged as once thought. We no longer regularly encounter measles virus and repeated revaccination is now required to maintain immunity.

References Graham BS, Ambrosino DM. History of passive antibody administration for prevention and treatment of infectious diseases. Curr Opin HIV AIDS 2015;10(3):129e34. Iwasaki A, Omer SB. Why and how vaccines work. Cell 2020;183:290e5.

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Further reading Abbas A, Lichtman A, Pillai S. Basic immunology: functions and disorders of the immune system. 6th ed. Elsevier; 2020, ISBN 9780323549431. Annunziato F, Romagnani C, Romagnani S. The three major types of innate and adaptive cellmediated immunity. J Allergy Clin Immunol 2015;135:626e35. Bloom BR, Lambert P-H, editors. The vaccine book. 2nd ed. Elsevier; 2016, ISBN 9780128054000. Center for Disease Control and Prevention CDC. Understanding how vaccines work. https://www. cdc.gov/vaccines/hcp/conversations/understanding-vacc-work.html. Poland G, editor. Vaccinations. Elsevier; 2018, ISBN 9780323662109. Tizard I. Vaccines for veterinarians. Elsevier; 2019, ISBN 9780323682992.

Chapter 2

Medical science at the beginning of the 18th century The practice of medicine long preceded the evolution of human culture. Chimpanzees have been shown to dress the wounds of themselves and others (Mascaro et al., 2022). Even the earliest humans would have made attempts to treat themselves when sick. Primitive human societies, without exception, employ shamans or medicine men to treat those who are unwell and ideally stave off premature death. Until recently, however, humans had no knowledge of the causes of disease. Infectious agents were unknown. Genetics were totally unheard of. Biochemical changes were inconceivable. This lack of hard information did not, of course, dissuade societies from seeking to treat and cure diseases. In the absence of facts, cultures generated many different theories as to how and why diseases developed and how they might be treated. These theories could range from relatively simple ones such as possession by evil spirits or a judgment of God, to exceedingly complex theoretical constructs. Irrespective of their complexity or indeed sophistication, they all had one feature in common. A total lack of objective evidence on which to base such theories. Their sole measure of success was the recovery of the patient. Given that many diseases are self-limiting, and a proportion of patients usually recover, diverse theories of disease and consequent treatments have been extraordinarily persistent. As a result, the practice of medicine in early 18thcentury Europe and the American colonies had barely budged from that practiced by the ancient Greeks and Romans. Inoculation against smallpox changed all thatdit worked!

Hippocratic medicine In ancient Greece, no physician was more widely admired than Hippocrates of Kos. Born around 460 BCE, Hippocrates is considered to be the “Father of Western Medicine.” He is credited with being the first to believe that diseases were natural phenomena rather than a result of the activities of the Gods. In effect therefore he separated medicine from religion. He argued that disease was a consequence of environmental factors. The successes of his treatments were based less on precisely describing the disease and more on patient care and passive treatment, in effect, nursing care. Hippocrates, in essence, relied A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00010-3 Copyright © 2023 Elsevier Inc. All rights reserved.

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20 A History of Vaccines and their Opponents

on the “healing power of nature.” Patients were prescribed rest and immobilization and treated with relatively mild drugs and herbs. Given that some treatments worked, irrespective of the cause of the disease, this approach was considered to be a great advance on prior treatments, especially in an age of low expectations. Hippocrates also is credited with certain theoretical concepts that persisted until the 19th century or later. For example, there is a point in the course of a disease where the illness would proceed to death or alternatively, the patient would begin to recover. This is a valid concept, especially in many infectious diseases where many patients die, but some live. Of course, relapses do occur, so patients may pass through many crises. This theory also suggested that crises should occur only on certain days; otherwise, a relapse would be predicted. Hippocrates also insisted on the maintenance of good records as well as the classification and correct descriptions of disease. Records of fever, pulse, and pain were taken as was a comprehensive case history. Hippocrates revolutionized the practice of medicine in his time, but thereafter, progress stalled and even regressed.

The humoral theory As a theoretician, Hippocrates considered the four recognized elements, air, fire, water and earth. He then put forward a theory suggesting that each element was associated with a body fluid. He concluded that differences in human behavior and moods are a result of imbalances in four bodily fluids, blood, yellow-bile, black-bile, and phlegm. Depending on which fluid predominated, the individual would have a different temperament. For example, lots of blood resulted in a sanguine individual who would be social and extroverted (and red faced). An excess of yellow-bile would result in a choleric individual with a bad temper and energy. Conversely, black bile resulted in melancholia, who rather than being sad and depressed would be creative and kind. Finally, those phlegmatic individuals would be dependable and affectionate. Hippocrates also suggested that menstruation was a process by which women were purged of bad humors. Following Hippocrates’ death, the next advances (or retreats) were promoted by Galen of Pergamon (Claudius Galenus), another Greek who lived from CE 129 to CE 200. Galen took Hippocrates’ humoral theories and ran with them. Thus, while Hippocrates was content to speculate on the benefits of blood loss in menstruation, Galen went one step further and developed the concept that disease was a result of an imbalance in the humors. As a result, he proposed this could be corrected by removing any excesses. He therefore introduced physician-assisted bleeding. He promoted the procedure of bloodletting and ultimately, wrote three books on the subject. His principal interest was however in anatomy, and he dissected pig and monkey cadavers. Galen also recognized the differences between arterial and venous blood.

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The written word is the most effective way to transmit knowledge to future generations and Galen was a prolific author. Although much of his work was lost, some was passed down, not in Western Europe, but through the Eastern Roman Empire and then from the Byzantine Greeks to the Turks. Medieval Islam was remarkably receptive to new ideas. As a result, the writings of the Greeks were preserved and studied by Islamic physicians. They incorporated this material into their practices and improved on it somewhat in several areas. Medieval Europeans eventually gained access to these Greek texts as well as the Islamic advances and also incorporated them into their own practices. Medieval medicine was also profoundly affected by both astrology and religion. Indeed, religion was central to the practice of medicine in Europe at that time. In the centuries that followed there was a gradual decline in the influence of both astrology and religion on medical treatments but what remained was a confusing mixture of fact and fantasy. None were objectively based and few if any medical procedures actually benefited patients. The greatest mysteries were the causes of infectious diseases and contagion. It was readily apparent to most that plague could be acquired by contact with sick individuals or with their belongings, clothes, and houses, but it was never understood just what the nature of this connection was. Gentile da Foligno, a physician of Pergua, suggested respiratory transmission when he proposed that the poison was “communicated by air breathed out and in.” (He was correct, for pneumonic plague!) In the absence of any concept of microscopic agents (no such thing as a microscope), Gentile suggested that the air was somehow corrupted by planetary influences. The problem was however that the alignment of the planets changed while the plague continued. Guy de Chauliac, the pope’s physician at the time of the Black death, theorized that the disease was transmitted by sight. He suggested that one could acquire infection simply by looking at the sick. Even 300 years later, Joshua Barnes, a 17th-century biographer of Edward III, wrote that the ability to infect had entered into light beams and “darted death from the eyes” (Tuchman, 1978). The Arab influence was especially influential in the widespread belief in astrologic influences (the word influenza comes from this perceived influence of the stars). Despite the opposition of the church, physicians clung to astrological explanations. Guy de Chauliac practiced medicine based on astrologic signs. Thus, he prescribed bleeding and purgatives on the basis of planetary alignments and suggested that chronic diseases were ruled by the sun while acute diseases were ruled by the moon. In October 1348, as the plague engulfed Europe, Philip VI of France asked the professors of the medical faculty at the University of Paris for a report on the cause of the disease. The committee studied the evidence carefully using the formal structure of thesis, antithesis, and proofs and eventually declared that the plague resulted from the conjunction of Saturn, Jupiter, and Mars in 1345. The professors were, however, unable to explain the effects of

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this conjunction “whose causes are hidden from even the most highly trained intellects” (Tuchman, 1978). This became the official version of events and while not popular (and totally useless), was the accepted “scientific” explanation at the time. The remedies prescribed by 14th-century physicians ranged from the practical and effective to the bizarre, but of course it was not possible to distinguish between the two at that time either. The church had tried to ban both anatomy and physiology, and especially dissection, but the “science” was kept alive by the study of Galen’s works as transmitted through Islamic treatises. As a result, there were limited opportunities for dissection and the study of anatomy. For example, one of the most distinguished medical institutions, the University of Montpelier, held an anatomy class every 2 years that lasted for several days while a surgeon dissected a cadaver. All this was done in defiance of the church. The theory of humors plus astrology dominated medical thought. Thus, “humors” in various permutations together with the signs of the zodiac, governed the functions of different bodily organs. They influenced body temperature, moisture, and masculinity or femininity (Tuchman, 1978). The humoral theory was thus a longstanding feature of Western medicine. Galen had proposed that disease resulted from an imbalance of the four humors. This was rational. The humoral theory was almost self-evident. If one was sick, one got rid of the bad material by coughing, sneezing, and even nose bleeds, or by vomiting and diarrhea. Galenic medicine therefore focused on extracting these unwanted fluids from the sick patient. If a patient was ill, then it made sense to rebalance the humors by bleedings, burnings, and enemas (Roberts, 2015). Bloodletting was therefore a favored treatment, but other methods such as blistering or cupping, together with the lavish use of emetics and severe laxatives, were also ways of ridding the body of unwanted humors. Patients were commonly given multiple enemas. Fluid could also be extracted by blisteringdthe application of corrosive mixtures, scalding hot cups, or even direct heat to the skin to form fluid-filled blisters. Even diseases such as smallpox were considered to be of internal origin. The appearance of smallpox lesions on the skin was considered to reflect the body itself trying to get rid of the smallpox “poison.” Another well accepted feature of the humoral theory was the concept of “laudable pus.” Thus, the production of copious amounts of thick, whitishyellow pus in a wound was considered a good sign. Once again, it was clear that the body was expelling the bad material. Hippocrates himself had commented that “if the pus is white and not offensive health will follow, but if it is sangious and muddy, death is to be looked for.” Galen was also supportive of this concept since he believed that abscesses ought to be drained. Few physicians questioned the concept of laudable pus. We now know that pus is usually generated as a result of bacterial infections caused by some Staphylococci and Streptococci. Infected tissues are now treated with antibiotics (Freiberg, 2017).

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The combination of humors and astrology plus a diverse array of “medicines” provided physicians with many treatment options. A physician was also expected to pay attention to diet and mental attitude. They could use primitive urinalysis for diagnosis. They could take a pulse and determine its regularity and strength. These were of course not all that was available. Physicians also employed supernatural cures and treatment using “medicines” with complex mixtures of metals, inorganic substances, herbs, and animal products. In general, substances that were offensive or foul were highly valued as were expensive ingredients. Thus, ringworm could be treated by washing with boy’s urine. Gout was treated using a plaster composed of goat dung mixed with rosemary and honey. Smallpox scarring could be prevented by wrapping the patient in red cloth and hanging their bed around with red fabric. The prime goal of many of these “treatments” was simply relief. Cure itself was considered to be in the hands of God. Psychological suggestion and the placebo effect were presumably also effective on occasion. If all else failed, there was always recourse to prayer, to the Virgin and to the Saints. (The patron saint of smallpox sufferers was St Nicaise of Rheims. He supposedly miraculously survived the disease only to be decapitated by the Vandals.) Commonly prescribed drugs included poisons such as arsenic and antimony and poisonous plants such as hemlock and deadly nightshade were commonly used. (After all, poisoning was also an ancient art). Tobacco smoke enemas were sometimes employed as well! Bland diets, avoiding excitement or anger, and mild exercise were likely derived from Hippocratic sources. Because of the miasma theory, swamps and places where the air was foul were to be avoided as much as possible. One way of combating the bad smells associated with miasmas was the use of pomanders made of exotic components and perfumes that were designed to mask these odors. There was also a curious belief that latrine attendants were immune to the plague, so many patients went to public toilets in the belief that the odors of feces kept the plague at bay. Few 17th-century physicians and scientists espoused any germ theories of disease causation. This was despite the fact that microorganisms (animalicules) had been seen under a microscope by Antonie van Leeuwenhoek in 1683. A few marginal figures asserted that diseases were contagious and could be spread by small creatures such as insects, worms, or animalcules, but this was never taken seriously by the Galenists. The prevailing view was that diseases resulted from interactions between individuals and their environment. They argued, for example, that smallpox in one location was different from smallpox elsewhere. Scholars might accept that diseases were contagious but did not believe that the infectious matter was living. There was simply insufficient evidence to support the concept that diseases were caused by living agents. Following the successful introduction of inoculation in the 1720s and the clear success of rigorous quarantine, the germ theory began to gain some traction, but it was far from being generally accepted (DeLacy, 2016).

24 A History of Vaccines and their Opponents

The status of physicians Despite their inability to deliver cures, physicians were highly regarded in European society. Many had years of expensive education, first obtaining a degree in theology before beginning their medical instruction. Thus, in Italy, they wore purple or red gowns with furred hoods. The sumptuary laws that regulated the way society dressed, permitted physicians additional luxuryd belts of silver thread, embroidered gloves, even gold spurs. The benefits of a medical degree also extended to their wives who were allowed greater expenditure on cloths. Much of this was a reflection of the high fees commanded by many physicians. One of the reasons for the high social status of physicians was the length of time required to obtain medical qualifications. It took 7 years to obtain a medical degree from Oxford or Cambridge. In general, education in medical schools such as Oxford or Cambridge in the 17th century was very little changed from medieval times (Allen, 1946). Theory and logic were considered superior to practical training for physicians. Surgery or the preparation of medicines were considered physical labor and beneath the dignity of English physicians. (European medical schools were considered much superior to the English schools and as a result many aspiring English physicians went to Leyden, Paris, or Padua in Italy or to the Protestant Dutch schools or even to Edinburgh.) Oxford and Cambridge Universities functioned under strict rules that required them to lecture primarily on the teachings of Hippocrates and Galen. Dissection and anatomy classes were brief and infrequent. Generally, dissection was left to inferior surgeons (Allen, 1946). Astrology was no longer required for a medical degree as it had been in previous centuries. However, medical students did receive some training on the use of medicinal herbs. Lucky charms were widely employed and encouraged by doctors. (Even during the 1918, influenza pandemic, some parents sought to ward off influenza in their children by hanging a clove of garlic around their neck). The church encouraged prayer, the more the better. Many unqualified individuals set themselves up as healers to the poor and sold “quack” cures. It is debatable however if this is a fair assessment since none of the treatments prescribed by qualified physicians worked either. Plague water was a popular cure as was powdered unicorn horn and frog’s legs. Putting the tail feathers of a live chicken into a bubo helped draw out the poison. The idea of drawing out the toxin was applied by making the victim sweat or applying a recently killed pigeon to the buboes. Leeches were considered highly effective in drawing out contaminated blood. Fifty years later, at the beginning of the 18th century, things were no better. Nevertheless, there was an increasing frustration with the shortcomings of accepted medical practice, and competing theories began to appear. Given the conservative nature of medical education, there were few challenges to the body of received knowledge. Once in practice however a physician could

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borrow therapies as he saw fit. Thus, in the American colonies, some physicians adopted some native American treatments. Some attempts were made to break the mold in Europe. Thus, the Dutch physician and professor, Herman Boerhaave tried to explain disease in terms of acidity or alkalinity or tension and relaxation. These theories represented an attempt to confine the sources of disease to a single source. This ideally would render a specific diagnosis unnecessary, the specific lesion or cause was immaterial, the nervous tension and the acidity just had to be balanced. The primary medicines available to physicians were calomel and jalap. Calomel is mercury chloride. It was used as a diuretic and laxative (purgative) throughout the 18th century and up until the 1860s. Vomiting would remove impurities from the body. Benjamin Rush, the American Physician and signer of the Declaration of Independence, was an enthusiastic user of calomel and employed it in large doses to treat yellow fever victims in Philadelphia. In sufficiently high and prolonged doses, it resulted in mercury poisoning. There was some controversy at the time as to what was the best treatment for yellow fever, bleeding, or calomel treatment. Jalap consists of a dried and powdered preparation of the roots of Ipomoea purga, a plant of the morning glory (Convolvulus) family that originated in eastern Mexico. It derives its name from the city of Xalapa. It is a very potent laxative and was thus popular with 18th-century physicians. In addition to diverse plant materials, some of which had a significant pharmacological effect, many physicians believed in the hidden power of certain specific powders. Thus, powdered unicorn horn or bezoar stone (the tears of a stag turned to stone), live worms, pulverized frogs, fox lungs, spider’s webs, swallows’ nests, and even the skulls of executed criminals were potent ingredients. One physician attempted to prevent smallpox by burning a pot of toads to ashes and then having his patients consume their remains (Stafford, 1643). Thus, the boundaries between tradition, faith, and magic were often very blurred. Clearly, many of these treatments extended into the realm of magic. This could also involve the use of magic words and rituals although as time passed practitioners had to be careful that they could not be accused of witchcraft. Theologians tended to be very skeptical of those procedures that they didn’t understand.

Witchcraft Throughout the middle ages, the power of the devil was a major cause for concern. Over time, the importance of evil spirits, demons, and astrology was gradually reduced in favor of the humoral theory (Diethelm, 1970). Nevertheless, in Puritan New England, all diseases were believed to be the ultimate result of supernatural forces. The sick were therefore required to consider their moral shortcomings since it was God’s will that people should suffer for their sins. If, however, they could not identify any such sins, then they would look to another, external cause. One such cause sanctioned by scripture and

26 A History of Vaccines and their Opponents

considered reasonable by most was witchcraft. This was especially the case with mental illnesses. As a result, physicians and surgeons were in many cases required to determine whether a disease was due to natural (God given) causes or supernatural (Devil given) causes. This was also the case in midwifery where men were generally excluded. Thus, female midwives were not uncommonly accused of witchcraft in cases where birth outcomes were not good. Women were excluded from medical practice by their gender, but many were believed to possess healing powers and hence were suspected of sorcery. As demonstrated by the Salem Witch trials, disease was also attributed to sorcery and witchcraft. One of the seven Salem judges was in fact a prominent physician while another was an apothecary (Gevitz, 2000). In general, it appears that physicians conformed to the rest of society in their beliefs on the supernatural causes of disease.

Seventeenth century By the beginning of the 17th century, many medical intellectuals who were aware of the inadequacies of medicine at that time began to question Galen’s theories. People like Jan van Helmond who identified gases suggested that they were perhaps capable of transmitting diseases, hence initiating the miasma theory by suggesting that disease was transmitted by poisonous air (Roberts, 2015). However, such theories were difficult to reconcile with the Galenic view. Doctors and patients both knew that disease was associated, not only with pain and suffering, but also with a loss of body fluids. How could they be assured of a cure unless they saw the fluid being removed from the body? Even during the Yellow fever outbreak in Philadelphia in 1793, the eminent physician, Benjamin Rush adhered to the somewhat old-fashioned methods of bleeding (at least a pint of blood) and purging with high doses of mercury salts to cause profuse diarrheadthe heroic treatment. If these didn’t work, he increased the dose and took more blood. The basic theory was that disease was like a fire so the way to put it out was to remove excess fuel by bleeding and purging (North, 2000). When Rush himself caught the disease, he complained that the doctors who treated him were taking insufficient blood. He recovered. However, some major advances in medical knowledge did occur during the 17th century. For example, in 1628, William Harvey in England discovered the circulation of the blood. This was a radical discovery and was not widely accepted for many years. Thomas Sydenham, another English physician, moved away from the Galenic theories to emphasize the importance of carefully recording the patient’s symptoms. With the development of primitive microscopes, Robert Hooke was the first to describe (and name) cells in 1665. In 1683, Antonie van Leeuwenhoek in the Netherlands developed a very effective microscopes and was able to observe red blood cells and diverse microorganisms including bacteria in body fluids. Interestingly Cotton Mather was one of the few to appreciate the significance of this discovery (Chapter 4) (Box 2.1).

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BOX 2.1 Cotton Mather (1663e1728) Born in Boston, Cotton, was the son of a famous Puritan minister, Increase Mather. He was a precocious child and entered Harvard at the age of 12. He had no problem mastering the entrance requirements in Latin and Greek. He received his MA at 18 from his father who was President of Harvard at that time. Intellectually he was interested in many different aspects of religion and medicine. He wrote multiple books, one of which, “Curiosa Americana” won him a fellowship in the Royal Society of London in 1713. Cotton Mather was one of the most influential clergymen in the American colonies in his time. While clearly an intellectual, Cotton Mather’s career was stained by his role in the Salem Witch trials. He was a leading accuser of Ann Glover who was accused of bewitching the children of the Goodwin family. Although she proclaimed her innocence, she would be the last person in Boston to be hanged for witchcraft. Mather vowed to “never use but one grain of patience with any man that shall go to impose upon me a Denial of Devils, or of Witches.” As the Witchcraft hysteria faded, Cotton Mather never expressed remorse for his actions. He had discouraged the use of the so-called spectral evidence but accepted it during the witchcraft trials. He appeared to be completely lacking in empathy for the accused. Even later in life when most people believed that they had killed innocent people, Mather still maintained that the trials were done correctly. An active minister as well as a Fellow of the Royal Society, Cotton Mather was the instigator of smallpox inoculation in Boston in 1721. It is interesting to speculate, how Mather explained to himself how smallpox inoculation worked without invoking some sort of magical process. Mather certainly had some concept of infectious disease since also wrote the following: It begins now to be vehemently suspected that the Smallpox may be more of an animalculated business than we have been generally aware of. The millions of which the microscopes discover in the pustules, have confirmed the suspicion.

This was, of course, pure speculation. Neither Mather nor anyone else could have seen the smallpox virus in samples from the pustules, as the virus is too small to be seen by a light microscopedthe first virus was seen using an electron microscope in 1938. Nevertheless, it also makes clear that Mather was not completely wedded to the humoral theories of Galen that dominated medical thought at that time. Was his support of inoculation a result of forward-thinking or simply gross overconfidence?

Variolation As described in the next chapter, into this world of fantasy, ignorance, imagination, religion, and magic appeared a method of preventing a lethal disease that actually worked! Variolation was the first small step in the development of modern medicine and the precursor of vaccination, the greatest lifesaver of all. It was an anomaly. It coexisted with the ancient humoral

28 A History of Vaccines and their Opponents

theories for at least another hundred years in Western societies; societies that had no concept as the how disease occurred or how they could be treated rationally. As an anomaly it inevitably incited opposition. Opposition that is with us to this day. Despite this, 18th-century physicians reconciled inoculation with the humoral theory. Thus, they suggested, almost everyone carried the “seeds” of smallpox within their body. Disease occurred when the “seed” or poison tried to escape through the skin. Miasmas were believed to activate these poisons. Inoculation provided the poisons with a safe way of getting out of the body. Once they had escaped, the inoculated person no longer needed to fear smallpox.

References Allen P. Medical education in 17th century England. J Hist Med Allied Sci 1946;1(1):115e43. DeLacy M. The germ of an idea: contagionism, religion, and society in Britain, 1600e1730. Palgrave Macmillan London; 2016. Diethelm O. The Medical teaching of demonology in the 17th and 18th centuries. J Hist Behav Sci 1970;6(1):3e15. Freiberg JA. The mythos of laudable pus along with an explanation of its origin. J Community Hosp Intern Med Perspect 2017;7(3):196e8. Gevitz N. “The devil hath laughed at the physicians”. Witchcraft and medical practice in seventeenth-century New England. J Hist Med Allied Sci 2000;55(1):5e36. https://doi.org/ 10.1093/jhmas/55.1.5. Mascaro A, Southern LM, Descner T, Pika S. Application of insects to wounds of self and others by chimpanzees in the wild. Curr Biol 2022. https://doi.org/10.1016/j.cub.2021.12.045. Morris T. Weird and wonderful medicine in 17th and 18th century England. 2020. https://www. historic-uk.com/HistoryUK/historyofEngland/weird-wonderful-17th-18th-century-medicine/. North RL. Benjamin Rush, MD: assassin or beloved healer? Baylor Med Center Proc 2000;13:45e9. Roberts J. Tryals and tribulations. 2015. https://w.w.w.sciencehistory.org/distillations/tryals-andtribulations. Stafford E. My Black powder against ye plague, small pox, purples, all sorts of feavers; Poyson; either by way of prevention, or after infection. Receipts to cure various disorders for my worthy friend Mr Winthrop, 1643. McCullen T. https://nrs.lib.harvard.edu/urn-3:hms.count: 27030121. Tuchman BW. A distant mirror: the calamitous 14th century. New York: Ballantine; 1978.

Further reading Thompson H. How witches’ brews helped bring modern drugs to market. 2014. https://www. smithsonianmag.com/science-nature/how-witches-brews-helped-bring-modern-drugs-market180953202/.

Chapter 3

Variolation: the early years in Britain and Europe Smallpox was a lethal human disease caused by a DNA-containing Orthopoxvirus (its latin name was Variola). The disease was eradicated from the globe in 1980 as a result of an international vaccination campaign. The smallpox virus was spread in respiratory droplets as well as in the dust from dried skin scabs. The incubation period was about 12 days. The virus first invaded the mouth, nose, and respiratory tract, then it entered the blood and lymphatic systems through which it spread throughout the body. Sickness began with aches, fevers, and prostration. Its characteristic clinical feature was the appearance of huge numbers of small skin lesions called pocks, which mainly affected the face, hands, and limbs. In severe cases, the patient was totally covered by them. They affected not just the exterior of the body but also the eyes, mouth, throat, esophagus, and vagina. The fluid-filled pocks killed the skin cells which then formed soft yellow crusts. The crusts sloughed off leaving agonizing raw wounds. If there were enough of these open oozing lesions, then the patient lost large amounts of fluid, became secondarily infected by bacteria, and died. Once these skin lesions appeared, the patient was highly infectious. The fluid in the sloughed pocks contained huge numbers of virus particles that could spread to others nearby by contact or inhalation. Eventually, the pocks dried with intense itching, formed scabs that then fell off. If the victim survived, the healed pocks left disfiguring pits and scars. Pocks that developed on the cornea of the eye resulted in blindness. Other complications included pneumonia and arthritis. Otherwise, the patient gradually recovered over about 2e4 weeks. Smallpox virus occurred in two forms with very different levels of virulence. The most significant and historically important form termed, variola major, caused the most severe disease and had a case-fatality rate of up to 30% e40%. In infants, however, this fatality rate could be as high as 98% depending upon the victim’s location and genetic background (Riedel, 2005). Variola minor was a mutant strain that appeared late in the 19th century in Europe and the United States (Marsden, 1967). Variola minor caused a much milder disease with only 1%e2% mortality. Smallpox was common in Medieval Europe, Asia, and Africa. It swept through each community killing huge numbers. Of Europeans who developed A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00014-0 Copyright © 2023 Elsevier Inc. All rights reserved.

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30 A History of Vaccines and their Opponents

the disease, up to 30% died, about 20% were scarred, blinded, or disfigured for life, while the remainder recovered and developed immunity. This population immunity gradually waned as more children were born and grew up. As a result, smallpox returned about every 20 years or so to cause new epidemics. Smallpox was brought to the New-World, on multiple occasions by the Spaniards, French, and English. It caused enormous losses among vulnerable Native Americans, especially in Mexico and Central America who had never been previously exposed to it. In Native Americans, the smallpox lesions were especially deep and severe and resulted in up to 95% mortality. During the 17th and 18th centuries, smallpox was the cause of frequent lethal epidemics in Western Europe, Native Americans, and in the American Colonies. It is estimated that it may have killed about 400,000 people annually and accounted for more than a third of cases of blindness. While especially lethal for children under 10, it did not spare adults and the nobility. For example, it killed Queen Mary II of England in 1694, Joseph I of Germany, Peter II of Russia, Louis XV of France, William II of Orange and the Elector of Bavaria (Behbehani, 1983). In North America where population density was much lower and the disease less frequent, it tended to affect persons in older age groups.

Immunity Variolation in Asia During the Plague of Athens in 430 BCE, the cause of which is still unknown, it was reported by the Greek historian, Thucydides, that those who survived the disease appeared to be resistant to subsequent infection and were therefore able to take care of the sick and dying. The same phenomenon was observed sometime around the year 1000 CE when it was noted in China that an individual only contracted smallpox once. Reports have it that a Buddhist nun, in the reign of Jen Tsung (1023e1063) devised a protective procedure that worked. The Chinese procedure initially involved blowing powdered dried smallpox scabs up the recipient’s nose (boys in the right nostril, girls in the left). The scabs used for this procedure were selected from the mildest cases of smallpox available. As a result, the child developed a mild case of smallpox but usually recovered within two to four weeks. Consequently, they were resistant for the rest of their lives. These nasally infected children were carefully isolated following the procedure in an effort to prevent disease spread to others. The procedure also appears to have been regarded as secret and as a result, was not widely publicized until about 1500 when it was first described in Chinese medical texts. This Chinese method of insufflation was a cumbersome procedure and the inhaled virus often produced severe symptoms in the recipients. As a result, this intranasal delivery was eventually superseded by a procedure in which the thick variola pus or dried scabs (both contain the

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virus in large amounts) were rubbed into a small cut or scratch in the recipient’s skin. This resulted in a milder disease and the development of skin lesions around the inoculation site. This technique was called either variolation or inoculation. The preferred site of inoculation varied depending on geography. In Africa, for example, inoculation sites could include the forehead, the arm, the leg, or the back of the hand. These could be multiple, and the incisions could simply be small scratches or even shallow needle punctures used to prick the skin in a circular pattern. All these routes of administration are very different from the natural, respiratory route by which smallpox was transmitted. The infected material inserted into a small incision resulted in a pustule developing at the site around the third day. The infected inoculum also caused secondary pustules to develop in the surrounding skin. The reasons for its lesser severity than naturally acquired disease are unclear but probably reflect the unusual route of exposure that slowed down the initial viral growth and gave the patient’s immune system sufficient time to combat the virus and restrict its spread. However, it is also important to note that the inoculated virus was still virulent and could infect others who came into contact with the patient. Thus, variolation resulted in local lesions developing around the inoculation site, but mortality from the procedure was significantly lower than from the natural disease. In the great majority of cases, variolated individuals recovered and as a result were immune to reinfection. Depending upon the technique employed, variolation resulted in between 0.5% and 2% mortality. This would be a totally unacceptable result for any modern vaccine but considering that natural smallpox killed up to 30% of its victims, inoculation was considered an acceptable risk at the time and for many years after. Obviously, nobody at the time had any idea as to how or why inoculation worked. As a result, the procedure was mystical and ritualized. For example, in Constantinople, the dried scabs were usually carried in a half walnut shell and their administration was accompanied by ritual incantations and prayers. The procedure was generally performed by old ladies in black costumes in the middle of the night. There is also evidence to suggest that this method of variolation originated independently in other parts of Asia such as India, the Middle east, and across North Africa. It may have had multiple origins, but the method was widely disseminated along the trade routes in Asia, the Middle East, and Africa. The use of this procedure gradually spread out of China along the Silk roads of central Asia. It eventually reached the Middle East, India, and Africa where it was widely employed by slave traders to prevent disease outbreaks among their captives. The process of variolation was therefore widely accepted across much of Asia and Africa long before information about it reached Western Europe. The Royal Society of London, the foremost European scientific society of its day, first learned of the Chinese method of inoculation in 1700 from several

32 A History of Vaccines and their Opponents

foreign sources including Joseph Lister, an East India Company trader living in China. They were also informed about the Turkish method by a Dr. Edward Tarry. There is also evidence indicating that a form of inoculation may have been carried out in some rural areas of Scotland and Wales prior to that time. However, none of these reports were published or widely acknowledged.

Emanuel Timoni’s letter In December 1713, Dr. Emanuel Timoni(us) (an Italian physician born on the island of Chios), working for the then British Ambassador in Constantinople (modern Istanbul), wrote a letter in Latin to the Secretary of the Royal Society, Dr. John Woodward describing the procedure of inoculation used in the Ottoman empire at that time (Boylston, 2012). The letter was considered of some scientific interest and as a result, it was translated and read to the members of the Society on June 3, 1714. (Dr. Timoni had medical degrees from Padua and Oxford and had been made a Fellow of the Royal Society in 1703 so he was considered a reliable informant) (Langer, 1976). Timoni’s letter, which was published in the Royal Society’s Philosophical Transactions, described the inoculation process in detail (Timoni, 1714). The writer of this ingenious discourse observes in the first place, that the Circassians, Georgians and other Asiatics, have introduced this practice of procuring the smallpox by a sort of inoculation, for about the space of forty years, among the Turks and others in Constantinople. . They that have this inoculation practiced upon them are subject to very slight symptoms, some being scarce sensible that they are ill or sick. And what is valued by the fair, it never leaves scars or pits in the face.

The members of the Royal Society were intrigued by Timoni’s account of the process but asked for more details as well as confirmation of the procedure. Clearly some were skepticaldthis was a radical novelty! The Secretary therefore sent a letter of enquiry to the British Consul in Smyrna (modern Izmir). In response he received a letter from a Venetian physician, Giacomo Pylarino (Jacobus Pylarinius) who was also a graduate from Padua in Medicine and Law. Pylarino’s letter was read at the May 24, 1716 meeting of the Royal Society and published in the Transactions in early 1717 (Behbehani, 1983). Both Timoni and Pylarino described how pus was taken from a patient with smallpox, kept warm, and then rubbed into small cuts on multiple body sites. (Timoni preferred the upper forearm.) Symptoms of smallpox appeared within 7 days. Pylarino had observed the practice in Constantinople and reported that the technique had been introduced into Constantinople by a Greek woman around 1660. Initially it was only used by poor Christians, but during a smallpox epidemic in 1700, the practice spread widely. Pylarino reported that inoculation was not used by pious Muslims because it was believed by them to

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interfere with divine providence (Boylston, 2012). (This may have been a local belief since it was not consistent with the widespread use of inoculation by Muslims in Tunisia and Algeria well before 1700.) The two letters regarding inoculation were published in the Philosophical Transactions of the Royal Society but otherwise elicited little comment. It is clear that the procedure as reported by Timoni and Pylarino was too “far out” and smacked of sorcery (Chapter 2). At that time, there was no obvious scientific basis for the procedure. It made no sense whatsoever and could not be fitted into the prevailing humoral theories of disease. The conservative British medical establishment was not interested. The described procedure in no way fit preconceived notions and was clearly very hazardous. The English medical profession was also skeptical of the idea that one attack of smallpox conferred immunity even although it was common to preferentially hire servants who already had had the disease. There the matter rested, for a while (Fig. 3.1).

Lady Mary Montagu The situation changed in 1717 as a result of the efforts of a remarkable woman, Lady Mary Wortley Montagu (1689e1762). Mary Montagu was a member of the English aristocracydthe daughter of the Duke of Kingston, Robert Pierrepont (Langer, 1976). When her husband, Edmund Wortley Montagu, was appointed to be the British Ambassador to the Ottoman Empiredthe Sublime Porte, in 1716, his wife accompanied him to Constantinople. They arrived in February 1717 and lived in Constantinople and Adrianople until June 1718. Lady Mary took a keen interest in everything she saw on her travels. Thus, she was impressed by the fact that the ladies of the Sultan’s harem had

Masseys negative sermons 1722 P of W daughters variolated Maitland and Nettleton 1722 began variolating patients

Lady Montagu arrived in Constantinople 1717 Lady Montagu’s Timoni’s letter Lady Montagu’sdaughter arrived son variolated variolated 1713 1721Royal Timoni’s Montagus Experiment letter returned to Newgate read to RS London 1721 1714 1718

1710

1720

1722 Jurin and Nettleton published variolation results 1722-1729

1730

FIGURE 3.1 A timeline of the events involving variolation in England between 1713 and 1730.

34 A History of Vaccines and their Opponents

unblemished complexions. They had no smallpox scars of the type that had disfigured Lady Mary and most other Britons. Upon enquiry she learnt about the process of inoculation. She described the procedure and its outcome in a letter to a friend Sarah Chiswell in April 1717 (Rosner, 2017). A propos of distempers, I am going to tell you a thing that I am sure will make you wish yourself here. The small-pox, so fatal, and so general amongst us, is here entirely harmless by the invention of ingrafting, which is the term they give it. There is a set of old women who make it their business to perform the operation every autumn, in the month of September, when the great heat is abated. People send to one another to know if any of their family has a mind to have the small-pox: they make parties for this purpose, and when they are met (commonly fifteen or sixteen together), the old woman comes with a nut-shell full of the matter of the best sort of small-pox, and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch), and puts into the vein as much venom as can lie upon the head of her needle, and after binds up the little wound with a hollow bit of shell; and in this manner opens four or five veins. The Grecians have commonly the superstition of opening one in the middle of the forehead, in each arm, and on the breast, to mark the sign of the cross; but this has a very ill effect, all these wounds leaving little scars, and is not done by those that are not superstitious, who choose to have them in the legs, or that part of the arm that is concealed. The children or young patients play together all the rest of the day, and are in perfect health to the eighth. Then the fever begins to seize them, and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark; and in eight days’ time they are as well as before their illness. Where they are wounded, there remain running sores during the distemper, which I don’t doubt is a great relief to it. Every year thousands undergo this operation; and the French embassador says pleasantly, that they take the small-pox here by way of diversion, as they take the waters in other countries. There is no example of any one that has died in it; and you may believe I am very well satisfied of the safety of the experiment, since I intend to try it on my dear little son. Sadly, Sara Chiswell was not inoculated and died of smallpox in 1726.

Lady Mary was clearly persuaded of its safety and effectiveness and decided that her son should be protected. She was likely aware of the Royal Society’s prior discussions on the matter (Grundy, 1994). As a result, she contacted Dr. Timoni who arranged for the procedure to be performed on her 4-year-old son Edward. The first opponent of immunization on record was the Embassy chaplain, Mr. Crosse, who opposed it on the grounds that it was an unchristian practice and would only work on infidels. Lady Mary however persisted, and on March 18, 1718, Edward was inoculated by a local Greek woman under the supervision of her Scottish physician (actually only a

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surgeon) Charles Maitland. The boy recovered uneventfully. She waited 5 days before informing her husband, who was away on diplomatic business. Her husband was not as success as Ambassador, so in June 1718, the Montagus returned home to England. Lady Mary was determined to spread the word about this remarkable procedure. She told everyone she met about their experiences. At numerous dinner parties and lunches with her friends, she told them about her adventures in the Ottoman Empire including the inoculation episodes. She told how old women gathered every autumn to inoculate groups of friends. She noted that inoculated individuals were rarely forced to lie in bed for more than 3 days. She reported that they developed very few pocks on their faces and that nobody died. Lady Mary also happened to be an acquaintance of the Princess of Wales, Caroline of Ansbach, the wife of the future George II. The Princess and her husband were paranoid about the health of their children and especially about the risks of them acquiring smallpox. After all, their predecessor Queen Mary had died of smallpox and her successor Queen Anne had lost several children including her son and heir to this disease. When a major epidemic of smallpox broke out in London a few years later, Lady Mary had her 3-year-old daughter Mary Alice, inoculated in both arms on April 1721 by Dr. Maitland in the presence of three members of the Royal College of Physicians. It went well. This was the first inoculation performed in Britain. While not publicly reported, the results were soon well known in professional medical circles. One of the attending individuals, an apothecary, Dr. James Keith, who had lost several children to smallpox was so impressed that he requested Dr. Maitland to inoculate his 6-year-old son as well. Lady Mary subsequently paraded her daughter through the homes of her aristocratic friends, most of whom strongly disapproved of this heathen practice. Her daughter observed “the open hostility” of “aunts and grandmothers” quoting the authority of “this doctor or that apothecary.” Many criticized her as being a bad mother for risking her children’s lives. Lady Mary also told Princess Caroline; the princess told her husband, the Prince of Wales, and together they agreed to sponsor a human experiment. The royal couple summoned Sir Hans Sloane, the President of the Royal Society, for a discussion. Sloane was instructed to inquire into the process and determine whether it actually worked. As a consequence, Charles Maitland was licensed to perform an inoculation trial on six prisoners in Newgate Prison (Weiss & Esparza, 2014). In an era when the death penalty was commonplace, Newgate Prison in London held plenty of condemned prisoners waiting to be hanged. Six of these individuals (three man and three women of similar ages) were approached and were offered a reprieve if they would submit to inoculation. There is no record of anyone refusing to “volunteer.” Thus, the prisoners were inoculated by Maitland on their arms and right legs using the technique described by Timoni. This was performed on August 9, 1721 in the presence of 25 physicians, surgeons, and apothecaries! Five of those

36 A History of Vaccines and their Opponents

inoculated developed mild smallpox. The sixth had had smallpox the previous September and did not develop any lesions. They were all released from prison on September 6. One of the women prisoners was however obliged to work as a nurse for smallpox victims and sleep in the same bed as an infected boy for 6 weeks! She remained healthy. They all proved to be immune. The experiment worked! The procedure appeared to be harmless (Maitland, 1722). That November, Princess Caroline arranged for a census of orphans in the Parish of St. James, Westminster. She then arranged to have those who had never had smallpox inoculated. The press heard about it and great excitement ensued, incited further by mixed reports of the results of inoculation in Boston Massachusetts. A similar successful study was conducted on five orphans in March 1722. As a consequence of these successful studies on felons and orphans, on April 17, 1722, Charles Maitland successfully inoculated the two daughters of the Princess of Wales, 11-year-old Amelia and 9-year-old Caroline (Riedel, 2005). The smallpox appeared on them on April 24 “with the most favorable symptoms imaginable.” Following this success, other members of the royal family underwent successful inoculation as did many of the English nobility. It was presumably entirely voluntary, and with the exception of the “Royal Experiment,” there was no obvious coercion required.

Inoculation progress Progress was slow at first, and there was no great rush in Britain to get inoculated. Thus, by 1722, only 182 individuals had been inoculated (Huth, 2006). Smallpox cases had declined and so had the impetus to inoculate. The general public considered inoculation to be complex and expensive, which it was. Inoculation was basically a relatively simple procedure. As a result, English physicians sought to turn it into a profitable procedure by making it both mysterious and complicated. Thus, it was usually preceded by purging, dietary restrictions, by severe bloodletting in order to “purify” the blood and to prevent a fever developing in the patient. At this time, English doctors still believed in Galen’s humoral theory of disease. As a result, they went to considerable trouble to prepare the patient for the operation. These preparations were designed to weaken the constitution and as a result patients were purged, bled, and starveddno animal food or strong liquors for about 6 weeks! Doctors also made deep incisions rather than scratches to better enable the morbid humors to escape (Fenner et al., 1988). The original inoculation method employed across Europe was to make a small incision in each of the patient’s arms. Into that incision was placed a thread impregnated with the pus from either a smallpox victim or someone recently inoculated. The wound was bandaged, and the thread removed about 48 hours later. As a result, the initial expense, duration, and complexity of inoculation generally kept it out of the reach of the poor. Consequently, smallpox continued to kill people in Britain

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by the thousands through much of the 18th century (Fig. 6.2). In general, its popularity rose and fell depending upon the severity of smallpox epidemics. As described in Chapter 4, a simultaneous “trial” of inoculation was going on in Boston, Massachusetts, under Cotton Mather and Zabdiel Boylston. The news from Boston was confusing and contradictory. The lack of enthusiasm for inoculation in England was reinforced when the first news of inoculation attempts in Boston were received. It was not good. The Boston physician Dr. William Douglass wrote a letter to Dr. Alexander Stuart that was read to the members of the Royal Society on November 16, 1721. At that stage, Douglass strongly opposed inoculation. He described in his letter the severity of the Boston smallpox outbreak and reported that of 60 persons who had been inoculated, some had died while others had developed severe disease. This letter plus the banning of the procedure by the authorities in Boston left a bad impression. London newspapers also reported on the negative testimony of Dr. Dalhonde, the French physician who reported falsely on the lethal consequences of inoculation in Europe (Miller, 1956). However, more positive reports from Cotton Mather and others received in early 1722 served to reverse this trend. James Jurin, the secretary of the Royal Society, requested more data from Boston which he published in early 1723. The importance of the inoculation results from Boston was reflected on the bestowing of a Fellowship of the Royal Society on Zabdiel Boylston when he visited London and published his results in 1726.

Early resistance to inoculation Not everyone was a believer. The Hanoverian king, George I was deeply unpopular and closely associated with the Whig party. As a result, attitudes toward inoculation were linked to party affiliations. Newspapers that supported the Whig Government generally supported inoculation, whereas Tory opposition newspapers opposed it (Grundy, 1994). (A pattern also seen with respect to COVID-19 inoculation 300 years later.) Thus, some gossip-column journalists insisted that the results had been rigged, the reports from Newgate were untrue, and that the Hanoverian monarchs were untrustworthy! (Willett, 2021). William Spencer, the son of Lord Sunderland died 19 days after being inoculated in late April 1722. While initially reported as being due to convulsions, the story changed attributing his death to smallpox and subsequently to “a new form of distemper not known in Former days.” The leading Tory newspaper, Applebees, commented in an editorial about “an unhappy experiment to this young Nobleman who might in all Probability have liv’d for many Years, if this dangerous Operation had not been practis’d upon him.” The editorial used the words “unchristian” and “murther” and suggested that as in Boston, inoculation be outlawed. Spencer’s death led the headlines for weeks. (Significantly, all of Spencer’s relatives promptly had their children inoculated) (Grundy, 1994).

38 A History of Vaccines and their Opponents

There was limited open opposition from the medical profession at this stage. Its opponents stressed its Islamic origins and the fact that it was being promoted by women. One physician, William Wagstaffe, published a letter in 1722 outlining the hazards of the procedure. He pointed out that it had “been cry’d up by those who are no Physicians and have not the least Knowledge of Distempers.” He claimed that it was “an Experiment practiced by a few ignorant women, amongst an illiterate and unthinking people.” He argued that English superiority made this an inappropriate importation and that they deserved to be treated by qualified physicians rather than by unqualified inoculators. Wagstaffe questioned Timoni’s and Pylarino’s results. He believed that there were several different forms of smallpox and that Timoni was ignorant of such diversity and so misdiagnosed the disease. He claimed that the reactions to inoculation were unrelated to true smallpox but then contradicted himself by claiming, correctly, that it transmitted the disease. Charles Maitland responded in another pamphlet in which he claimed that Wagestaffe was “not quite so well qualify’d to write upon this subject”! (Courgeau, 2018). Sir Hans Sloane was more courteous in suggesting that Wagstaffe lacked sufficient experience to judge the matter. Throughout 1722 as the smallpox epidemic raged, the debate continued in the newspapers. Each side demonized the other and accused them of lying. William Wagstaffe and Isaac Massey (the preacher’s brother) each accused Maitland of exploiting their patients for profit. They suggested that it was all part of a plot to kill young children and steal their inheritance! Edmund Massey passed on a rumor that 6 months after inoculation, the young princesses were not on a good state of health. Wagstaffe considered inoculation a “sure Method of silently communicating any Poyson” and that that is why the Turks had used it (Grundy, 1994).

Edmund Massey When Lady Mary Montagu had her daughter inoculated in April 1721, some of the English clergy were horrified. This was clearly impious. Mankind was seeking to take power from the hands of God. Dr. Edmund Massey, an Anglican minister in London, was the leader of the opposition. In a series of sermons that were subsequently published he railed against, “The Dangerous and Sinful Practice of Inoculation.” For example, in a sermon given on July 8, 1722 at the Church of St Andrew in Holborn, London, he called inoculation. a diabolical operation which usurps an authority founded neither in the laws of nature or religion and which tends to anticipate and banish Providence out of the world and promotes the increase of vice and Immorality. Massey E. A sermon against the dangerous and sinful practice of inoculation. Preach’d at St. Andrew’s Holborn; July 8, 1722. https://quod.lib.umich.edu/e/evans/NO2782. 0001.001/1:2

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Edmund Massey preached against sinfully seeking to thwart God’s will by intervening presumptuously. He concluded that Satan was the first inoculator (Job 2:7) and by extension that Job actually had smallpox. So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown.

Massey went on to preach that smallpox was a punishment from God and that as a result a fear of smallpox kept people safe and pious. An inevitable consequence of this is that absence of smallpox would result in people becoming more sinful. In addition to condemning inoculation as the deliberate spreading of the disease (hence breaking the sixth commandment), he claimed that it didn’t really work anyway. Massey unfortunately extended his thinking to medical intervention of all types and suggested that most patients would be better off if physicians stopped treating them and prayed for them instead (Moxham, 2013). I will venture to recommend this old practice and affirm that the Lives of Mankind would be no less secure if all the guardians of Health should pray for all those committed to their charge.

Massey denounced the fact of exposing a person in perfect health to a potentially fatal disease. He compared such an act to that of a man who jump’d out of a window when his house was not on fire, only to try what he might perhaps be forced to do hereafter?

Unfortunately for Massey, he was raging against what was probably the first medical intervention that worked as advertised (Chapter 4). Massey’s sermons were published and widely distributed, not only in England but also in the American Colonies (Massey, 1722). The leading inoculator, Charles Maitland, replied that he was unable to find any command in the Gospels clearly forbidding Christians from undergoing inoculation. Hence, he also wrote, if the Diminishing the fear of Dying of Disease catch’d by Irregularity, is an evil, then an able Physician is a common Nuisance.

Edmund Massey was the most prominent of the anti-inoculators. His sermons were described by pro-inoculators as “the mad Ravings of a fanatic Priest, bigoted to party tenets” (Grundy, 1994). While Lady Mary remained an ardent advocate for inoculation, her opportunities for promoting it were limited. Women at that time were largely excluded from the print media and so she primarily worked among the members of her social network and friends. As opposition developed, Lady Mary Montagu was heckled when she was walking on the streets of London. Some simply considered inoculation as a passing fad of the aristocracy rather that a legitimate medical procedure. It has been reported that when Lady Mary

40 A History of Vaccines and their Opponents

was scolded at some London social occasion for having “dirty hands.” She replied, “You should see my feet”! (Bingham, 2020). Her one known public statement was outspoken. Lady Mary, who distrusted physicians in general, wrote an anonymous article for a London Newspaper, the Flying Post, entitled “A plain account of the Inoculation of the Smallpox by a Turkey Merchant.” She was concerned about its complexity and cost. She promoted the “Constantinople Methoddno fees, no preparation, no fatalities, an old nurse and the scratch of a needle.” She even went as far as claiming that the method used by English physicians was “murder for money” (Grundy, 1994). This was her only public foray into the fight. There was some considerable concern in society because of the fact that inoculated patients were capable of transmitting the disease. People were scared and as a result, patients leaving the London Smallpox Hospital after inoculation were often beaten or insulted in the nearby streets. They were obliged to leave after nightfall. Likewise, inoculators were often attacked or forced to move (Courgeau, 2018). A surgeon, Lehard Sparham wrote a pamphlet entitled “Reasons against the Practice of inoculating the smallpox” and argued that it was inappropriate to insert poisons in wounds and bartering health for diseases (Behbehani, 1983).

Endorsement of inoculation Counterarguments were made by Charles Maitland as well as by other clergymen. They asserted that inoculation was, in fact, a gift from God. A gift given to man to permit him to protect himself. Refusal to inoculate was a sin since it was a refusal of God’s gift. Inoculation was also seen as part of a parent’s responsibility to protect their children. Not inoculating one’s children was to neglect one’s duty to protect them. (This argument was, as will be seen later, the basis for vaccine mandates in a later era.) Population growth was also seen as God’s will and inoculation a tool to promote it (Eriksen, 2013). As early as 1722, Charles Maitland began inoculating people “under Royal sponsorship” and published his visiting hours and locations of patients in the London Gazette. He encouraged visitors to see for themselves that inoculation produced only a mild form of smallpox that was readily controlled (Storm, 2011). The Royal Experiment had demonstrated, on a small number of individuals, that inoculation worked. The small numbers meant that the data was certainly unconvincing to the skeptical. That was not the end of the story. Proponents of inoculation had to counter opposition by providing evidence that their procedure was both safe and efficacious. This evidence was first produced by a Dr. Thomas Nettleton who had inoculated at least 40 people in Halifax, Yorkshire, over the winter of 1721e22. They all developed mild smallpox and survived. He sent a report of his results to a friend in London

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who passed them on to James Jurin, the Secretory of the Royal Society who, incidentally, was also a mathematician. Jurin was very interested and consequently, he and Nettleton began to correspond (Boylston, 2017). June 16, 1722 Sir, I doubt not that when you have collected a sufficient number of observations . You will be able to demonstrate, that the Hazard in this method is very inconsiderable, in proportion to that in ordinary way by accidental Contagion, so small that it ought not to deter any Body from making use of it.

Nettleton therefore began to collect data on the numbers and case-fatality rates of smallpox in Yorkshire. He found that 270 out of 1245 smallpox patients had died but none of his (by then) 60 inoculated patients. The inoculation controversy was at its height at this time. James Jurin recognized the significance of these results and thereupon set out to collect and publish all the comparative data he could. By December 1722, he and Nettleton had data showing that 856 out of 4626 patients suffering natural smallpox, while only two out of 182 inoculated patients, had died. The data was convincing and was an effective counter to the individual adverse reports regarding single patients. Jurin kept going. He advertised, asking anyone with experience of inoculation or natural smallpox to send the details to the Royal Society (Boylston, 2017). He requested pertinent data such as age, method of inoculation, days of illness, number and kind of pustules, outcome etc. (Behbehani, 1983). He received over 129 such letters between 1722 and 1729. During the 1720s, Jurin published annual reports comparing the danger associated with natural smallpox with that associated with inoculation. Jurin reported that the death rate for inoculated cases was between 1 in 48 and 1 in 60 cases while the death rate from natural causes was a consistent 1 in 6 cases (Fig. 3.2). Jurin’s publications represent the first documented use of statistics to analyze and support Public Health measures. Gradually, however, the number of inoculations performed in England dropped. Jurin lost his position as the Secretary of the Royal Society at the end of 1727 and gave up collecting the data. However, his successor, Dr. John Scheuchzer continued to do so for two more years. (He died in 1729.) Jurin’s data had several notable effects. First, the efficacy of inoculation became well recognized. It was difficult to argue against the facts and as a result, the controversy about the procedure died down somewhat. Second, these results suggested that inoculation was part of divinely ordained natural law and thus an effective counterargument to the argument that death by smallpox was God’s will. Third, it was used by many defenders of inoculation to justify the use of inoculation in the face of smallpox epidemics. Thus, this use of quantitative data, for the first time, was an excellent example of thinking in the age of enlightenment. One could choose one’s own fate, inoculation, or death from smallpox. Benjamin Franklin recognized this many years later in Philadelphia.

42 A History of Vaccines and their Opponents

FIGURE 3.2 Between 1723 and 1729, James Jurin conducted annual surveys of the comparative mortality caused by natural smallpox and by inoculation. Overall, he calculated that the chances of dying of natural smallpox was between 2 in 17 and 2 in 11. The risk of dying of smallpox as a result of inoculation was 1 in 50. He summarized his results in his 1727e28 report above (page 33). These figures suggest that mortality due to smallpox was 1 in 12 while mortality due to inoculation was 17 out of 845 (1 in 20). Note however that the mortality was much greater in 1722e23 than in 1727e28. The procedure clearly became safer with time and experience (Jurin, 1729).

British physicians also struggled to reconcile the results of inoculation with their Galenic humoral theories as to the cause of smallpox. One such explanation was that rather than a means of preventing smallpox, inoculation was simply a way of producing a mild form of the disease at a convenient time and place. The humoral theory suggested that most humans carried the seed of smallpox in their blood. In the natural disease the seed sought to escape from the body by causing the development of pustules in the skin. Inoculation simply provided the seed with an easy and safe way out! This theory also resulted in the procedure becoming overcomplex. Thus, physicians such as Nettleton believed that each victim accumulated the seeds of the disease over their lifeline and a deep incision had to be made to let them out. This, plus significant preparation was required to obtain the optimal results. The prolonged fasting, purging (lots of emetics and laxatives), and bloodletting that served the same purpose, made the procedure expensive, and largely restricted

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its use to practicing physicians and their wealthy clients. Phlegmatic individuals required a somewhat different preparation than sanguine individuals. Physicians considered themselves the only persons sufficiently skilled to analyze the interactions between the humors within the patient’s body. As a result of this complexity (and price), it was not widely adopted initially, especially when smallpox was not around. Despite the patronage of the Royal family and the efforts of inoculators only a few hundred persons were inoculated during the 1720s (Brunton, 1990). By 1729, fewer than 900 people had been inoculated in Britain. Most of those inoculated were children and servants of the gentry. The prosperous insisted on protection for themselves and their families and could afford the complex procedure. Those opposed to inoculation suggested that there were major differences between natural and inoculated smallpox. Thus, they argued that inoculated individuals did not develop “true smallpox” but just a rash of pimples. It would puzzle anyone to conceive how ‘tis possible the smallpox can ever be prevented by it. They also gleefully recorded cases of smallpox in anyone who had previously been inoculated (Brunton, 1990). Other opponents relying on humoral theories suggested that the severity of smallpox depended upon the state of the victim’s blood, and this was unaffected by inoculation. The public were being misled. A con game! Proponents suggested that inoculation did not make the patients sick. It simply cleansed the blood of the smallpox “seeds” by allowing them to escape through the inoculation wound (Brunton, 1990). Instead of making punctures with needles, British inoculators use a lancet (scalpel). This made a small wound about half an inch deep that was kept open to allow the morbid humors to escape. The pus from lesions was absorbed on a piece of lint and the lint then inserted in the incision for a few hours. As time passed, the incisions became deeper and irritating dressings were used to keep them open. Consistent with the medical hierarchy at the time, surgeons made the incisions and performed the operation, while physicians prepared the patients for the procedure in an effort to minimize the development of a fever. As a result, inoculation became even more expensive, but that was the best possible medical care. Lady Mary Wortley Montagu in her anonymous article in The Flying Post accused practitioners of needlessly elaborating inoculation in order to line their pockets (Brunton, 1990). Physicians disregarded her comments. From 1730 to 1770 methods of inoculation used in Britain progressively changed and the procedure became more standardized. Physicians belatedly began to recognize that smallpox was a single disease with diverse manifestations. During this period, the medical establishment remained divided over whether inoculation was effective or not. Jurin had stopped collecting reports on the results of inoculation in 1727 as its use diminished. The use of inoculation began to revive significantly in the 1740s. This resulted, at least in part, from a visit to London by Dr. James Kirkpatrick, a physician from Charleston, South Carolina. Kirkpatrick brought with him

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details of a smallpox epidemic in Charleston in 1738. He published his “Essay on Inoculation” in 1743. In it, he showed how inoculation had brought the epidemic under control and how his inoculation methods had evolved in the process (Miller, 1956). He and his American colleagues had simplified the procedure, reduced the severity of the reactions, and as a result, rendered it safer. Despite opposition, the preparatory period was shortened. Thus, the scratch was made in one arm only. Thread was not used, they simply applied fresh pus from another inoculated patient and bandaging was no longer required. The procedure induced milder local infections. Kirkpatrick had inoculated about 800 individuals of whom eight died. This mortality was less than half that of the earliest English procedures. As a result of Kirkpatrick’s enthusiasm, the London Smallpox and Inoculation Hospital was established in 1746 to encourage inoculation. From the outset, this Hospital was a major center for instructing physicians from all over the world on the correct technique of inoculation. It was helped by the fact that the heir to the throne, Prince George, the future George III, caught the disease in November 1743. This resulted in the immediate inoculation of his brother and sister. As time passed, demand increased. Smallpox returned in full force in England in the 1740s, and as a result, the demand for inoculations suddenly increased. Following the publication of data on its effectiveness, opposition to the procedure among the medical profession declined precipitously. The number of those inoculated rose rapidly and spread across the country. Thomas Frewen said, the Success with which it has been attended for some Years past, seems, at this time, to have established it on so firm a basis, as to stop in the mouths of its Antagonists and to let it make its own way. Brunton DC. Pox Brittanica: smallpox inoculation in Britain, 1721e1830. Publicly Accessible Penn Dissertations. 999. 1990. https://repository.upenn.edu/dissertations/999

Inoculation was increasingly described in major Medical textbooks. It began to be used in institutions such as the London Smallpox Hospital that provided it free of charge to the poor beginning in 1753 (Fig. 3.3). By 1760, the Hospital was performing over 200 inoculations a year (Brunton, 1990). The Royal College of Physicians of London officially endorsed the procedure in 1755. Dr. Richard Mead (1673e1754) was a leading British physician. He was a strong supporter of the establishment of a home for unwanted childrendthe Foundling Hospital in 1739. He was also an enthusiastic inoculator. At that time, smallpox was endemic in London and the leading cause of death among children of whom it killed about one in four. When the hospital opened, it was recognized that housing large numbers of children in dormitories presented a serious risk. As a result of Mead’s efforts, as well as those of Sir Hans Sloane, in January 1743, compulsory inoculation was introduced for the children

Variolation: the early years in Britain and Europe Chapter | 3 Kirkpatrick’s essay on inoculation 1743 Compulsory inoculation at London Foundling Hospital 1743

1740

1750

Catherine the Great Inoculated 1768

London hospital offered free inoculation 1753 Endorsed

London Inoculation Hospital Founded 1746

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Sutton’s method advertised

by Royal College of Physicians Lady Mary 1755 Montagu died 1762 1760

Dimsdales book published 1769

1770

FIGURE 3.3 A timeline of events involving the progressive adoption of inoculation (variolation) in England, 1740e80.

housed at the Foundling Hospital (McClure, 1981). The governing committee of the hospital instructed their physician Dr. Richard Conyers to determine the best method of inoculation. He successfully inoculated some children so that the governing committee instructed him to proceed as rapidly as possible with inoculating all children on admission. During this period, infants were put out to wet nurses to be breast fed. However once weaned, generally between ages three and five, they were returned to the hospital. All children aged three or older who were returned to the hospital after infant care elsewhere had to be inoculated before they were readmitted if they had not yet caught smallpox (Miller, 1956). (Other hospitals would not generally inoculate children under seven.) Of the 247 children inoculated at the hospital by April 1756, only one had died of smallpox (Foundling Hospital Museum). The Governing committee was so proud of this record that they sent the details to the newspapers for publication. Given the costs, time required, and complexity, of being inoculated, the poor could rarely afford it. As a result, they tended to depend upon amateur “variolists” and itinerant physicians. In addition, few of the poor could afford to take 2e3 weeks off work and perhaps longer, for convalescence. Eventually, in 1769, a physician named Daniel Sutton advertised a much simpler, safer, less traumatic, and cheaper method that became widely adopted. He used a short preparation period and relatively shallow incisions. Sutton was however criticized for his flamboyant advertising and for seeking to keep his methods secret. It is estimated that he earned 8000 guineas in the first 2 years of his variolation practice (worth about £900,000 today)! (Baxby, 1979) The Suttonian method was standardized and it, because of its lower price and relative simplicity, progressively replaced the older complex procedures (Brunton, 1990). Thomas Dimsdale, (he who inoculated Catherine the Great of Russia, Box 3.1), was also an advocate of these much simpler, safer methods and

46 A History of Vaccines and their Opponents

BOX 3.1 Catherine the Great Catherine the Great was the wife of Czar Peter III. She was incredibly smart while he was an idiot. He was also pockmarked and incredibly ugly as a result of smallpox scarring. This might have been a small part of her motives for deposing and killing her husband and assuming the throne of Russia in 1762. She was very scared of the disease. The Empress therefore instructed her ambassador in London to seek a physician who would inoculate her and her son and heir, the Grand duke Paul. Dr. Thomas Dimsdale, the author of a recent pamphlet on the procedure, took the job and arrived with his son in St Petersburg in 1768. Everything he needed was waiting for him. He offered to test the procedure on other women first, but Catherine refuseddit would take too much time. He inoculated the royal pair on October 12, 1768, using infected lymph taken from a 6-year-old boy and directly inoculated into the Empresses’ arm. She duly went through the resulting sickness but recovered uneventfully and was back at work by November 1. (Catharine had ordered that a secret carriage be kept waiting, ready to help Dimsdale and his son Nathaniel flee Russia in case she died during the procedure. She worried that her courtiers would execute Dimsdale if things went wrong.) Dimsdale and his son were each lavishly rewarded with a baronage, an award of £1000, plus £2000 for expenses, and an annual pension of £500. When he got back to London, Dimsdale was so rich that he could afford to open a smallpox inoculation clinic and a bank! Voltaire congratulated Catherine on being inoculated: “You have been inoculated with less fuss than a nun taking an enema.” Thomas Dimsdale subsequently made a second visit to St Petersburg in 1781 to inoculate Catharine’s grandsons and other members of the Russian nobility. With all these members of ruling families being inoculated, there was a growing awareness among politicians and the Russian public of its benefits.

wrote a book on the subject in 1769. (Some physicians were however worried that if the reaction was too mild, insufficient smallpox “seed” would escape so inoculation would not work) (Eriksen, 2013). Dimsdale and Sutton both advocated the “cold” method in which inoculated patients were kept cool and given cold drinks (just like the Hindu goddess Shitala, Chapter 21).

Skepticism While James Jurin’s numbers comparing mortality in inoculated and noninoculated individuals were impressive and in effect represented the first scientific proof of a treatment that worked, there was also some relevant criticism. Thus, Dr. Isaac Massey, the apothecary to Christ’s Hospital, London, and not a fan of inoculation, published a letter to Jurin in 1723 pointing out that the death rates among unvaccinated individuals might have been much lower if they had been treated with equal care to those that were inoculated. He

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suggested rightfully that “to form a just Comparison, and calculate right in this case, the Circumstances of the Patients, must and ought to be as near as may be on a par” (Hasselgren, 2020; Huth, 2006). In effect he was asking for true randomization.

Persistent opposition Despite the data generated by Jurin and Needham, the London newspapers persisted in publishing lurid details regarding the deaths of prominent victims of inoculation. Thomas Nettleton read in one such newspaper that one of his patients had died as a result of smallpox acquired by inoculation. He responded rapidly, writing to Jurin who then paid for space in The London Daily Journal refuting the assertion and providing documentation to prove that his patients were still alive. Misinformation is not just a 21st-century phenomenon (Moxham, 2013). By the 1750s, religious and medical opposition to the procedure had largely disappeared. Isaac Maddox, the Bishop of Worcester, wrote a pamphlet in which he argued that inoculation was totally consistent with proper religious conduct. It was a Christian’s duty to protect their own life. Since inoculation saved lives and had been revealed by God, it was a Christian duty to practice inoculation (Brunton, 1990). Even after the cheaper, safer, and simpler Suttonian method of inoculation was introduced in the 1760s, apathy and resistance still persisted. There was a fatalistic attitude, especially among the poor who expected to lose some children from smallpox. Some working people persisted in deliberately exposing their children to mild cases of the natural disease hoping that the resulting disease would be mild (Brunton, 1990). A similar hesitancy was seen in rural Scotland where people approached inoculation very cautiously. Thus, although the medical profession professed the procedure to be both simple and safe, the country folk believed it improper to bring disease, trouble, or distress to helpless infants. As a result of this hesitancy, children were often only inoculated when they were at extreme risk during an epidemic. This was often a last-minute procedure left too late. Once the epidemic was over, inoculation lapsed (Brunton, 1990). Many of the poor still retained deep religious objections to the practice. Again, there was a widespread belief that disease was a punishment from God. Inoculation both tempted providence by deliberately inducing a dangerous disease, while at the same time interfering with God’s ability to send disease. These ideas, similar to those raised when inoculation was first introduced, were still strongly held in Scottish rural communities. They reflected strict Calvinist theology that was revived by secessionist churches leaving the mainstream Church of Scotland. Even when encouraged by their ministers, there was a general refusal to adopt the practice.

48 A History of Vaccines and their Opponents

Resistance and acceptance in Europe Smallpox was as great a killer on continental Europe as it was in Britain. As a result, the Royal Experiment attracted great attention, especially in the German States. However, the French philosopher Voltaire, known for his sarcastic wit, lived in London between 1726 and 1728. He summarized European attitudes in 1733 thus: It is inadvertently affirmed in the Christian countries of Europe, that the English are fools and madmen. Fools, because they give their children the small-pox to prevent their catching it; and madmen, because they wantonly communicate a certain and dreadful distemper to their children. Merely to prevent an uncertain evil. Weiss & Esparza (2014).

Voltaire (the pseudonym of Franc¸ois-Marie Arouet) (1694e1778) was an extraordinary French writer, historian, and philosopher. He was an ardent fan of Lady Mary Montagu and conversely a critic of French reluctance to take up inoculation (Voltaire foundation, 2020).

France The French were especially reluctant to embrace the bizarre British practice of inoculation. However, in fairness, it must be pointed out that the two countries were at war for much of the 18th century and relations were rarely amicable. In Britain, the physicians themselves were enthusiastic advocates, whereas in France, local corporations tended to control medical practice and were conservative in their approach to novel ideas (Eriksen, 2013). However, philosophers such as Voltaire were very interested in the procedure even though they were not physicians. In a letter sent in 1734, Voltaire chastised the French for not following the English example. However, his text was banned in France and was only published abroad. While some thought inoculation fashionable, stories of adverse events and bad experiences tended to dampen enthusiasm. French opposition was eventually largely overcome by the activities of the eminent mathematician and naturalist Charles Marie de La Condamine who in 1754 began a campaign by submitting a paper on inoculation to the Academy of Science using Jurin’s figures to suggest that nearly a million deaths could have been avoided in France if it had adopted inoculation (Fenner et al., 1988). He aggressively attacked the clergy’s “Will of God” attitude. There had been a significant smallpox epidemic in Paris in 1753. La Condamine delivered his speech on inoculation to the French Academy in April 1754. In it he pointed out that according to James Jurin, natural smallpox killed around 1 in 10, but when inoculated, killed only one in 1000. The speech sparked interest and was hotly discussed in Paris and across France. The Parlement de Paris, the chief French court, appointed a commission from the University of Paris to investigate the

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matter. After considerable debate, the commission came out in favor of the procedure. That same year, the pastor of the French protestant church in the Hague published a defense of inoculation. The kings and princes of continental Europe began to take an interest. Beginning in 1755, a growing number of the French nobility began to get themselves and their families inoculated. In the spring of 1756, the Duke of Orleans decided to have his son and daughter inoculated. A physician who had trained in England, Dr. Theodore Tronchin, was summoned from Geneva to Paris to perform the operation. The procedure worked well and helped the credibility of inoculation in Europe. French aristocrats lined up at Tronchin’s door to get themselves and their children inoculated. Soon inoculation became the rage in French high society. Unfortunately, the Seven Years’ War between France and Britain broke out that year and reinforced the opponents of inoculation. In that war, Britain and Prussia fought France and Austria. The war was not associated with any major smallpox outbreaks and the British troops had largely been inoculated. Those in France and Austria who had reservations about the procedure maintained an upper hand. Nevertheless, inoculation persisted in French aristocratic circles. An outbreak of smallpox in Paris in 1762e62 increased the demand for inoculation. Angelo Gatti, a Venetian and Professor from the University of Pisa, was an ardent inoculationist (Gatti, 1758). However, he appears to have been somewhat careless. Thus, when he inoculated the Duchess of Bouffiers, she developed smallpox (Walton, 2017). As a result of the uproar that followed, in June 1763, the Parlement de Paris imposed a ban on inoculation within the city limits until it had been first approved by the Faculties of Medicine and Theology, of the University of Paris. Voltaire and his colleagues opposed the ban. The Faculty of Theology declined to rule on the matter, but the Faculty of Medicine took their task seriously. They sent out questionnaires to physicians around Europe. In the end, the committee was divided. The minority opinion wanted the ban on inoculation to continue, the majority however by a vote of two to one wanted to permit it. The deadlock continued and was never formally broken, but by late 1768, the inoculation ban in Paris was rescinded and inoculation gradually resumed. While inoculation was increasingly practiced elsewhere in Europe, the French Royal family remained very reluctant. Louis XV who was 60 in 1770 was very opposed to the procedure but caught smallpox and died in May 1774. It was evidently an agonizing and undignified death (Byrne, 2015). His rotting blackened body was covered with alcohol and linens and buried in the basilica of Saint Denis at night without the usual ceremonials. As a result, his successor, Louis XVI, was soon inoculated and he and his wife Marie Antoinette, who was an enthusiastic advocate, had all their children inoculated as well. Marie Antoinette celebrated the king’s inoculation by commissioning a towering headdress, a “Coiffeure a inoculation” with red spotted ribbons and a serpent wrapped around an olive tree! (Walton, 2017).

50 A History of Vaccines and their Opponents

Germany Germany at that time was a confederation of small independent states. The rulers of these states gradually adopted inoculation to ensure the survival of their heirs. These included Saxe-Gotha in 1759, Denmark in 1760, and Saxony in 1763. Prussia employed it widely under Frederick the Great. In 1774e75, Frederick invited English physicians to Berlin to demonstrate the procedure to Prussian physicians but although authoritarian, he left inoculation procedures up to parents and individuals. Another English inoculation team was summoned to Vienna by the Empress Maria Theresa (Box 3.2). The first inoculations in the twin monarchy of Norway and Denmark were performed in Trondheim in 1754. In Copenhagen, a royal inoculation house was established in 1755 but was underutilized and closed 5 years later (Eriksen, 2013). BOX 3.2 Wolfgang Amadeus Mozart Mozart’s father Leopold was reluctant to have his son inoculated. Thus, in February 1764, Leopold Mozart wrote to a friend, They are trying to persuade me to let the boy be inoculated with smallpox. But as I have expressed sufficiently clearly my aversion to this impertinence, they are leaving me in peace. Here inoculation is the general fashion. But for my part I leave the matter to the grace of God. It depends on his grace whether He wishes to keep this prodigy of nature in this world in which He has placed it or to take it to Himself.

As a consequence, in October 1767, young Mozart and his sister Nannerl contracted smallpox, but both fortunately recovered (Wikiwand). A few years after his death, Nannerl wrote a description, “My brother was a very pretty child. But after he had smallpox, he was much disfigured, ..” Interestingly, none of the surviving portraits of Mozart appear to show these lesions.

References Behbehani AM. The smallpox story: life and death of an old disease. Microbiol Rev 1983;47(4):455e509. Bingham S. How libels take hold. 2020. https://salliebingham.com/how-libels-take-hold. Boylston A. The origins of inoculation. J R Soc Med 2012;105:309e13. https://doi.org/10.1258/ jrsm.2012.12k044. Boylston A. Smallpox inoculation: prelude to vaccination. In: Hektoen International; 2017. https:// hekint.org/2017/02/01/smallpox-inoculation-prelude-to-vaccination. Brunton DC. Pox Brittanica: smallpox inoculation in Britain, 1721e1830. Publicly Accessible Penn Dissertations. 999. 1990. https://repository.upenn.edu/dissertations/999. Byrne A. The deathbed of Louis XV. Fr Hist 2015;29(4):491e509. https://doi.org/10.1093/fh/crv016. Courgeau D. Inoculation, vaccination and public hygiene against smallpox. In: Seguy I, Ginnaio M, Buchet L, editors. Les conditions des populations du passe´. Environments, maladies, prophylaxies et politiques publiques. Antibes: Editions APDCA; 2018.

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Eriksen A. Cure or protection? The meaning of smallpox inoculation, ca 1750e1775. Med Hist 2013;57(4):516e36. Edward Jenner, William Woodville and the origins of vaccinia virus. J Hist Med Allied Sci 1979;34:134e62. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. World Health Organization; 1988. Foundling Hospital Museum. https://foundlingmuseum.org.uk/object/portraits-dr-richard-mead. Gatti A. New observations on inoculation. 1758. https://commons.wikimedia.org/Wiki/File:Newobservations-on-inoculation. Grundy I. Medical advances and female fame: inoculation and its after-effects. Lumen 1994;13:13e42. https://doi.org/10.7202/1012519ar. Hasselgren P-O. The smallpox epidemics in America in the 1700s and the role of the surgeons: lessons to be learned during the global outbreak of COVID-19. World J Surg 2020;44:2837e41. https://doi.org/10.1007/s00268-020-05670-4. Huth E. Quantitative evidence for judgements on the efficacy of inoculation for the prevention of smallpox: England and New England in the 1700’s. J Roy Soc Med 2006;99:262e6. Jurin J. Account of the success of inoculating the smallpox in Great Britain. London: J. Peele; 1729. Langer WL. Immunization against smallpox before Jenner. Sci Am 1976;234(1):112e7. Maitland CM. Maitland’s account of inoculating the small pox. London: J. Downing; 1722. Marsden JP. Variola minor in the United States. Clin Pediatr 1967;6(9). https://doi/10.1177/ 000992286700600902. Massey E. A sermon against the dangerous and sinful practice of inoculation. Preach’d at St. Andrew’s Holborn; July 8, 1722. https://quod.lib.umich.edu/e/evans/NO2782.0001.001/1:2. McClure RK. Pediatric practice at the London foundling hospital. Stud 18th Cent Cult 1981;10:3610371. Miller G. Smallpox inoculation in England and America: a reappraisal. William Mary Q 1956;13(4):476e92. Moxham N. Job’s boils and washballs. 2013. https://royalsociety.org/blog/2013/06/jobs-boils/. Riedel S. Edward Jenner and the history of smallpox and vaccination. BUMC proceedings 2005;18:21e5. Rosner L. Lady Mary Wortley Montagu and immunization advocacy. 2017. https:// nyamcenterforhistory.org/2017/03/28/lady-mary-wortley-montagu. Storm AE. Religious conviction and the Boston inoculation controversy of 1721. Undergraduate thesis. College of William and Mary; 2011. https://scholarworks.wm.edu/honorstheses/400. Timoni E. An account of the procuring of the small pox by incision, or inoculation: as it has been for some time. Practiced at Constantinople. Being an extract of a letter from Emanuel Timonius, Oxon. and Patav. M.D.S.R.S. dated Constantinople, December 1713. Communicated by John Woodward, M.D. and S.R.S. Phil Trans Roy Soc 1714;29:72e82. Voltaire Foundation. Voltaire’s letters on the English and the story of smallpox. 2020. https:// voltairefoundation.wordpress.com/2020/05/27/voltaires-letters. Walton G. Smallpox inoculation in 18th century France. 2017. https://www.geriwalton.com/8456. Weiss RA, Esparza J. The prevention and eradication of smallpox: a commentary on Sloane (1755) “an account of inoculation”. Phil Trans R Soc B 2014;370. https://doi.org/10.1098/rstb.2014.0378. Wikiwand. Wolfgang Amadeus Mozart. https://www.wikiwand.com/en/Mozart-and-smallpox. Willett J. The pioneering life of Mary Wortley Montagu: scientist and feminist. Pen & Sword; 2021, ISBN 9781526779380.

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Chapter 4

Variolation in New England While variolation was being introduced in England, almost simultaneously it was being seriously considered in the American Colonies, specifically in the city of Boston. As in England, the driving force was not a physician but a scientifically minded individual, the minister of the Old North Church, Cotton Mather.

Cotton Mather Cotton Mather (1663e1728) was probably the most eminent preacher living in Boston at the time of the 1721 smallpox epidemic. He had been involved in the Salem Witch trials of 1693 and he himself had played a prominent role in the execution of 14 women and 6 men. As described in Chapter 2, Mather firmly believed in the existence of witches. He also believed that prior to the coming of the Europeans, America was in the territory of the devil. As a result, God actively intervened to support the developing colonies. He believed that the early colonists were, in effect, a chosen generation. The Salem witch trials reinforced this point of view since he believed that the demonic possession of these unfortunate individuals represented Satan’s counterattack. Mather also thought of witchcraft as a form of contagious disease. He wrote a book entitled The Wonders of the Invisible World. In it, he sought to justify the Salem Witch trials. Mather was, however, also an avid reader of medical texts and in that respect was probably as well read as most of Boston’s “doctors.” It should also be noted that Mather was a prolific author publishing 444 works that ranged from full-length theology texts to simple pamphlets. He fancied himself as a scientist. Another eminent citizen of Boston at that time was a Scottish physician, Dr. William Douglass, a graduate in medicine who had studied at the Universities of Edinburgh, Leyden, Paris, and Utrecht. Douglass had brought copies of the Royal Society’s Proceedings containing Timoni’s and Pylarino’s letters with him when he arrived in Boston in 1718. In 1721, Cotton Mather asked to borrow them. Douglass obliged, although he did not regard Mather highly. (A man whom he privately called “a vain and credulous preacher.”) To Douglas’ dismay, Mather began to make use of them almost immediately. The Reverend Mr. Cotton Mather pushed hard for variolation. In addition to his theological studies, Mather considered himself to be a man of science A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00009-7 Copyright © 2023 Elsevier Inc. All rights reserved.

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with an interest in medical innovation. He was proud to have been nominated as a Fellow of the Royal Society in 1713. (He was the first native-born American to have been elected to a fellowship.) Mather corresponded with Dr. John Woodward of the Royal Society in July 1716 wondering why inoculation had not yet been introduced in Britain. He reckoned that it would be a worthwhile procedure to try based on the information contained in the letters from Constantinople. Another reason for his enthusiasm was the information he had received from his African slave Onesimus. Once he had read Timoni’s letter in the philosophical transactions he wrote to the Royal Society reporting on a conversation he had had many years earlier with Onesimus. In his 1716 letter to Dr. Woodward, Mather proposed: “ye Method of Inoculation” as the best means of preventing smallpox and noted that he had learned of this process from “my Negro-Man Onesimus, who is a pretty Intelligent Fellow” in a conversation several months earlier. (Boylston, 2012) Onesimus explained that he had undergone an Operation, “which had given him something of ye Small-Pox, and would forever preserve him from it, adding, that it was often used among [Africans] and whoever had ye Courage to use it, was forever free from ye Fear of the Contagion. He described ye Operation to me and showed me in his Arm ye Scar.” Onesimus told Mather: “People take the Juice of the Small Pox, and Cut the Skin, and put in a drop; then by ’nd by a little sick; then few small pox; and nobody dye of it; no body have small pox anymore.”

Onesimus was said to be a Guaramante (possibly from a tribe from what is now the Fezzan region of Southern Libya) who had been given to Mather as a gift by his congregation in 1707. Mather and another minister, Benjamin Colman, confirmed Onesimus account after discussions with several other African slaves. Mather then went on to say in the letter to Woodward. For my own part, if I should live to see the Small-Pox again enter our City, I would immediately procure a Consult of our Physicians, to Introduce a Practice, which may be of so very happy a Tendency.

Smallpox returned to Boston, 5 years later (Blake, 1952).

Smallpox in Boston While smallpox epidemics were common in the North American colonies and recurred every few years, there was a disease-free interval of 18 years between 1703 and 1721. This interval enabled a whole new generation of Bostonians to grow up without being exposed to, or developing immunity against the virus. As a result, when smallpox returned in April 1721, it was especially severe. This was the same month that Lady Mary Montagu in London had had her daughter inoculated by Dr. Charles Maitland (Chapter 3).

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21 First enquiry at town house 26. Boylston inoculated 3 people

April I

May I

22. HMS Squirrel arrived. Epidemic begins

June I

July I

6. Mather’s letter to Boston Physicians

55

Epidemic peaked News of Royal Experiment arrives

12 Mathers son inoculated Aug Sept I I 7. Boylston told to stop 24. Douglass’ letter published

17. Boylston’s letter to the Gazette

Oct I

Nov I 18 Mather’s house bombed

Dec I

Jan I

Feb I

Mar I

Epidemic declared over

August, Sept, Oct, Mather kept inoculating

FIGURE 4.1 A timeline of the events in Boston following the arrival of smallpox on HMS Squirrel in April 1721.

The epidemic began on April 22, 1721, when a British ship, HMS Seahorse, arrived in Boston from Barbados (Fig. 4.1). One of its crew had the disease so that by late May, a major smallpox outbreak had developed in the city and begun to kill its victims. Eventually, out of a population of about 12,000, 4917 smallpox cases were recorded in Boston resulting in 842 deaths. It was one of the deadliest smallpox epidemics in colonial America. As elsewhere, physicians were at a loss as to how to treat it. Civic and commercial activity was completely disrupted. As the disease began to spread through the city, Mather, encouraged by his father, Increase Mather, decided to carry out his plan. Consequently, on June 6, he sent a letter to the physicians of Boston proposing inoculation and summarizing the letters of Timoni and Pylarino to the Royal Society. (He knew nothing of the activities of Lady Mary Montagu.) He asked to meet with them for a consultation to discuss which of them should first attempt the procedure. William Douglas was irritated at this presumption from someone who was not even medically qualified. He declined to cooperate, and asked for the return of his copies of the Philosophical Transactions and Mather complied. Mather’s proposal received a negative reception from the Boston medical community. “Whatever their reasons, they made no reply” (Blake, 1952). The physicians rejected the concept of variolation as hazardous and unproven, and ignored Mather’s letter. As the only physician who actually possessed a medical degree in the city, William Douglass was bitterly opposed to the concept. (The other “physicians” in the city were qualified by virtue of having been apprenticed to a qualified physician. Thus, their levels of medical

56 A History of Vaccines and their Opponents

knowledge were highly uneven.) It must be remembered that physicians at that time had no concepts of viruses or immunity. It was incompatible with the humoral theories of disease. It would have seemed to them as foolish and irrational folklore. The fact that Mather had also learned of the variolation concept from Onesimus, an African slave, also provoked racist skepticism as well as the idea that this was exotic sorcery.

Zabdiel Boylston Zabdiel Boylston (1679e1766) was an apprentice-trained physician/apothecary in Brookline. He had been trained by his father (the first medical school in North America would not be founded until 1765). He was by all accounts something of a maverick being the first American surgeon to perform gallstone surgery in 1710 and surgically removed a breast cancer in 1718 (Courgeau, 2018). Like Lady Montagu, he was a smallpox survivor (Grundy, 1994). Boylston was however impressed when Mather sent him a personal letter on June 24 and decided to try the procedure despite never having seen it performed previouslyda risky and with hindsight, a somewhat irresponsible decision. Two days later, on June 26, 1721, Boylston variolated his 6-year-old son Thomas, as well as two of his slaves, Jack (aged 36) and Jack’s son Jacky (aged 2 and a half). All three developed a mild fever at 7 days (July 1) and developed smallpox lesions around the inoculation site on day 9. “about an hundred a piece; after which their Circumstances became easy, our Trouble was over and they soon were well.” Douglass and the rest of Boston were aware of what Boylston had done that very evening!! Between July 12 and 19, Boylston inoculated seven more individuals including his other son, John. The population was aroused! Mobs, some drunk, gathered outside Boylston’s home and shouted abuse “Murderer”! “House of Filth”! In the streets of Boston, Boylston was jeered, jostled, and followed with cries of “Pox spreader” and “poisoner!” On the 17th of July, Boylston published a letter defending his actions against the “Clamour and Ralary” in The Boston Gazette. He justified them by pointing out that inoculation was “recommended from Gentlemen of learning and which well agrees to reason.” He also described the procedure and the reports from Turkey although Douglass refused to let him see the published letters. He pointed out that the African slaves in Boston knew all about it. “I know not why it is unlawful to learn of Africans.” Boylston also indicated his intentions to inoculate more people, which upset people still further and triggered a violent response. as the practice was new, and the Clamour, or rather rage of the people against it so violent that I was put into a very great Fright;

Cotton Mather was also subjected to abuse. He pointed out that people reacted like “idiots and Fanaticks.” He interpreted the protests against

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inoculation as evidence that Boston was a community suffering from evil and corruption and determined to prevent a procedure that, in Mather’s opinion, was ordained by God to save lives and prevent suffering. He described the antiinoculation protests as the work of the devil (Koch, 2016). Mather prayed for God’s compassion “to a Town already under dreadful Judgements but ripening for more”(Sivils, 2011).

Responses Boston society responded in divergent ways. Most physicians and some clergy were horrified. Self-inoculation made no sense at all. Antagonistic pamphlets were distributed widely. Men were interfering with God’s will. Besides it was immoral to deliberately spread the disease. It was willful tampering with death and tantamount to murder! Some clergy supported Boylston whereas the medical community was dead-set against him. This was unethical and “unscientific” and as a result, the city council members (Selectmen) warned him privately to stop inoculating people. . for a man to infect a family in the morning with smallpox and to pray to God in the evening against the disease is blasphemy; that the smallpox is ‘a judgment of God on the sins of the people,’ and that ‘to avert it is but to provoke him more; ’ that inoculation is ‘an encroachment on the prerogatives of Jehovah, whose right it is to wound and smite.

Additional attacks against inoculation and inoculators were published in the weekly New-England Courant edited by James and his younger brother Ben Franklin. While supposedly neutral, James Franklin writing in his paper criticized the Puritan ministers for supporting inoculation. He wrote a short poem: Who like faithful shepherds take care of their flocks By teaching and practicing what’s orthodox Pray hard against sickness, yet preach up the POX! This caused considerable offense. The ministers of Boston thought that this article was oversensational. They claimed that it was “freighted with Nonsense, Prophaneness, Immorality, Lyes and Contradictions.” They did not “turn the other cheek” but sued. As a result, James Franklin was put in prison for 4 weeks while his apprentice, 15-year-old Ben, published the paper in his absence (Best et al., 2004). As described in Chapter 5, young Ben Franklin did not get on well with his brother and eventually ran away from Boston and became an active supporter of inoculation. When the Selectmen of the city learned that Boylston planned to variolate more people despite their warning they ordered him to report to the Boston Town House for an inquiry on Friday, July 21. He was questioned about the risks associated with inoculation. Douglass was present as well to question him.

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Boylston defended himself and the procedure. Boylston reported, however, that a French physician, at that same enquiry, a former French military surgeon, Dr Lawrence Dalhonde had testified to the Selectmen on July 21 that he had seen inoculation performed many times in Italy, Flanders, and Spain 25 years previously and that it was invariably lethal. This was completely untruedinoculation was unknown in those countries at that time. (Perhaps he was confusing it with the plague.) However, as a result, Boylston, who had already inoculated 10 individuals, was reprimanded and ordered to stop. The Selectmen took the view propounded by the other Boston physicians that inoculation caused serious illness and death in addition to spreading the disease to others. They severely reprimanded Boylston and threatened to charge him with murder should any of his patients die! The Select Men in duty bound to take Cognizance of the Matter, desire a Meeting of all the Practitioners in Town, to have their Opinion whether the Practice ought to be allowed or not; they Unanimously agreed that it was rash and dubious, being entirely new, not in the least vouched or recommended (being merely published, in the Philosophick Transactions by way of Amusement) from Britain, tho’ it came to us via London from the Turk, and by a strong viva voce Evidence, was proved to be of fatal and dangerous Consequence. B—n is desired by the Select Men to desist. The New-England Courant, Aug 7, 1721.

Douglass was aggrieved that he had not been consulted by Mather before he wrote his letter to the city’s physicians. Three days after the meeting with the Selectmen, he wrote a statement for the Boston News-letter opposing variolation that was published on July 24 (Douglass, 1721). The method was untested and unscientific. It no-way fitted with current medical knowledge or theories. However, on the 31st, Increase and Cotton Mather as well as four other clergymen replied to Douglass in the Gazette and strongly defended Boylston. They argued that inoculation should be accepted “with all thankfulness and joy as the gracious discovery of Kind Providence to Mankind ..” Clearly, not all clergymen thought it an offense against God. William Douglass next responded with a pamphlet accusing “Six men (commonly call’d the six inoculation ministers)” of claiming that inoculation should become universal. He attacked the Puritan ministers whose ‘infatuation’ led to the hanging of those suspected of witchcraft, about the year 1691.” Douglass went on to suggest that Boston could relapse into the same errors by introducing inoculation. Notwithstanding the opposition of the physicians, the news was out! Smallpox could be prevented! As a result, many parents came quietly to Boylston to have their children variolated. On August 12, Boylston inoculated Mather’s son Samuel. It continued to work well but was by no means free of risk. However, he continued doing so on everyone who asked him, including

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people from out-of-town. He inoculated 19 persons that August, 31 in September, and 18 more in October, but stopped later that year when the Boston physicians, encouraged by Douglas averred that the procedure had caused the death of many persons and “had brought distemper upon many others”. The words “malignant filth” were used for the first time. But the epidemic raged on. By the time the epidemic was over, Boylston had inoculated 244 persons. Two other physicians, Thompson in nearby Cambridge and Roby in Roxbury had inoculated an additional 36 (Fig. 4.2). Despite the claims of the Boston physicians, only six of Boylston’s patients had died.

William Douglass Dr. William Douglass (1691e1752) led the medical profession’s opposition to Boylston and Mather. He was vastly more qualified than any other Boston physician on the medical theories and procedures of the time. Born in Scotland and a graduate of Edinburgh University, he was the only holder of a medical degree in Boston. He had also studied at Utrecht where he obtained his MD in 1712. He settled in Boston in 1718. As a distinguished physician, Douglass’ practice flourished. Much of his opposition to inoculation was a result of resentment against Mather for meddling in medical matters (Sivils, 2011). As a result, he and Mather had a long-running argument, generally through the medium of opposing pamphlets. Douglass and a local apothecary John Checkley formed “The Society of Physicians Anti-inoculators,” that met at local coffee houses to denounce the procedure and those who performed it (Best et al., 2004; Behbehani, 1983). Douglass also wrote a letter to the Royal Society in London that September in which he updated members on the smallpox situation in Boston and

Persons in- Had the Had an Im- Had no Ef- Suspected oculated Small-pox perfect small fect. to have died by Inocu- Pox. of Inoculalation tion.

Total Inoculated by Drs Roby and Thomp son

Total

244

238

00

06

06

36

36

00

00

00

280

274

00

00

06

FIGURE 4.2 Boylston reported the results of 280 inoculations performed in Boston during the 1721 smallpox epidemic in a booklet published in 1726. The inoculated individuals were aged between 9 months and 67 years. Those that failed to react to the inoculation were probably already immune as a result of having had the smallpox previously. There were six deaths associated with the inoculation process. Boylston Z., a historical account of the smallpox inoculated in New England, upon all sorts of persons, whites, blacks, and of all ages and constitutions (Chandler, 1726).

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reported negatively on Boylston’s first inoculation results. On November 16, 1721 this was read at a meeting of the Royal Society. It provided some encouragement for the opponents of inoculation since Douglass exaggerated the dangers of the procedure and Boylston’s recklessness (Miller, 1956). To counteract this, on October 30, the news of the results of the Royal Experiment in London were published by the Boston newspapers. The demand for inoculation continued to grow. However, the Selectmen held another meeting on November 4 and required that anyone who came to Boston with the intention of being inoculated should be confined to the pesthouse unless they went home (Blake, 1952). But the epidemic raged on. The news that Cotton Mather’s son Tommy as well as others had been inoculated by Boylston in August set off another flurry of protests in Boston. The local physicians encouraged these protests. As the excitement grew, men patrolled the streets of Boston with halters and threatened to hang Boylston from the nearest tree. He was forced at one point to hide in a “private place” in his own house when men searched for him. He could only visit his patients at night and in disguise. On November 14, 1721, a small homemade explosive device was thrown through the window of Cotton Mather’s home in Boston. It landed in a room where Mather’s nephew the Reverend Mr. Walter of Roxbury was recovering from inoculation. Fortunately, the fuse became detached from the explosives, and it failed to go off. Attached to the device was a note that read “Cotton Mather, you dog, dam you! I’ll inoculate you with this; with a pox to you.” Clearly, someone in Boston was seriously upset by the use of inoculation (Harvard, 2014).

Subsequent reconsideration The Boston smallpox epidemic peaked in October and then case numbers began to drop. The Selectmen declared the epidemic over in that city in late February. However, in April 1722, the Boston Selectmen also reprimanded several ministers who had been encouraging people from the surrounding countryside to come to town to be inoculated (Miller, 1956). On March 21, 1722, the House of Representatives of the Province of Massachusetts had passed “An Act to prevent the spreading of the Small pox by Inoculation.” They sent it to the Council for their approval; however, the Council rejected the Act. In May 1723, the Boston Selectmen placed the practice of smallpox inoculation under official control and made Boylston promise not to variolate anyone else without prior approval.

Medical arguments In 1722, Douglass published his first Pamphlet entitled “Inoculation of the Small Pox as practiced in Boston.” In it he did not discuss the hazards of the procedure but emphasized Boylston’s and Mather’s lack of qualifications.

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As the only physician in Boston with a medical degree, he was clearly insulted that he had not been consulted by a pair of rank amateurs (Storm, 2011). In Douglass’ view, they were clearly unqualified to make such decisions and inappropriately meddling in medical affairs. Douglass also took the opportunity to emphasize the hazards of the procedure. It had become generally accepted that while lawful, inoculated individuals could spread the disease to others. This was a rational concern since deliberately exposing healthy individuals to the disease could be considered highly unethical and a breach of the 6th Commandment. As a result, it was demanded that inoculated individuals must be isolated while they were contagious. A related complaint from Douglass suggested that Boylston was responsible in some way for the persistence of the pox in Boston. Douglass and other physicians also countered inoculation on the grounds that it was untested, bore no relation to current medical knowledge about smallpox, and was based purely on superstition and folklore. It was, in short, unscientific based on medical knowledge at that time. By 1730, William Douglass had changed his mind! Given the data available, he finally recognized that inoculation was an effective measure and published a somewhat ungracious essay entitled “A practical essay concerning the Small pox” (Miller, 1956). He never forgave Mather or Boylston. how mean or rash soever the beginning of inoculation may have been, if many years practiced by old women only and neglected by the sons of art in Turkey; if in another part of the world of no literature, of habitual rashness from the third hand hearing of an overcredulous person, first attempted it indifferently to all who would pay for it without regard to age, sex, constitution or other circumstances and cautions, which tryals of such consequences require, as it is one of the inconveniences of human life that all the world over ignorance assurance and rashness pushes on some to attempt without fear or discression what would make the most exquisite artist tremble to touch, nevertheless if in the event by repeated experiments it ought to prove useful, It ought to be embraced. And the Rev Dr, Cotton Mather surreptitiously without the knowledge of his informer, himself, that he might have the honor of a newfangled notice sets an undaunted operator to work and in this country about 290 were inoculated.

This recantation effectively ended much of the opposition of physicians in the American colonies to the procedure. With each ensuing smallpox epidemic, more and more individuals chose to get inoculated. Douglass himself began to personally inoculate patients.

Religious arguments The contentious public debate that was triggered by Mather and Boylston reflected in large part the total lack of understanding of the nature of the disease. While the most significant opposition came from the medical community, as in England, some of the clergy also opposed it as well. Religion was

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a major force in Boston in the early 18th century. The city was devoutly Puritan, and the sermons preached by her ministers were significant and authoritative. The development of inoculation raised important issues regarding its religious implications. Cotton Mather’s position as a distinguished minister and theologian served to significantly dampen religious opposition to inoculation. Several of his colleagues tended to support his viewpoint that inoculation was a gift from God. Nevertheless, there were some vociferous opponents who made their positions known publicly. The Reverend John Williams was the most notable of these (Williams, 1721b). Thus, the Reverend Williams preached that inoculation was the work of the devil since it enabled the wicked to escape the wrath of God. (He believed that it was a form of delusion similar to witchcraft.) Williams wrote “There is no Rule in the Word of God to found Inoculation upon. Therefore, Inoculation cannot be according to the Will of God, nor according to Knowledge”. Many, but not all of the opposing ministers, also argued that inoculation attempted to flout God’s will, as to who should live and who should die. (This was the first medical procedure that could be seen to be effective and was thus revolutionary. It raised previously unconsidered issues). Prayer, repentance, and reform were considered the only reasonable responses to smallpox. “Therefore, confess your sins to each other and pray for each other so that you may be healed. The prayer of a righteous person is powerful and effective” (James 5:16). A version of this argument was that disease was a punishment for sin and thus well merited. An alternative objection to inoculation was simply the fact that it injured innocent people. (It is unclear how many believed this, given the horrendous nature of medical treatments at that time. Medical treatments were accepted as being painful just as in more recent times, effective medicines were expected to taste awful.) The Reverend Mr. Williams wrote, in association with James Franklin (Ben Franklin’s brother), a 1721 treatise entitled. “Several arguments for proving, that inoculating the small pox is not contained in the law of physick, either natural or divine, and therefore unlawful.” He stated that “Inoculation is unrighteous and unholy” and should not be practiced nor encouraged (Williams, 1721a). He may have been one of the first instigators of the anti-vaccination movement in America, but not the last. He was also not the last to consider immunization a form of witchcraft. I do seriously believe it’s a Delusion of the Devil; and that there was never the like Delusion in New-England since the Time of the Witchcraft in Salem. (Williams, 1722)

Williams argued that the outflow of pus at the inoculation incision site was not a sign of corruption leaving the body. It simply revealed the presence of the “living and more venomous corruption” that inoculators had foolishly introduced into the body. While bloodletting and purging were not directed against

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God’s providence, he argued that inoculation, instead of preventing disease actually spread it together with corruption. Williams asserted correctly that a careless inoculated patient could actually spread the disease to their neighbors. An additional, simple negative argument was that since inoculation was not mentioned in the Bible it must therefore be ungodly. The next year Williams broadened his argument by asserting that inoculation was the devil’s work since it allowed evil people to avoid God’s wrath. (He possibly got this idea from Massey’s sermons in London.) Some Bostonians also argued that inoculation could not be considered a valid practice if it originated in Africa. Thus, William Douglass attached no merit to Mather’s reports of his conversations with black slaves and other Africans. The major opposition on Boston centered on the concept that since variolation was a deliberate “infection” of healthy persons with a very serious disease, then it offended both God and man.

Arguments for variolation Cotton Mather himself argued that variolation was, in effect, mandated by the sixth commandmentdThou shalt not kill. Basically, he argued that given the proven efficacy of variolation, anyone who argued against it was effectively murdering those who could have been saved. He argued further that inoculation was therefore a means of obtaining God’s favor while at the same time confounding the devil (Tindol, 2011). Others argued that neither humans nor the devil could invent a procedure more powerful than God. No human could devise a procedure that overcame God’s will in order to punish people. Thus, since humans could never outwit God then inoculation must therefore be a gift from God (Storm, 2011). Another theory invoked a “second cause.” This suggested that God did not directly cause smallpox but that it resulted from some other mechanism thus not blaming God directly for the suffering it caused. Because of the second cause, inoculation was not interfering directly with the will of God and prevention of disease was therefore lawful. In effect second causes were controlled only indirectly by God. Many religious leaders gave God the credit for teaching humans about inoculation in order to save them from death. As a result of God’s mercy, they get a second chance to live a holy life (Storm, 2011).

Actual results When the epidemic began to abate, Boylston and Mather began to gather their data. In April 1722, Mather wrote to the Royal Society in London affirming the success of the method. His report, “The way of proceeding in the Small Pox Inoculated in New England” was published in the Transactions of the Royal Society. This served to further encourage inoculation in England at that time (Fig. 4.2).

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Zabdiel Boylston traveled to London in 1725 carrying with him a letter of introduction to Dr. James Jurin from Cotton Mather. Jurin then introduced him to Sir Hans Sloane and other prominent members of the Royal Society (Miller, 1956). As a result of the encouragement of Sloane, in 1726, Boylston published his results in a small booklet entitled An Historical account of the Small-Pox inoculation in New England Upon all Sorts of Persons, Whites, Blacks and of all ages and constitutions (Boylston 1726). The results were clear-cut. By the time the epidemic ended in 1722, Boylston himself had variolated 287 individuals and only six of them had died (2.4%). Of the six that died, Boylston wrote, “Although they had not all the Small-pox only by inoculation, as we have Reason to believe, but were some of them infected in the natural Way, before inoculated” (Boylston, 1726). Over the same period of time, the Boston mortality rate was 14.8% (Harvard, 2014). There were 842 deaths among 4917 naturally infected smallpox cases (Best et al., 2004). This was the first use of numbers to objectively measure the outcome of a clinical trial. As such, it was revolutionary and effectively initiated the decline of Galen’s humoral theories. It was always clear that inoculation was a hazardous procedure and chances of developing lethal smallpox were not insignificant. The procedure was however clearly much less hazardous than was the natural disease (Riedel, 2005). A week after the publication of this work, Zabdiel Boylston was elected a fellow of the Royal Society.

More Boston epidemics Smallpox epidemics hit Boston several times during the 18th century. The outbreaks of 1721, 1752, and 1775 were especially severe. In the 1721 epidemic, those who were infected had 15% mortality, and in the city as a whole 842 (w8%) died of the disease (Hasselgren, 2020). While knowledge of inoculation was widespread, as in Britain and France, people generally did not resort to it except during smallpox epidemics. In the smallpox epidemic of 1730, over 2000 Bostonians defied the ban on inoculation. Likewise in Philadelphia, over 500 people were inoculated. In the 1735e36 epidemic, 129 Philadelphians were inoculated and only one proved fatal. During the epidemic in Charleston in 1738, about 800 people were inoculated. Many slaves were inoculated, presumably by demanding masters. As a result of his experience in Charleston, James Kirkpatrick returned to London in 1743 as a recognized expert on the subject. Because of the improvements made by American inoculators, using shallower cuts and less severe preparation of the patient, the American method was soon adopted in Britain, and it is estimated that the case fatality rate of inoculation dropped from around 1% to about a tenth of that (Fig. 4.3). In 1759, Benjamin Franklin was asked by Dr. William Heberden in London about the results of smallpox inoculation in Boston in the 1750s. Franklin

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FIGURE 4.3 As inoculation became more widely accepted, cases of naturally acquired smallpox dropped as did the smallpox death rates in cities such as Boston dropped progressively. With permission, Matthew Niederhuber, Department of Systems Biology, Harvard Medical School.

reported that among 5059 uninoculated white people, 452 had died (8.9%). Among 1974 inoculated white persons, only 23 had died (1.2%). The mortality numbers for uninoculated and inoculated black people were 12.8% and 5%, respectively. As a result of figures like this, by the time Boston was hit by yet another smallpox epidemic between December 1763 and July 1764, inoculation was much more widely accepted. The outbreak developed slowly, and it was only in January 1964 that the legislature adjourned to nearby Cambridge. As a consequence, the Royal Governor, Sir Francis Bernard, arranged for a group of physicians led by the patriot, Dr. Joseph Warren, to inoculate those who could not afford to pay and establish a hospital for inoculation. The townspeople voted to allow inoculations beginning on March 13. Inoculations therefore took place in the hospital established at Castle William on an island just south of Boston. Inoculees were essentially quarantined and were not free to leave until their last skin lesions had healed, 6e8 weeks later (Tandy, 1923). The Boston Gazette reported that “near 2500 people” were inoculated in the first week since Liberty was granted to administer it. By the end of the epidemic, nearly 5000 inhabitants had been inoculated, and among these were 1025 poor citizens (cared for by the overseers of the poor). 29-year-old John Adams,

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the future President, traveled to Boston in 1764 to be inoculated by Dr. Warren as did Paul Revere. The doctors who performed these free inoculations were rightly regarded as local heroes (Wildrick, 2009). After a slow start, inoculation was increasingly accepted in the cities of New England, especially Boston. The technique was refined and, as in England, its safety improved gradually. The final smallpox epidemic of the 18th century broke out in Boston in 1792. Most inhabitants were inoculated within a few days. Only 284 citizens died out of a population of 19,300 with a death rate of 1% (Courgeau, 2018).

References Behbehani AM. The smallpox story: life and death of an old disease. Microbiol Rev 1983;47(4):455e509. Best M, Neuhauser D, Slavin L. “Cotton Mather, you dog, dam you! I’l inoculate you with this: with a pox to you” Smallpox inoculation Boston, 1721. Qual Saf Health Care 2004;13:82e3. https://doi.org/10.1136/qshc.2003.008797. Blake JB. The inoculation controversy in Boston: 1721e1722. New Engl Quarterly 1952;25(4):489e506. Boylston A. The origins of inoculation. J R Soc Med 2012;105:309e13. https://doi.org/10.1258/ jrsm.2012.12k044. Boylston Z. An historical account of the smallpox inoculated in New-England, upon all sorts of persons, Whites, Blacks and of all ages and constitutions. London: S. Chandler; 1726. Courgeau D. Inoculation, vaccination and public hygiene against smallpox. In: Seguy I, Ginnaio M, Buchet L, editors. Les conditions des populations du passe´. Environments, maladies, prophylaxies et politiques publiques. Antibes: Editions APDCA; 2018. Douglass W. Anti-inoculation letter by W. Philanthroper. Boston News-Letter; 1721. Grundy I. Medical advances and female fame: inoculation and its after-effects. Lumen 1994;13:13e42. https://doi.org/10.7202/1012519ar. Harvard University. Graduate school of Arts. Death rates from smallpox in Boston MA 1702e1920. Available from: https://sitn.hms.harvard.edu/flash/special-edition-on-infectiousdiseases. Hasselgren P-O. The smallpox epidemics in America in the 1700s and the role of the surgeons: lessons to be learned during the global outbreak of COVID-19. World J Surg 2020;44:2837e41. https://doi.org/10.1007/s00268-020-05670-4. Koch P. Experience and the soul in eighteenth-century medicine. Church Hist 2016;85(3):552e86. Miller G. Smallpox inoculation in England and America: A reappraisal. William Mary Q 1956;13(4):476e92. Riedel S. Edward Jenner and the history of smallpox and vaccination. Bayl. Univ. Med. Cent. Proc. 2005;18:21e5. Sivils MW. Dissecting the pamphlet literature of the Boston smallpox inoculation controversy. Lit Med 2011;29(1):39e57. Storm AE. Religious conviction and the Boston inoculation controversy of 1721. Undergraduate thesis pater. College of William and Mary; 2011. Available from: https://scholarworks.wm. edu/honorstheses/400. Tandy EC. Local quarantine and inoculation for smallpox in the American colonies (1620e1775). Am J Publ Health 1923;13:201e7.

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Tindol R. Getting the pox off all their houses. Cotton Mather and the rhetoric of puritan science. Early Am Lit 2011;46(1):1e23. Wildrick GCD. Joseph Warren: leader in medicine, politics, and revolution. SAVE Proc 2009;22(1):27e9. Williams J. Several arguments proving that inoculating the small pox is not contained in the law of physics, either natural or divine, and therefore unlawful. Boston. 1721a. Printed and sold by J. Franklin, at his Printing-House in Queen-Street over against Mr. Sheaf’s school. Williams J. An answer to a late pamphlet intitled, a letter to a friend in the country, attempting a solution of the scruples and objections of a consciencious or religious nature, commonly made against the new way of receiving the small pox. Boston. 1721b. Printed and sold by J. Franklin, at his Printing-House in Queen-Street over against Mr. Sheaf’s school.

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Chapter 5

Variolation and American independence Smallpox epidemics continued to ravage American coastal cities as well as Native Americans throughout the 18th century. For example, Boston suffered additional outbreaks in 1728, 1751, 1764, and 1769, in 1775 during the British wartime occupation, and in 1792. During the 1728 outbreak William Douglass, having been converted to inoculation, also began performing the procedure himself. The results were clear. Inoculation protected you and your children against smallpox. As a result, over time, inoculation became increasingly acceptable and local bans on inoculations were eventually lifted. As a result, during the 1792 Boston epidemic, there were only 232 natural cases of the disease. However, even at that stage, there were still a few objectors who believed that inoculation would provoke divine punishment. In 1722, the modified inoculation technique pioneered by Dr Charles Maitland in England was tried for the first time in Charleston, SC. by a Dr Mowbray and Dr James Kilpatrick. They used material from the pustules of a variolated person rather than from natural cases of smallpox. Kilpatrick repeated the process six times and saw no evidence of loss of effectiveness in the procedure (Behbehani, 1983). During another smallpox epidemic in 1838, Kilpatrick also simplified his inoculation procedure, thus reducing the severity of the reactions, and making it safer. The mortality resulting from Kilpatrick’s method was about half that of the earliest English procedures. As described in Chapter 3, Kilpatrick left Charleston and moved to London in 1742. He changed his name to Kirkpatrick, and in 1743, he published an essay on the subjectd“An essay on inoculation occasioned by the smallpox being brought into South Carolina in the year 1738.” He obtained his MD degree and helped establish the London Smallpox and Inoculation Hospital in 1746. His essay achieved wide recognition and was translated into German, French, and Dutch. In 1756, Kirkpatrick was invited to Paris to inoculate members of the French nobility. Kirkpatrick’s modifications represented a significant advance in the inoculation technique and materially increased its adoption in the American Colonies as well as in Britain (Kirkpatrick, South Carolina Encyclopedia).

A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00023-1 Copyright © 2023 Elsevier Inc. All rights reserved.

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Boylston’ legacy Legislation and inoculation As smallpox epidemics continued to recur, the demand for inoculation grew and despite persistent opposition, inoculating hospitals were established by many communities to serve this need. The first such hospital in New England was opened in Cat Island near Marblehead in 1773 (Tandy, 1923). Nevertheless, opposition persisted so that the next year it was burnt to the ground because of local apprehension that it would be a source of the infection (Tandy, 1923) (Chapter 10). Inoculation hospitals were also set up at Point Shirley and Castle William near Boston, but the latter was eventually moved to Noddles Island. As new inoculation hospitals continued to be built, local governments established ordinances to restrict the application of inoculation (Woodward, 1932). They generally recognized the right of individuals to choose to be inoculated, but they were primarily concerned with the spread of the disease to other, noninoculated individuals. It was an obvious transmission risk to any close contacts. Thus, in Boston, it was charged that inoculated persons “should not come or walk abroad in the streets, lanes, or alleys within the towns until their incisions” were “well cleansed and healed” (Blake, 1952). Inoculation had other significant drawbacks including its cost, the time spent in preparing the patient for the procedure and then a recovery period from the induced illness. Other ordinances placed restrictions on inoculating hospitals. For example, they were generally located in isolated areas or even on islands. In 1797, it was decreed that if an inoculated person could not be moved to a hospital, then persons living nearby could be moved away by the Board of Health. Anyone who had been inoculated was required to be moved to an inoculation hospital, and it was also required that homes with such cases display red flags, and the authorities must also be notified (Woodward, 1932). Inoculation was initially embraced in South Carolina. However, when an outbreak of smallpox lingered in 1738, this was blamed on inoculation. As a result, under public pressure, the General assembly enacted legislation that ruled that nobody in Charleston or within two miles of the city limits, should inoculate any person or permit himself to be inoculated under penalty of a fine of £500 (Over $100,000 today!!). However, the practice persisted, “The people of Charles Town were inoculation mad ..” A similar situation occurred following another epidemic in 1760. Initial enthusiasm followed by a ban on the practice by the legislature. This ban did not work very well either! (Watson, 2013). Massachusetts soon followed South Carolina’s example. For example, in an act of 1763e64, the Selectmen enacted an ordinance that prohibited anyone from inoculating or being inoculated in the city of Boston. However, the

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penalty for violation was considerably lessdonly £50 (Over $10,000 today!). A smallpox epidemic raged through Boston from December 1763 to July 1764. By that June, there had been at least 170 deaths. The outbreak began slowly, but by January, the Selectmen realized that they had a major problem and promptly adjourned across the Charles River to Cambridge (Archer, 2010). By February 1764, the situation was so dire that the Selectmen recognized that the disease could not be stopped. As a result, they rescinded the ban on inoculation on March 13, and permitted residents to inoculate their families. Boston physicians also agreed to establish an inoculation hospital. Inoculated individuals could either stay at the hospital or in another quarantined dwelling. They had to remain isolated for 3e6 weeks during their recovery. The Boston Gazette reported that “near 2500 people were inoculated in the first week” since Liberty was granted to administer it. By the end of the epidemic over 5000 inhabitants had been inoculated. These inoculations resulted in 42 deaths, whereas the mortality in the pandemic from natural disease was 124 persons out of 699 cases. The disease eventually spread to Cambridge where 649 persons were inoculated and only two deaths resulted (Archer, 2010). New York also passed several ordinances restricting inoculation. For example, in 1772, the colony prohibited inoculation within a quarter of a mile of any dwelling house, public road, or landing place within Westchester, Duchess, and Orange counties. The fine was even less, only £5 plus costs! (Tandy, 1923). However, nothing in this law could be construed as preventing any family from being inoculated within their own dwellings. A year later, the law was repealed in the borough and town of Westchester. The local inhabitants observed that “the law had a bad tendency.” That same year Albany passed a law to regulate inoculation within that city. A license was required of any persons intending to use any house or building within the city as an inoculating hospital. Again, however, any person could be inoculated within their own private dwelling. Pennsylvania issued no ordinances and as a result variolation was widely adopted in Philadelphia. In 1774, Dr Benjamin Rush, Professor of Medicine at the University of Pennsylvania and an aspiring politician, helped found the Society for Inoculating the Poor, in association with other like-minded physicians. The previous year smallpox had killed more than 300 in the city. Rush had learned the new Suttonian method of inoculation while studying in London. Unlike the inoculations performed by Boylston and his successors, the new method used a much smaller cut and much less purulent material. Rush and his colleagues gave free inoculations every Tuesday morning from 10 to noon in the State House. Rush was, for a time, Surgeon General to the Continental Army and a signer of the Declaration of Independence. In 1781 he remarked, “the smallpox which once proved equally fatal to thousands, has been cheked (sic) in its career and in a great degree subdued by the practice of inoculation.” In effect, once the initial reflex opposition had subsided and the

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benefits of the procedure became obvious, inoculation was accepted as being an effective, albeit a somewhat hazardous, procedure. Perhaps the most significant anti-inoculation legislation was undertaken by the Commonwealth of Virginia. Thus, in 1769, the Virginia legislature passed an Act that imposed a fine on anyone who imported any “variolous or infectious” matter into the state for the purpose of inoculating someone (Virginia, 1777). They created a system of permissive inoculation through licensing. However, the civil authorities could refuse permission, or if granted, establish appropriate restrictions and regulations. The penalty for inoculating or procuring inoculation without a license was £100. Two people who strongly opposed this law were George Washington and Thomas Jefferson. Eleven years earlier, in 1766, Jefferson had been obliged to travel to Philadelphia, a 10-day journey each way, in order to be inoculated (Washington, 1777b). Given the success of his compulsory inoculation of the Continental armies, George Washington wrote to his brother John in early June 1777 saying that he was bothered by the Virginia Law that restricted inoculations. “Surely that Impolitic Act, restraining Inoculation in Virginia, can never be continued e If I was a member of that Assembly, I would rather move for a law to compel the Masters of Families to inoculate every Child born within a certain limited time under severe Penalties.” Washington was almost 100 years ahead of his time in expressing this sentiment. As a result of both Jefferson’s and Washington’s opposition, the Virginia legislature repealed the law in December 1777. This was also in large part a result of the demonstration that inoculation was actually safe and effective. “It hath been proved by incontestable experience that the late discoverys and improvements therein have produced Great Benefits to Mankind.” Basically, the new law permitted inoculation provided permission was obtained from nearby housekeepers, and that strict isolation procedures were followed. A sign should be placed nearby indicating the presence of an inoculated person. Persons who came into contact with an inoculated person were also obliged to be isolated. The bill became law in January 1778. The first record of variolation in Canada occurred in Quebec in 1765. By 1769, a British Military surgeon, James Latham, trained in the Suttonian method had variolated 303 people in Quebec (McIntyre and Houston, 1999). When Latham left Canada in 1770, he had variolated 1250 people. In addition, many of the British troops stationed in Canada had also been variolated.

Washington’s dilemma Smallpox and the revolutionary war As described above, by 1776, many of the colonies and cities had officially prohibited or strictly regulated inoculation. When the revolution broke out and the newly formed Continental Army began to besiege Boston in 1775, other

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Americans decided to “liberate” Canada and so form a 14th state. An expedition under General Richard Montgomery was therefore sent to Quebec in the fall of that yearda bad time to visit Canada weatherwise. Montgomery’s troops easily occupied Montreal in November and then moved on to besiege the British stronghold of Quebec City. There he joined another American force of 1100 commanded by Benedict Arnold. However, Montgomery was killed, and Arnold seriously injured while attacking the city in late December. To make matters worse, smallpox-infected refugees carried the disease to the American forces (Some accounts say they were prostitutes!). The defending British and German troops coming from a society where the disease was endemic were mainly immune. American troops from isolated rural farms and plantations were not. Outside the coastal cities of Boston, Philadelphia, and Charleston as well as some slave plantations in the south, their chances of contracting smallpox were low. As a result, by the spring of 1776 about half the American troops in Quebec were sick and new recruits had no immunity. Without adequate shelter, thousands died and were buried in mass graves located along their line of retreat. When the troops retreated after losing about 3000 men, they brought smallpox back to Boston with them. Montgomery’s successor, Major General John Thomas, had been appointed by Congress in the hope that he could turn the tide. He banned inoculation on the grounds that his men would not have time to recover from it before the British attacked. Since Thomas had never had smallpox, congressional staffers recommended that he too got inoculated. Out of solidarity with his men he declined, caught smallpox soon after arriving in Canada, and died too (Boston NHP). Smallpox had preserved Canada for the British Empire. While the British army did not mandate inoculation, some regiments strongly encouraged it. For example, while technically voluntary, it is likely that very few soldiers refused to obey a direct order (Mitchell, 2005). The First (Royal) Regiment of Foot Guards was inoculated in 1756. Even when the regiment was fairly healthy, if smallpox was suspected, the Regiment took no chances and all who had not already had the disease were ordered to volunteer to be inoculated. For example, once the Americans had evacuated Montreal, they left some smallpox victims behind. Whereupon the commanding officer of the Guards ordered all susceptible men inoculated, about 12e14 of them (Thursfield, 1940). Likewise, when the regiment occupied Fort Niagara in 1785e86 and smallpox was present in the surrounding countryside, their commander ordered that all the susceptible men, women, and children in the fort were to be inoculated, 32 people in all.

The first immunization mandate George Washington was acutely aware of the damage that smallpox could cause since he had suffered from the disease as a young man of 19. In November 1751, he had traveled to the Island of Barbados with his brother

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Lawrence. (Lawrence had tuberculosis and it was hoped that the island climate would help cure him -it didn’t). On arrival, George was sick for 25 days with the usual fever and chills, headache, and backache, as well as the typical smallpox rash and foul-smelling pustules. He survived, but the disease left him with a scarred nose in addition to being immune. Washington assumed command of the Continental Army at Cambridge in the summer of 1775, Washington assured the President of the Continental Congress that he had been “particularly attentive to the least Symptoms of the Small Pox” (Mt Vernon Library, 1775). However, during the siege of Boston over the winter of 1775e76 a smallpox epidemic raged within the city. As a result, at least 2000 British troops were sick (Thursfield, 1940). Washington made sure that any refugees from the city stayed well away from his camp. He quarantined any of his troops showing signs of the disease; and set up a special smallpox hospital. In March, when the British eventually evacuated Boston, Washington, suspected a trap, so he first occupied the city with 1000 troops who had recovered from the smallpox and were therefore immune. Washington also wanted very much to liberate the other major American cities that the British had subsequently occupied, especially New York, and Providence. With the experience of Quebec in his mind he realized that British soldiers were largely immune while his own soldiers were not (It has been estimated that less than a quarter of the Continental army had had smallpox.) (Filsinger and Dweak, 2009). His Chief Physician, John Morgan, encouraged him to have his troops variolated. Washington resisted for two reasons. First, it was illegal in many states and cities, and he was not prepared to break the law. Second, variolation sickened patients for up to a month, during which time they could not fight (Roos, 2020). He worried that if he variolated all his men, the English would attack when his soldiers were sick and his armies totally vulnerable. As a result, in May 1776 Washington wrote to Congress thus: The General presents his Compliments to the Honorable The Provincial Congress, and General Committee, is much obliged to them, for their Care, in endeavoring to prevent the spreading of the Small-pox (by Inoculation or any other way) in this City, or in the Continental Army, which might prove fatal to the army, if allowed of, at this critical time, when there is reason to expect that may soon be called to action; and orders that the Officers take the strictest care, to examine into the state of their respective Corps, and thereby prevent Inoculation amongst them; which, if any Soldier should presume upon, he must expect the severest punishment. Any Officer in the Continental Army, who shall suffer himself to be inoculated, will be cashiered and turned out of the army, and have his name published in the Newspapers throughout the Continent, as an Enemy and Traitor to his Country.

After the dismissal of John Morgan for other reasons however, (Morgan was a very irritating man), Washington completely reversed himself. A risky but smart move. Initially, he required that all new recruits be variolated

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immediately after enlistment. Hopefully, they would be fully immune by the time they reached the army. Overcoming his fears, on February 5, 1777, he wrote to inform congress that he had decided to get everyone inoculated as quickly as possible. (This was technically illegal, but Congress passed the necessary resolution at once.) The next day, February 6, 1777, Washington sent a letter to Dr William Shippen Jr, John Morgan’s successor as Chief Physician of the Army ordering him to have all troops passing through Philadelphia inoculated. Finding the smallpox to be spreading much, and fearing that no precaution can prevent it from running through the whole of our Army, I have determined that the troops shall be inoculated. This expedient may be attended with some inconvenience and some disadvantages, but yet I trust in its consequences will have the most happy effects. Necessity not only authorizes but seems to require the measure, for should the disorder infect the Army in the natural way and rage with its usual virulence, we should have more to dread from it, than from the Sword of the Enemy. Under these circumstances I have directed Doctr. Bond to prepare immediately for the inoculating this Quarter, keeping the matter as secret as possible and request, that you will without delay, inoculate all the continental troops that are in Philadelphia and those that come in, as fast as they shall arrive .. I would fain hope that they will soon be fit for duty, and that in a short space of time we shall have an Army not subject to this, the greatest of all calamities that can befall it, when taken in the natural way. (Washington, 1777a)

While wintering near Trenton in early 1777, Washington had his men inoculated and quarantined over a period of months. His troops in Morristown and Philadelphia were variolated en masse. The soldiers were inoculated in batches at the two churches in Morristown that were used for isolation purposes. The order appears to have been received enthusiastically and there are no recorded instances of objection (Thursfield, 1940). In this first mass inoculation, 4988 men were variolated and only 18 died as a result (0.36%)! Washington’s men were indeed sickened by the procedure but the mass variolation was kept a strict secret and the British did not learn about it until after they all had recovered and were again fit for action. The prevalence of smallpox in the Continental Army dropped from 17% to 1% (Riedel, 2005). By the end of 1777 at least 11 inoculation hospitals had been built for the Army. Thereafter, smallpox was no longer a major factor in the war. It has been estimated that among the Continental regulars, 90% of deaths were a result of disease. Smallpox was the most severe of these (Filsinger and Dweak, 2009). Some of Washington’s generals failed to follow his orders regarding inoculation and as a result he was chronically short of manpower later that summer. For example, Patrick Henry, the Governor of Virginia, failed to do so.

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As a result, an outbreak of smallpox in that state meant that it could not supply troops for that summer’s campaigns. Washington wrote to Henry, “The apologies you offer for the deficiencies of troops, are not without some Weight. I am induced to believe that the apprehensions of the Small pox and its calamitous consequences . [may] be easily done away, by introducing innoculation into the State” (Washington, 1777c).

Major influencers Benjamin Franklin and his son Way back in 1721, as described in the previous chapter, young Ben Franklin was working in his older brother’s printing business in Boston where they produced the New-England Courant. The elder Franklin brother, James, aggressively criticized Mather and Boylston’s inoculation procedure and its supporters in their paper. As a result, the legislature forbade James Franklin from publishing it. Consequently, the paper was published in Ben’s name. However once Zabdiel Boylston’s results became available, the objective, and scientifically inclined Ben saw the data and began to support inoculation. As a result of this and other serious disagreements with his brother, Ben “ran away” to Philadelphia in October 1723 and after several false starts, established his own printing business. He eventually produced his own, very successful, newspaper, the Philadelphia Gazette. In 1730, he married Deborah Read, On November 21, 1736, Francis “Franky” Franklin, the son of Benjamin and Deborah died of smallpox, a month after his fourth birthday. While his father was very much in favor of inoculation, young Franky was fragile and had suffered from chronic gastroenteritis. As a result, his father, not unreasonably, postponed initiating the process. It has been suggested however that his wife Deborah was strongly opposed to inoculation since their relationship seriously deteriorated after Franky’s death! (Coss, 2017). The rumors began to spread in Philadelphia. It was claimed that Franky Franklin had died as a result of inoculation and that his pro-inoculation father was trying to hide the fact. The gossip reached such a point that his father felt obliged to clarify the matter in the pages of his newspaper, the Pennsylvania Gazette on December 30, 1736. “[he] intended to get [Francis] inoculated as soon as he should have recovered from the flux with which he had been long afflicted.” I do hereby sincerely declare that he was not inoculated but receiv’d the Distemper in the common way of infection. Franklin’s decision is currently known as “omission bias.” Thus, given a choice people would rather do nothing that actively do something with the potential to do harm (Best et al., 2007; Asch et al., 1994). Nevertheless, Ben Franklin was devastated by the loss of his youngest son to smallpox and regretted it for the rest of his life. More than 50 years later he wrote in his autobiography.

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In 1736 I lost one of my sons, a fine boy of 4 years old, taken by the small-pox in the common way. I long regretted and still regret, that I had not given it to him by inoculation, which I mention for the sake of parents, who omit that operation on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that therefore the safer should be chosen.” “If the chance were only as two to one in favour of the practice [of inoculation] among children, would it not be sufficient to induce a tender parent to lay hold of the advantage? But when it’s so much greater, as it appears to be by these accounts (in some even as thirty to one) surely parents will no longer refuse to accept and thankfully use a discovery GOD in his mercy has been pleased to bless mankind with.

Benjamin Franklin was not a physician although he was a member of the Royal Medical Society of Paris and an honorary member of the Medical Society of London, in addition to being an ardent promoter of fresh air and exercise (Wright, 1939). He was very much interested in inoculation and the control of smallpox. Motivated by the loss of Frankie, Franklin took multiple steps to encourage inoculation. He reported objectively on the effects of inoculation in the 1730 smallpox epidemic in Boston. (Four died out of hundreds inoculated whereas the case mortality of the natural disease was 30%.) During the 1750s, he collaborated with an eminent English physician, William Herberden, to collect quantitative data on its efficacy. In 1759, they published a pamphlet in London entitled “Some account of the success of inoculation for the small-pox in England and America: Together with plain instructions by which any person may be enabled to perform the operation and conduct the patient through the distemper.” The pamphlet was widely distributed in America. Herberden wrote the text. Franklin wrote the four-page preface (Herberden, 1759). In the preface, Franklin provided the statistical data from the 1753e54 epidemic in Boston. Franklin commented, Upon this, all that inclined to Inoculation for themselves or families hurried into it precipitously, fearing that the infection might otherwise be taken in the common way; the numbers inoculated in every neighborhood spread the infection likewise more speedily among those that did not chuse Inoculation; so that in a few months the distemper went thro’ the town, and was extinct; and the trade of the town suffered only a short interruption, compar’d with what had been usual in former times, the country people during the seasons of that sickness fearing all intercourse with the town.

This masterly summary compared the relative mortality associated with naturally acquired smallpox (Fig. 5.1). A small Pamphlet wrote in plain language by some skillful Physician, and publish’d, directing what preparations of the body should be used before the Inoculation of children, what precautions to avoid giving the infection at the

78 A History of Vaccines and their Opponents Franklins Results Boston 1764

Smallpox White

Black

5059

485

Died White

Inoculated

Black

White

Black

462

62

1974

139

9.1%

13.4%

Died White

Black

23

7

1.1%

5%

FIGURE 5.1 The results of inoculation in Boston during the 1754 smallpox pandemic as reported in Dr. Heberden’s pamphlet on inoculation by Benjamin Franklin. February 1759.

same time in the common way, and how the operation is to be performed, the incisions dress’d, the patient treated, and on the appearance of what symptoms a Physician is to be called, &c. might by encouraging parents to inoculate their own children, be a means of removing that objection of the expence, render the practice much more general, and thereby save the lives of thousands.

Franklin was clearly concerned that many people would not be able to afford the doctor’s fees associated with inoculation, so he took care to provide detailed instructions for any “amateur” to do it. The pamphlet was distributed for free, and Franklin also launched the Society for Inoculating the Poor Gratis.

Abigail Adams and her children In June 1776, John Adams wrote, “The small-pox is ten times more terrible than Britons, Canadians, and Indians together.” As a direct consequence, he and his wife Abigail decided to have their four children variolated (Adams himself had been variolated in 1764. Interestingly, Zabdiel Boylston was the uncle of John Adams’ mother Susanna Boylston Adams.) (Housman, 2020). This was a major decision. Abigail wrote “God grant that we may all go comfortably through the Distemper.” Abigail and the children were living in Boston while John was in Philadelphia at the continental congress. Abigail 11, John Quincy 9, Charles 6 and Thomas 4. On July 12, they were inoculated by Dr Thomas Bullfinch, who was considered an expert on the procedure. Three children got very sick with fevers, body aches, and skin pustules as a result but eventually recovered. Thomas and Charles had to be reinoculated since it had “not taken” the first time. One son, the future President, John Quincy Adams, evidently had the least severe response. It took some time to obtain the results since the inoculation doctors were so busy. The children had largely recovered by the end of August to everyone’s relief. Their mother Abigail eventually died of typhoid fever.

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The state of medicine It is relevant to note at this stage that the “science” of medicine had scarcely changed over the course of the 18th century. The humoral theory still dominated medical thinking. Despite the total absence of objective data, physicians continued to speculate about the causes of disease. This speculation was of necessity entirely philosophical in nature and did not result in either a change in accepted therapeutic procedures nor in improved results. It would have been clear, even to the least observant physician that things were not working. Educated physicians were probably well aware and frustrated with their lack of success. Even Benjamin Rush, whose drastic treatments hastened the end of so many yellow fever victims, likely had significant doubts. Doubts that a physician would almost certainly choose to carefully hide from his patients. Given the self-evident nature of the failure of current medical practice, thoughtful physicians began both to question the basic principles of Galenic medicine and begin to speculate about alternative theories of disease. What they generated in the absence of hard data seems strange to us, but it must be viewed sympathetically. Thinking physicians were searching for something, anything, that worked. For example, during the yellow fever epidemic in Philadelphia in 1793, the preeminent American physician of his time Benjamin Rush attributed the disease to the smell of rotting coffee beans. Controversy arose as to the best way to treat the disease. Benjamin Rush adhered to the somewhat oldfashioned methods of bleeding (at least a pint of blood) and purging with high doses of mercury salts to cause profuse diarrheadthe heroic treatment. If these didn’t work, he simply increased the dose and took more blood. The basic theory was that disease was like a fire, so the way to put it out was to remove excess fuel by bleeding and purging. Others such as Alexander Hamilton took the “Bark and wine cure.” This involved taking Chinchona bark containing quinine and diluted Madeira wine. This was the treatment recommended by experienced French doctors. Neither treatment would have cured the disease, but the bark and wine treatment was probably somewhat safer and much less stressful. There was debate as to whether the disease was contagious, but it was considered best to avoid the sick as much as possible. Regular citizens simply smoked cigars or chewed a garlic clove. It was difficult to fit the process of variolation into the humoral theory of medicine although many tried. Most theories centered on the discharge of pus and fluid from the inoculation site and believed that this reflected the escape of smallpox toxins (or seeds) from the body. Once they were gone, then the individual was no longer susceptible. One medical practice that originated around this time was homeopathy. As discussed later, its treatments were much less painful than the tortures inflicted by the practitioners of allopathic medicine, but it was all theoretical and had minimal impact on the results of treatment. It was however antithetical to

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vaccine use and in later years, homeopaths were among the staunchest opponents of vaccination (Chapter 14).

References Archer R. As if an enemy’s country: the British occupation of Boston and the origins of the revolution. Oxford University Press; 2010. Asch DA, Baron J, Hershey JC, Kunreuther H, et al. Omission bias and pertussis vaccination. Med Decis Making 1994;14:118e23. Behbehani AM. The smallpox story: Life and death of an old disease. Microbiol Rev 1983;47(4):455e509. Best M, Katamba A, Neuhauser D. Making the right decision: Benjamin Franklin’s son dies of smallpox in 1736. Qual Saf Health Care 2007;16:478e80. https://doi.org/10.1136/ qshc.2007.023465. Blake JB. The inoculation controversy in Boston: 1721e1722. N Engl Q 1952;25(4):489e506. Boston National Historic Park. Smallpox, revolution, and the revolutionary war. https://www.nps. gov/articles/0000/smallpox-revolution-revolutionarywar. Coss S. What led Benjamin Franklin to live estranged from his wife for nearly two decades?. 2017. https://www.smithsonianmag.com/history/benjamin-franklin-estranged. Filsinger AL, Dweak R. George Washington and the first mass military inoculation. 2009. https:// www.loc.gov/rr/scitech/GWandsmallpoxinoculation.html. Herberden W. Some account of the Success of inoculation fir the small-pox in England and America: together with plain instructions by which any Person may be enabled to perform the Operation and conduct the Patient through the Distemper. London: Printed by W. Strahan; 1759. Housman T. Variolation vs vaccination: 18th century developments in smallpox inoculation. Beehive, Massachusetts Historical Society; 2020. https://www.masshist.orgh/beehiveblog/ 2020/05/variolation-vs-vaccination. Kilpatrick (Kirkpatrick) J. South Carolina Encyclopedia. https://www.scencyclopedia.org/sce/ entries/kilpatrick-kirkpatrick-james/. McIntyre JWR, Houston C. Smallpox and its control in Canada. Can Med Assn J 1999;161(12):1543e7. Mitchell B. The control of smallpox in the British army during the nineteenth century based on records from the Windsor garrison. J Soc Army Hist Res 2005;83:152e7. Mt Vernon Library. Smallpox: Washington to President, Continental Congress. 1775. Riedel S. Edward Jenner and the history of smallpox and vaccination. BUMC proceedings 2005;18:21e5. Roos D. How crude smallpox inoculations helped George Washington win the war. 2020. https:// history.com/news/smallpox-george-washington-revolutionarywar. Tandy EC. Local quarantine and inoculation for smallpox in the American Colonies (1620e1775). Am J Publ Health 1923;13(3):203e7. https://doi.org/10.2105/ajph.13.3.203. Thursfield H. Smallpox in the American war of independence. Ann Med Hist July 1940;2(4):312e8. Virginia Legislature. Bill concerning inoculation for smallpox. December 27, 1777. https:// founders.archives.gov/documents/Jefferson/01-02-02-0040. Washington G. 1777a. https://founders.archives.gov/documents/Washington/03-08-02-0281. Washington G. 1777b. https://founders.archives.gov/documents/Washington/03-09-02-0583.

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Washington G. 1777c. https://founders.archives.gov/documents/Washington/03-09-02-0142. Watson AD. Smallpox and the protection of public health in North Carolina, 1750e1825. N C Hist Rev 2013;90(1):26e48. Woodward SB. The story of smallpox in Massachusetts. Mass historical Society; 1932. https:// www.massmed.org/About/MMS-leadership-history/The-story-of-smallpox. Wright RE. “Dr” Franklin. The Health Officer 1939;3(10):178e83.

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Chapter 6

The introduction of vaccination in Britain and Europe While inoculation was increasingly accepted in both Britain and North America over the last three decades of the 18th century, it was also generally agreed that it was an inherently hazardous procedure. As described in the previous chapter, it was often adopted in the face of an imminent smallpox epidemic but was otherwise avoided. Refinements in the inoculation technique, especially the greatly simplified Suttonian method, resulted in lower morbidity and mortality. Nevertheless, it was clear that inoculation was not the perfect solution to the smallpox problem. Inoculation was a miserable experience with the patient being starved, purged, and bled to get rid of any potential bad humors before the inoculation process even began. However, changes were coming.

Vaccination Observant country physicians and even some farmers eventually came to appreciate that cowpox, a skin disease of cattle, could be transmitted to individuals such as dairy maids who came into close contact with the cowpox lesions. Not only that, but that a cowpox infection, self-limiting in humans, appeared to confer immunity to smallpox, hence the widespread reputation of dairy maids for their beauty and an unblemished complexion (Weiss and Esparza, 2015). However, these farmers and physicians did not make their observations known to others, nor did they undertake or publish the results of any trials.

Edward Jenner Edward Jenner (1749e1823) was not just any ordinary country doctor. He was well trained as a scientist and had spent a couple of years in London studying under the famous surgeon, John Hunter. He had been made a Fellow of the Royal Society in 1789 for his studies on bird behavior, most notably cuckoos (Rusnock, 2016). Jenner practiced in the west of England, in Gloucestershire, a county noted for its dairies and milk production. Both men and women managed and milked these cows and as a result, occasionally contracted the A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00001-2 Copyright © 2023 Elsevier Inc. All rights reserved.

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viral skin disease, cowpox. Jenner began to investigate a widespread local belief that an attack of cowpox could prevent smallpox. He demonstrated that cowpox scabs (and sometimes horsepox scabs) could replace variola in the variolation process thus inventing vaccination, a very much safer procedure. The “official” story of this discovery was that in May 1796, a dairymaid called Sarah Nelmes reported to Jenner that one of the cattle she milked, a cow called Blossom, had recently been infected with cowpox. As a result, Sarah developed pustules on her right hand, the hand she used for milking the teats. Jenner took some of the pustule fluid from Sarah’s hand and used it, in a manner akin to inoculation. Thus, on May 14, he scratched it into the arm of an eight-yearold boy, James Phipps, the son of his gardener. Seven days later, James developed skin lesions, swollen lymph nodes, and a mild fever but recovered uneventfully. Jenner subsequently exposed the boy to smallpox by variolating him twice. Once after 7 weeks and a second time, some months later. Neither inoculation caused lesions to developdJames Phipps was resistant to variola (Much to Jenner’s relief, no doubt. Later in life, Jenner presented Phipps with a cottage as a reward.) (Rusnock, 2016). We now know that cowpox is a skin disease caused by an Orthopoxvirus related to variola. Cowpox and variola viruses are sufficiently closely related that antibodies and T cells produced against the antigens of one virus can also bind to the antigens of the other and cause its destruction. This phenomenon is called cross-reactivity (Box 6.1). Vaccinated humans develop such a level of immunity to cowpox virus that they also become resistant to smallpox. Thus, the immune response to one virus confers immunity to the other. Jenner presented his findings on his vaccination process to the Royal Society in 1797, but they were received with some skepticism, and he was advised to do more work on the subject. He made some changes and eventually published his observations on June 21, 1798, in a 64-page book called “An Inquiry into the Causes and Effects of the Variolae Vaccinae, a Disease Discovered in Some of the Western Counties of England, Particularly Gloucestershire, and Known by the Name of the Cow Pox.” The next year Jenner followed this up with a second manuscript entitled “Further Observations on the Variolae Vaccinae” in which he described how to recognize cowpox lesions. A year later in 1800, he published a third manuscript “A Continuation of Facts and Observations Relative to the Variolae Vaccinae or Cow Pox.” In this third manuscript, he described the successful efforts of his physician friends in vaccinating patients. His last publication, published in 1801, was “The Origin of the Vaccine Inoculation.” These four publications were widely distributed and read, not only across Britain but also across Europe and North America (Riedel, 2005) (Fig. 6.1). In addition to the story recorded above, in his first book Jenner presented 23 case histories of individuals who had accidentally acquired cowpox and of seven who had been deliberately inoculated with it. Four of these individuals, Jenner reported, had subsequently been exposed to smallpox and were

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BOX 6.1 Why does cowpox protect against smallpox? The finding that vaccination with fluid from cowpox lesions could confer resistance to human smallpox was entirely serendipitous. Jenner had no idea what he was doing. It was only after the sciences of virology and immunology developed that a rational explanation for the phenomenon was found. You will recall from Chapter 1 that foreign material (antigens) are recognized by the B cells and T cells of the adaptive immune system. For this purpose, these cells use specialized antigen receptors. These receptors each have a unique antigen-binding site that will only bind an antigen of the correct shape like a key in a lock. An antigen will only trigger an immune response if it can bind to cells with receptors whose binding site shape can match the antigen. These shapes do not however have to match perfectly. The better the fit, the stronger the stimulus to the cell and the greater the immune response. However even if an antigen does not fit the receptor perfectly it can still stimulate B and T cells and trigger an immune response (Kitamoto et al., 1984). Cowpox and smallpox viruses are closely related large, enveloped, doublestranded DNA viruses called orthopoxviruses. They all look identical, but they are genetically different which means that the proteins encoded by their DNA are also different. These structural differences result in cowpox preferring cattle cells while smallpox prefers human cells to grow in. These preferences are a result of minor differences in the amino acid sequences in the viral surface proteins. These amino acids determine the shape of the surface protein molecules. These are the molecules recognized by the immune system. When a vaccinated individual responds to cowpox inoculation, they eventually make large numbers of T and B cells with receptors that can tightly bind to the major cowpox surface antigens. However, these same T and B cell receptors are flexible so they can also bind to similar major surface antigens of smallpox virus. This phenomenon called a cross-reaction. The T and B cells do not bind the smallpox antigens quite as strongly as the cowpox/vaccinia ones, but the strength of binding is sufficient to trigger a protective immune response. Thus, the immune response against cowpox/vaccinia is sufficient to confer protection against variola.

apparently resistant. Jenner concluded that cowpox vaccination confers lifelong protection against smallpox (it didn’t) and that vaccination was much safer than variolation (it was) (Behbehani, 1983). While the official story of the origins of vaccination is given above, it was actually more complex than that and began many years earlier. In 1768, John Fewster, a physician also working in Gloucestershire, and his colleagues began to inoculate their patients against smallpox. They found however that many farming patients did not react to inoculation by developing a local skin response with its accompanying sicknessdthey appeared to be “immune”! Upon enquiry, Fewster found that many of these patients reported having been previously infected with cowpox. Fewster reported his observations to the

86 A History of Vaccines and their Opponents Army and Navy adopted Vaccination Extensive positive results reported Jenner’s second reward

Jenner’s four Publications

I 1795 Woodville began vaccinating

I 1800

I 1805 Rowley’s ox-faced boy

I 1810

I 1815

The pope endorsed vaccination

I 1820

I 1825

Jenner’s death

Mosley’s bovine syphilis Jenner’s First reward

FIGURE 6.1 A timeline of the events following Jenner’s introduction of vaccination until his death.

local Medical Society, but he did not fully recognize its significance, it was not investigated further, and he never published his findings. (Fewster continued to perform inoculations that worked well, and he declared in 1798 that saw no need for a substitute.) Among Fewster’s audience however, there was a young physician’s apprentice called Edward Jenner. Years later, Jenner remembered Fewster’s talk and decided to investigate the phenomenon for himself. In 1774, an English farmer, Benjamin Jesty living in Dorset, a county far from Gloucestershire, performed the first documented substitution of cowpox for smallpox in inoculation (Pead, 2006). He obtained the scab material from a cow of a neighbor and inoculated his wife and two sons in the arm. He never wrote an account of this and did not attempt to determine whether she was immune! When the news was revealed, Jesty’s neighbors jeered and threw mud and stones at him. The widespread acceptance of this method did not come for another 24 years. There is no evidence that Jenner had ever heard of Jesty before he published his papers on vaccination. Cowpox, otherwise known as vaccinia (“vacca” is Latin for cow), is a pox virus-mediated skin disease of cattle. Affected animals generally develop large weeping ulcers on hairless skin areas such as the udder. When these infected cows are hand milked, the vaccinia virus in the ulcer exudate can readily enter cuts or abrasions on the milker’s hands. Humans infected by this virus subsequently develop a localized weeping lesion that scabs over and heals within a few weeks.

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Edward Jenner began a systematic study on the protective effects of vaccination and as described, submitted his first results to the Royal Society in 1797. His paper was rejected on the grounds of insufficient data. Jenner added a few more cases (nine) and published his first results at his own expense. The scientific method was not well established in the late 18th century. Thus, Jenner published what, in effect, was a series of case reports on vaccination. This drew immediate attention since the method worked well and was clearly much safer than variolation. Despite some initial opposition, the vast majority of physicians and surgeons of London enthusiastically supported Jenner, and as a result, vaccination was rapidly adopted in Europe and the Americas while variolation was gradually discontinued. The news spread worldwide. Jenner quite properly received credit for publishing the vaccination process, one of the most important medical discoveries ever. However, his biographer invented the myth that Jenner alone had discovered the process by talking to Sarah Nelmes. It must be emphasized that Jenner had no concept of microbiology, viruses, or immunity. Jenner like his contemporaries ascribed infectious diseases such as smallpox to the escape of “morbid poisons” from within the body. It is also fair to say that the duration of immunity conferred by vaccination was not as persistent as Jenner and his promoters first imagined. However, cases of smallpox that occurred in previously vaccinated individuals were generally very mild.

Subsequent studies Rapid adoption While some of the initial responses by physicians to Jenner’s paper were negative, others rapidly took up the cause, and confirmed Jenner’s preliminary results. The rapid adoption of vaccination in England and elsewhere was a result of subsequent studies performed on much larger numbers of patients by physicians such as Drs William Woodville (1752e1805) and George Pearson (1751e1828) at the Royal Smallpox and Inoculation Hospital in St Pancras, London. (In 1848, the hospital was moved to Islington to make room for the modern Railway Terminal). Woodville conducted the first extensive clinical trial of vaccination. He found animals with cowpox in a dairy herd in Gray’s Inn Lane in London in January 1799. Woodville used this material to vaccinate over 600 individuals and then followed that by inoculating them with smallpox. His results were somewhat confusing since the interval between vaccination and variolation Woodville used was too short, and as a result, the vaccine he used appears to have been contaminated with smallpox (Rusnock, 2016). Nevertheless, Woodville did confirm that vaccination could successfully protect against subsequent variolation. In effect, vaccination conferred all the benefits of variolation with few of the drawbacks. It produced only a single

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scar at the inoculation site. It produced a much milder disease, and the patient did not need to be isolated. The vaccinia lesion did not form a pustule and rather than producing pus, it produced a circular dark brown scab that eventually fell off leaving a characteristic scar. Unlike the previous method of inoculation, no preparation of the patient was required. Nobody in England at that time including Jenner himself could have explained how vaccination worked. There was no regulatory authority that could investigate and regulate vaccines, or the claims made for and against it. There was no germ theory, and sterility and disinfection were simply not recognized concepts. The benefits of vaccination and its obvious superiority over inoculation meant however that it immediately became popular among the upper classesdthose that had previously espoused inoculation. While widely adopted, it did not however immediately replace inoculation everywhere. The conservative poor were especially reluctant to forgo inoculation. In fact, both procedures coexisted in Britain for several decades. The factor that eventually made the difference, in addition to safety, was that vaccinated individuals did not need to be isolated for several weeks. The vaccine industry flourished. Back in 1721 when inoculation was first introduced, the idea that one could deliberately infect a patient with a disease in order to induce protection was completely foreign, but by 1800, this had been accepted for many years. As a result, vaccination was rapidly adopted and encouraged by most religious leaders in England and elsewhere. Not only did physicians adopt vaccination very rapidly, but the clergy were also enthusiastic. Minor local objections to vaccination were rapidly overcome by its success and ease of use. Large numbers or clergymen actually performed the new procedure on members of their congregation. For example, a Mr. Reed, Curate at Leckhamstead, a village west of London, vaccinated 1578 persons in one year! Rev GC Jenner claimed to have vaccinated over 3000. Enthusiastic amateurs took it up like the vicar of Finmere near Oxford who vaccinated 300 parishioners in 1799 (Larsson, 2021). In rural Scotland, physicians encouraged the clergy to vaccinate their flocks. In 1804, the General Assembly of the Church of Scotland distributed vaccination instructions to all its ministers. Even the country gentry, both male and female, vaccinated their poor neighbors. In marked contrast to the mere 900 inoculations carried out in Britain between 1721 and 1729, it has been estimated that up to 60,000 vaccinations had been performed by 1801. The pope himself endorsed vaccination during a smallpox epidemic in Rome in 1814 (Fenner et al., 1988). Priests were told to remind parents of their responsibility to maintain their children’s health. Priests also led their congregations in processions to vaccination sites. While physicians (including Jenner) were totally unaware of how vaccinia worked, it did not stop them from seeking to use this methodology to prevent

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other diseases (Jenner, 1809). Many believed vaccinia to be an effective treatment for unrelated diseases in humans including the plague and cholera. General George Custer, of Little Bighorn fame, recommended it as a preventative for canine distemper (Duggan, 2019).

Methodology It should be pointed out that in the early 19th century, vaccination was not simply a matter of injecting a vaccine solution into a child’s arm. The first vaccinators used a lancet to cut a deep incision into the skin and underlying muscles of a child, often in multiple locations. They would then smear infected fluid from a cow into the open wound before bandaging it up. They could also insert a pus-soaked thread. It was a brutal process in a preanesthetic era, especially when the concepts of wound infection, contamination, disinfection and sterility were still far in the future. It should also be pointed out that when performed on malnourished infants such as those of the Victorian working class, there were also likely to be more severe adverse effects. This was especially the case with those living in crowded, unsanitary conditions where it was almost impossible to keep clean, and any water available was often dirty and polluted (Durbach, 2004). Later, fortunately, the medical profession eventually recognized that the wounds inflicted need only be shallow scratches. The expansion of vaccination program was however hindered by the difficulties encountered in providing a consistent supply of cowpox material. Sick cows were in high demand. In 1799, Woodville actually infected a cow with cowpox and used the material from that animal to vaccinate patients at the London Smallpox Hospital. Jenner himself, working in Gloucestershire, sought to provide a steady supply of vaccine material (lymph) to provide to other practitioners, but cowpox outbreaks were erratic and unpredictable. As a result, vaccinators resorted to the method that had worked well for inoculation, human arm-to-arm transmission. The material from one individual’s lesion was simply transmitted to the arm of the next person. This was more easily accomplished in institutions than by individual physicians. As a result, the London Vaccine-Pock Institution offered free vaccinations to the poor (presumably in return for their lymph and scabs), and also provided vaccines to vaccinators on request (Rusnock, 2009). Human arm-to-arm transfer carried with it risks of transmitting other infections including erysipelas, tetanus, tuberculosis, and syphilis. This latter disease, while relatively rare (750 cases per 100 million vaccinations), obviously attracted a lot of negative attention and provided ammunition to fervent anti-vaccinationists such as Charles Creighton and Bernard Shaw (Page 11). Arm-to-arm transfer of smallpox vaccine was only prohibited in Britain by the Vaccination Act of 1898.

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Horsepox Jenner noted that cowpox occurred in farms where there were both cattle and horses. The same workers looked after both and he believed that cowpox was transmitted from horses to cattle. Jenner therefore believed that a skin disease of horses colloquially called “The grease” was the source of the cowpox. It is probable that he confused this disease with horsepox. However, Jenner clearly believed that horses were the original source of cowpox and, as a result, he obtained some of his vaccine material from horses! Horsepox was a common equine skin disease at that time in which, like other poxviruses, it caused multiple skin lesions. Jenner continued to believe in “equination” and in his later years tended to prefer the use of equine material rather than cowpox for immunization. As a result, while cowpox was the preferred material for vaccination through the 19th century, equine material was used on occasion. For example, subsequent to Jenner’s discovery, the British government decided to vaccinate all their soldiers. The contract to produce this vaccine was given in 1801 to a Dr John Loy who used material from horses exclusively. For the entire 19th century, no effort was ever made to standardize vaccine stocks. They were produced by unregulated commercial enterprises. They were imported freely and mixed as necessary. Their quality and safety were highly variable (Esparza, 2020). Over time, these viruses mutated. As a result, the precise origin of modern vaccinia virus strains remains unclear. At least some of the vaccinia stocks historically used in humans were of equine origin. Analysis of several stored vials of smallpox vaccine from the early 20th century has indicated that they actually contained horsepox (Schrick et al., 2017). Strains of vaccinia virus as currently available for laboratory studies differ significantly from circulating cowpox virus strains. While horse pox has become almost extinct, it has been shown that a Mongolian strain of horsepox is also related to, but distinct from, vaccinia. Several horsepox genes are present in different vaccinia strains and most vaccinia strains are more closely related to horsepox than to cowpox (Fig. 15.2). It is clear that horsepox is partially ancestral to currently available vaccinia strains.

Initial responses Hostility As with any new and poorly understood discovery, not everyone supported Jenner’s claims. Professional hostility to Jenner and vaccination took two forms. First, there were many physicians who were jealous of Jenner’s fame and awards and made strenuous efforts to belittle his discovery and demonstrate that he was by no means the first to recognize that cowpox could prevent smallpox. Many of these actively promoted Benjamin Jesty’s claims. Second, there were those who did not believe that vaccination worked or could be an effective substitute for variolation. They were especially

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concerned about the introduction of animal matter into a human. Despite the enthusiastic reception given to vaccination described above, not everyone was convinced that cowpox vaccination could safely protect against smallpox. After all, neither Jenner nor his contemporaries had the conceptual framework needed to understand how the vaccine might have worked. There was a broad chasm between the empirical evidence of efficacy and any explanation of its mechanisms. Just as the opponents of inoculation argued that inoculated smallpox was a very different disease from the natural infection, so the opponents of vaccination argued that smallpox and cowpox were radically different diseases, and one could not protect against the other. It should also be pointed out that this early vaccination was a very unhygienic procedure, especially when the supply was maintained by the arm-to-arm method. (In fairness, cowpox is not the only infectious agent to produce ulcers on cow’s udders. There are very many bacterial causes as well. At a time when these were not diagnostically differentiated, it is entirely likely that some vaccinated individuals received pus containing other, different bovine pathogens.) Many opponents of vaccination also had a financial interest in maintaining inoculation and as a result spread scare stories about adverse effects, both real and imagined. Two major sources of disinformation came from Drs William Rowley and Benjamin Moseley.

Dr William Rowley A major argument first made against vaccination was that it was unnatural and thus inappropriate to introduce a “bestial humor” into humans. Some opponents suggested that vaccinated humans might, as a result, take on bovine characteristics. In 1805, Dr William Rowley (1743e1806), an eye physician working at the Marylebone hospital, described the case of an “ox-faced boy.” His illustration shows a boy with elongated eyes, one is bloodshot while the entire left side of his face is swollen. In effect, this probably involved swelling of the salivary glands and lymph nodes. He might have looked a bit like a cow, but the poor lad likely suffered from mumps. However, Rowley attributed his condition to cowpox (Eisen, 2021). Rowley and others reported on “cowpox mange,” abscesses, and ulcers as well as other severe diseases caused by “ulcerous stinking horrid” cowpox. A later version of his pamphlets shows a vaccinated woman, Ann Davis, sprouting horns. Rowley insisted that mental horns and cloven hoofs frequently appeared in response to vaccination. Perhaps, the most effective of these stories regarding the vaccinated individuals taking on bovine features was the famous cartoon by the caricaturist James Gillray that was published by “ye Anti-vaccination Society” dated June 12, 1802. This shows a scene at St. Pancras hospital in London in which an oblivious physician, most likely Dr Woodville, is vaccinating a fearful young woman. The vaccinated men and women in the room are either sprouting

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horns, or having bovine heads emerge from diverse regions of their anatomy. A wall painting shows the Israelites worshiping the golden calf. Gillray appears to be satirizing the anti-vaccination movement, especially Benjamin Moseley’s claims regarding vaccinated persons acquiring bovine characteristics. The Anti-vaccination Society cited in the caption is possibly another exaggeration of the claims of anti-vaccinationists. Many other cartoonists depicted vaccination in the form of a Golden calf and predicted the downfall of those who embraced it (Cruikshank, 1889). This opposition to vaccination was relatively mild in the early days when it was voluntary. Things changed drastically once the authorities mandated its use. As expected, those who objected to vaccination were quick to publicize cases where vaccinated individuals developed smallpox. For example, William Rowley reported over 400 cases of either post-vaccination smallpox or other bad side effects. Some objective pro-vaccination practitioners also acknowledged that not all vaccinated individuals were protected. The opponents of vaccination generally preferred a return to the methodology they were comfortable withdinoculationdthey believed it to be safer and more efficacious.

Dr Benjamin Moseley Another of Jenner’s fiercest and loudest opponents was Dr Benjamin Moseley (1742e1819). Moseley was a physician at the Royal Military Hospital in Chelsea. Beginning in 1799, he published a series of pamphlets expressing doubt about cowpox and the speed with which it had been adopted. He issued lurid warnings that the cowpox vaccine contained a bovine venereal disease. He articulate a belief that persists to this day that vaccines are unnatural, dirty, and toxic and can damage healthy bodies. He compared cow-pock to cowdung. The classical technique of fear mongering. Subsequent analysis of these vaccine-mediated adverse events by Moseley identified four new diseases: cowpox face (facies bovilla), scabies bovilla, cowpox itch or mange (tinae bovilla), and elephantiasis bovilla (Eisen, 2021). He also claimed that in addition to physical lesions, it caused mental illness. I have seen children rendered nearly ideots by the cow-pox poison, Some adults have had their intellects impaired by it; and some have suffered insanity. (Moseley, 1805).

In 1805, Moseley wrote a treatise on cowpox which he called lues bovilla (bovine syphilis)da bestial humor. Like many after him he wondered about its long-term effects. In his treatise he warned of long-term consequences. For example, he predicted vaccinated women wandering in cow pastures hoping to have sex with bulls! Moseley ridiculed the idea that cowpox could prevent smallpox. They were completely different diseases and patients risked their health for nothing. Objectors pointed out that vaccination had not been

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subjected to extensive trials. Remember nobody had any conception of immunity or cross-reactivity, and it was not unreasonable therefore when Benjamin Moseley attacked vaccination “as an amulet against the smallpox.” He argued that it was totally ineffective and that its use was promoted by enthusiasts suffering from cow mania. He claimed that vaccination caused whooping cough and insanity. His speculations were likely inspiration of that famous satirical cartoon by James Gillray. Moseley and Rowley formed a team that traveled the country giving lectures that warned about the perils of vaccination. It is of interest to note that both practiced variolation. Another fervent opponent of vaccination was Dr Ferdinand Stuart. Ferdinand Stuart (1745e1814) was a highly eccentric physician who claimed to be the great-grandson of King Charles II. He was an avid supporter of Moseley. He published a story about a young boy who changed his behavior after vaccination: “he ran upon all fours like a beast, bellowing like a cow, and butting like a bull.” Stuart published several antivaccination pamphlets. He also sought to link vaccination in some way to Napoleon Bonaparte, the archenemy of the British! He died in 1814 as a result of being run over by a carriage (Wikipedia, Stuart). Another significant opponent of vaccination was a surgeon John Birch (1745e1815). He too was an enthusiastic variolator who published numerous anti-vaccination pamphlets. Birch was the author of Serious Reasons for Uniformly Objecting to the Practice of Vaccination. He persisted in his opposition until his death believing that vaccination was merely a public infatuation. Thus, Birch was one of the first medically trained individuals to oppose vaccination on the grounds that vaccines are dangerous and ineffective. He has had many successors that use the same arguments (Wikipedia, Birch). Theological objections continued. As with the introduction of variolation, it was still argued that “Smallpox is a visitation from god” (Rowley, 1805). Rowley went on to write “but the cow-pox is produced by presumptuous man: the former was what heaven ordained, the latter is, perhaps, a daring violation of our holy religion” (Rowley, 1805). Anti-vaccinators were horrified at the mixing of animal matter with the human bodyda direct violation of God’s will. The Creator stamped on man the divine image, but Jenner placed on him the mark of the beast. (Eisen, 2021)

In 1806, a new journal, The Medical Observer was published and took a strident anti-vaccination stand. Moseley and Birch featured prominently in its pages. By 1808, it was pointing out that there was an increase in the numbers of smallpox cases occurring in vaccinated individuals. This was in conflict with Jenner’s belief that vaccination conferred lifelong immunity. It probably also reflected a total lack of standardization and quality control of the vaccine itself. The problem was not resolved for many more years (Howard, 2003).

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Despite the opposition described above, the anti-vaccinationists were not organized and usually acted as independent individuals. As a result, they had a very limited impact in the face of a growing medical consensus that vaccination worked and was safe. In response to the imposition of vaccine mandates in England and Wales during the 1850s, opposition to vaccination resurfaced with a vengeance. Given that physicians, even then, had absolutely no idea how or why vaccination worked, it is unsurprising that those who held unorthodox medical opinions were among the leaders opposing the process.

Charles Creighton Eighty years after its introduction, another significant opponent of vaccination surfaced. Charles Creighton (1847e1927) was a founder of modern epidemiology in Britain. An eminent scholar and arguably, one of the most learned medical scientists of the 19th century. In 1881, he published a major scholarly work in two volumes: “The History of Epidemics in Britain”ddescribed as a classic of unimpeachable accuracy. He was a remarkable scholar although he persisted in his belief in miasmas as the cause of diseases. However, he also had a unique problem. He believed that generally accepted medical ideas were usually false. He clashed frequently with his professional colleagues. As late as 1887, opponents of smallpox vaccination were still making outrageous claims regarding the nature of cowpox. In that year, Creighton published a text entitled “The Natural History of Cow-Pox and Vaccinal Syphilis” (Creighton, 1887). In effect, Creighton claimed that the occasional cases of vaccinal sores developing on the arms was evidence of a relationship between cowpox and syphilis (A bacterial disease restricted to humans and caused by a bacterial spirochete called Treponema pallidum) (Baxby, 1979). Creighton argued that vaccination was “a foul poisoning of the blood with contaminated material, which could provide no protection from the disease caused by effluvia arising from decaying organic matter.” He cited numerous examples of what he considered to be vaccinal syphilis and claimed that vaccination was a cause of increased mortality in infants. Remember that viruses were unknown at this time, so Creighton was making the claim that “The real affinity of cow-pox is not to the small-pox but to the great pox.” He suggested that a vaccinal ulcer was “to all intents and purposes, a chancre.” He went on in a subsequent work “Jenner and His Vaccination” to seek to discredit Jenner including Jenner’s observations on cuckoos. He claimed that Jenner was little better than a criminal and money-grabber who had duped Parliament and the medical community into believing in a mythical method (Porter and Porter, 1988). Creighton compounded this folly when he wrote an article in the Encyclopedia Britannica, in which he claimed that cowpox had nothing to do with smallpox and afforded no protection against it. Antivaccinators rejoiced, but as a result, he was subsequently ostracized by the

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medical profession. Creighton spent his last years in professional isolation in a tumble-down cottage in rural England (Underwood, 1947). Another significant opponent of vaccination late in the 19th century was Edgar Crookshank (1858e1928). Crookshank was the first Professor of Bacteriology at King’s College London. He also sought to demonstrate that vaccination did not work and in 1889 published a two-volume text The History and Pathology of Vaccination in which he argued that vaccinia was a totally distinct disease from smallpox and vaccination was thus unprotective. Thus, both Creighton and Crookshank believed that Jenner had successfully perpetrated a great hoax by persuading his colleagues that cowpox could protect against smallpox. They were, of course, completely wrong (Baxby, 1979).

Positive responses Vaccination however had many defenders. They either pointed out that the anti-vaccine objector’s theories were absurd, or they sought rational explanations for its apparent failures. They sought to reassure the public and emphasized that it did not produce filthy diseases. They pointed out that many who objected had financial motives. Moseley and Rowley were practicing inoculators. Expensive inoculation was seriously threatened by the much safer and cheaper vaccination. In 1804, the Vaccine Pock Institution in London issued a document with the title: “A statement of evidence from trials by inoculation and vaccine matter, to judge of the question, whether or not a person can undergo the small pox after being affected by the cow pock” (Physicians, 1804). The physicians in the Institution investigated cases of smallpox in children that had died of smallpox following vaccination. Their results were highly encouraging, and they were very much in favor of vaccination and dismissive of claims that it did not work (Courgeau, 2018) (Fig. 6.2). “Vaccinae vindicia or Defense of Vaccination”: The defense of vaccination was a text published in August 1806 by the Medical Council of the Royal Jennerian society and largely written by another physician John Thornton. It was illustrated with cartoons reflecting the ridiculous claims of the antivaxxers, Rowley and Moseley (Thornton, 1806). Thornton had previously written other books including Facts Decisive in Favor of the Cow Pock and Proofs of the Efficacy of the Cow-pox (Smith, 2011). (It should be noted that Jenner never reported any failures in his vaccination procedure. This was often pointed out by vaccinationists when expressing skepticism regarding Jenner’s results.) Cases of vaccinated individuals who subsequently developed smallpox were generally investigated. In many cases, those lesions that developed soon after vaccination were shown to be chickenpox (a disease caused by a herpesvirusdherpes zoster) or post-inoculation smallpox. In other cases, it was clear that the techniques employed by the vaccinators were flawed.

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FIGURE 6.2 Mortality due to smallpox in children in the city of London between 1700 and 1900. The graph is highly irregular since each epidemic episode is followed by a period where survivors are immune. Smallpox percentages appear to have dropped slightly in the years just prior to the introduction of vaccination, possibly as a result of inoculation. The rapid decline after the introduction of vaccination speaks for itself. The outbreak in 1870e73 was the last major smallpox epidemic in Britain and Europe. Opposition to vaccination rose as the prevalence of the disease declined. Source: Guy (1882) and several Registrat-General summaries of causes of death in London compiled by Our World in Data; Guy WA. Two hundred and fifty years of smallpox in London. Statistical Society of London. Sept 1882. 399e447.

The vaccine material may have been stored for too long or taken too late in the bovine disease or that only a localized skin lesion had been induced. They countered claims that it did not induce immunity by pointing to natural cases of cowpox that could give many years protection. However, they could not explain all such cases. Failures in vaccination certainly did occur. However, they were apparently rare, and the vast majority of recipients were well protected. Many religious figures were enthusiastic supports of Jenner and vaccination. One of the most significant promoters of vaccination was the Reverend Rowland Hill (1744e1833). Rowland Hill was a popular preacher and a close friend of Jenner (Williams and Nussbaum, 2019). Once he had learnt about vaccination, Hill saw it as his Christian duty to promote it. Vaccination was expensive both in terms of physician’s fees and days lost from work. As a result, in the summer of 1804, Hill began preaching in favor of free vaccination while holding a lancet in the pulpit. Between 1804 and 1806, he vaccinated

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thousands and taught other ministers how to perform vaccination, especially on the urban poor. He produced a 72-page booklet Cow-Pock Inoculation: Vindicated and Recommended from Matters of Fact. Hill subsequently became a Director of the Royal Jennerian Society. In his sermons, he frequently attacked the persistent variolators such as Benjamin Moseley, John Birch, and the radical agitator John Gale Jones. Like other early vaccine enthusiasts, he believed that vaccination provided lifelong immunity and tended to downplay its adverse effects. In 1800, vaccination was adopted by the British army and Royal Navy. Unlike the problems with inoculation that had so bedeviled George Washington, vaccination did not require soldiers and sailors to isolate or be taken away from their normal duties. Thus, in June 1800, Jenner himself vaccinated all the soldiers of the 85th foot regiment who had not previously had smallpox prior to their going to India. Hardly any men sickened but poor Jenner had to wait for well over a year to be paid. In June that year, the Commander in Chief, the Duke of York, instructed all officers in command of regiments “to use their best endeavors to cause the whole of the men, in their respective regiments, on whom there were no marks of their having had one or other of the disorders, to be immediately inoculated with the Vaccine Matter” (Mitchell, 2005). In 1802, a Parliamentary Committee, having heard evidence of the efficacy of vaccination from multiple physicians, voted Jenner a grant of £10,000 in recognition of his discovery (Worth about £1.2 million today!). Five years later, he received a second grant of £20,000. The National Vaccine Establishment was formed in 1807 with Jenner as its first Director. However, it tended to replace the individual voluntary organizations that promoted vaccination (Howard, 2003). Thus, enthusiasm for vaccination gradually waned over the next decades. Much of the public remained unconvinced. This was especially the case where inoculation had been seen to be effective. In some parishes, families were offered a choice of either inoculation or vaccination. In many such cases, especially among the poor, inoculation was preferred. In fact, in the 1820s, when it became clear that the protection afforded by vaccination was not permanent, inoculation staged a comeback. Generally, however, vaccinated individuals in such cases developed only a mild disease and recovered promptly. Vaccination was actively encouraged, but there was little enthusiasm for revaccination. In the end, vaccination replaced inoculation. This was in large part due to the establishment of vaccine institutions that vaccinated the poor for free and provided the vaccine “lymph” for the practitioners. The London smallpox hospital began offering vaccination in 1799. The Vaccine Pock Institute that only provided vaccination was established in 1800. It performed 317 vaccinations in its first year. The Royal Jennerian Society for the Extermination of the Small-Pox was founded in 1803. Within 18 months, it had vaccinated 12,000 persons.

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Jenner continued to promote vaccination for the next 25 years and provided cow pox material to any physicians who requested it. He died in January 1823 at the age of 74. Parliament outlawed variolation in 1840 (Smith, 2011). In 1853, a bust of Edward Jenner by the sculptor Calder Marshall was exhibited at the “Great Exhibition” in London. This gained the attention of the medical community who went on to commission a memorial statue. In 1858, Prince Albert, the Prince Consort of Queen Victoria, unveiled the statue of Edward Jenner in Trafalgar Square in central London with much ceremony. This resulted in many protests, not only from anti-vaccinationists, but also from the Army and Navy who believed that Trafalgar Square should be reserved for military heroes. As a result, in 1861, the statue was moved to a quiet site in nearby Kensington Gardens where it remains to this day (Wiki, Statue).

Vaccination in Europe Despite the ongoing Napoleonic wars, smallpox vaccination was rapidly taken up in the countries of Western Europe. Clinical trials or demonstrations were conducted in cities such as Hanover in Germany, Geneva in Switzerland, and Vienna in Austria with similar positive results (Rusnock, 2016). In 1803, the Prussian Emperor William III published a decree requiring the authorities to actively pursue vaccination. Within a year or two it was widely used and the number of cases of smallpox in Prussia dropped rapidly. It was made compulsory in some countries: Bavaria in 1807, Baden in 1815, Wurttemberg and Naples in 1818, and in Sweden, vaccination of infants was made compulsory in 1816. In France, in August 1800, the government established “Le Comite´ Central de la Vaccine” to determine if vaccination worked. The committee tested the procedure on orphans in Paris. Vaccinated children were sent to live with families in which smallpox was present. Other children were vaccinated and subsequently variolated. The committee report in 1803 confirmed that vaccination was effective and recommended its use (Rusnock, 2016). The Government established a “Hospice central de vaccination gratuite” (Lentz, 2020). There the doctors administered vaccine every Tuesday and Thursday afternoon free of charge. In 1804, they established provincial Comite´s. These organizations acted under the supervision of the Ministry of the Interior and established depots in major towns across France that could provide vaccine to physicians on request. Physicians began immunization under the direction of Departmental Health officers. Hospitals, charities, and lyce´es were ordered to offer vaccination to whoever wanted it. The French clergy were also engaged in encouraging the procedure as a gift from God. In 1809, the Ministry published a vaccination decree and even provided a vaccination budget. Napoleon Bonaparte was first told about Jenner’s experiments by Dr Guillotin, an enthusiastic supporter of vaccination (and wrongly credited with

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the invention of the decapitating machine) (Lentz, 2020). He was very enthusiastic and encouraged the French to get vaccinated without making it compulsory. (Smallpox vaccination only became compulsory in France in 1902.) As a result, Jenner was able to request from Napoleon, the release of selected British prisoners-of-war. Napoleon famously said, “Ah Jenner, je ne puis rien refuser a Jenner” (I can refuse nothing to Jenner) (Nixon, 1939). In 1804, Napoleon mandated vaccination for army recruits. As might be anticipated a special vaccination program was established for members of the Imperial guard and the French Army but without coercion, coverage was relatively low. Thus, in the French Army based at Boulogne in preparation for the invasion of England in 1805, only 6000 out of 100,000 were vaccinated despite the Emperor’s encouragement. In May 1811, the Emperor had his son and heir, the King of Rome, vaccinated shortly after his birthda wellpublicized event. By 1815, when the Napoleonic Empire collapsed, it is estimated that about half of all French children had been vaccinated. As a result, smallpox that had accounted for 4.8% of deaths at the time of the French revolution was responsible for only 1.8% by the end of the Empire (Lentz, 2020). Despite the fact that between 1803 and 1850 there was an ongoing campaign to vaccinate peasants across rural France, vaccination was not always accepted by the population, nor was it compulsory. As a result, vaccination coverage was relatively low in France for much of the 19th century (Darmon, 2001). This had consequences during the smallpox pandemic of 1870e74 when the Franco-Prussian War broke out. The vaccinated Prussians suffered an estimated 300 deaths from smallpox compared to an estimated 23,000 deaths in the French Army (Imperial Health Office, 1898). During the Prussian siege of Paris, 10,331 Parisians are estimated to have died of smallpox. In total, it has been estimated that at least 90,000 deaths from smallpox occurred in France during that war (Rolleston, 1933). Given their successes in the Franco-Prussian war and the subsequent unification of Germany, it is unsurprising that the German Empire mandated vaccination of all 2-year-old children in 1874. Smallpox vaccine reached Spain in December 1800 and was widely adopted across that country over the following years. In 1803, King Carlos instructed the Council of the Indies, the branch of government that dealt with Spain’s colonies, to evaluate how vaccination could be introduced into their American colonies as well as the Philippines. This was successfully accomplished by an Expedition led by Francisco de Balmis in 1803e13 who relied on arm-to-arm transmission. It was through this effort that smallpox vaccination reached San Antonio, Texas, in 1805 (Mark and Rigau-Perez, 2009). British efforts to send vaccine to India were much less organized. Jenner shipped vaccine to Bombay in 1799, but unfortunately, the ship burned en route. The first vaccine in the form of an inoculated child arrived in Bombay in 1802. There was initial resistance from many Brahmins who had been

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performing inoculations for many years. Nevertheless, vaccination was eventually widely adopted despite some issues with those who worshiped Sheetala, the Hindu Goddess of smallpox (Chapter 21).

References Baxby D. Edward Jenner, William Woodville and the origins of vaccinia virus. J Hist Med Allied Sci 1979;34(2):134e62. Behbehani AM. The smallpox story: life and death of an old disease. Microbiol Rev 1983;47(4):455e509. Courgeau D. In: Seguy I, Ginnaio M, Buchet L, editors. Inoculation, vaccination and public hygiene against smallpox. Les conditions des populations du passe´. Environments, maladies, prophylaxies et politiques publiques. Antibes: Editions APDCA; 2018. Cruikshank EM. The history and Pathology of vaccination, 2 vols. London; 1889. Creighton C. The natural history of cow pox and vaccinal syphilis. London: Cassell and Company Limited; 1887. Darmon P. The beginnings of vaccine diffusion in France (1800e1850). Bull Acad Natl Med 2001;185(4):767e76. Duggan BP. General Custer, Libbie Custer and their dogs. Jefferson, NC: McFarland and Co; 2019. Durbach N. Bodily matters: the anti-vaccination movement in England, 1853e1907. Duke University Press; 2004. ISBN: 978-0-8223-3412-5. Eisen EX. “The mark of the beast”: Georgian Britain’s anti-vaxxer movement. Public Domain review; 2021. https://publicdomainreview.org/essay/the-mark-of-the-beast-georgian-britain. Esparza J. Three different paths to introduce the smallpox vaccine in early 19th century United States. Vaccine 2020;38:2741e5. Fenner F, Henderson DA, Arita I, Jezek Z, et al. Smallpox and its eradication. World health Organization; 1988. Howard CR. The Impact on public health of the 19th century anti-vaccination movement. Microbiol Today 2003;30:22e4. Imperial Health Office. Smallpox and vaccination in Germany. Br Med J 1898;2(1957):25e8. Jenner E. Observations on the distemper in dogs. Med Chirurgical J 1809;1:265e70. Kitamoto N, Goto E, Tanimoto S, Tanaka T, et al. Cross-reactivity between cowpox and vaccinia viruses with monoclonal antibodies. Arch Virol 1984;82:129e36. Larsson P. https://www.uncomfortableoxford.co.uk/post/anti-vaccers-vaccine-resistance; 2021. Lentz T. Talking point with Thierry Lentz. In: Vaccination: when Napoleon declared war on smallpox; 2020. https://www.napoleon.org/en/history-of-the-two-empires/articles/talk-smallpox. Mark C, Rigau-Perez JG. The world’s first immunization campaign: the Spanish Smallpox Expedition, 1803e1813. Bull Hist Med. 2009;83(1): Special Issue. Reassessing smallpox vaccination 1789e1900:63e94. Mitchell B. The control of smallpox in the British army during the nineteenth century based on the records from the Windsor garrison. J Soc Army Hist Res 2005;83(334):152e7. Moseley B. A treatise on the lues bovilla, or cow pox. 2nd ed. 1805. https://wellcomecollection. org/works/kyy75ndh. Nixon JA. Jenner and Napoleon. Proc Roy Soc Med 1939;32:877. Summarized in Brit Med J, 1939; 144: 278. Pead PJ. Benjamin Jesty: the first vaccinator revealed. Lancet 2006;368(9554):P2202. https:// doi.org/10.1016/s0140-6736(06)69878-4.

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Porter D, Porter R. The politics of prevention: anti-vaccinationism and public health in nineteenth century England. Med Hist 1988;32:231e52. Physicians. The Vaccine Pock Institution in London: “ A statement of Evidence from trials by inoculation and vaccine matter, to judge of the question, whether or not a person can undergo the small pox after being affected by the cow pock”. London: W. Blackader for Cuthnell and Martin; 1804. https://wellcomecollection.org/works/sst4nws9. Riedel S. Edward Jenner and the history of smallpox and vaccination. BUMC Proc 2005;18:21e5. Rolleston JD. The smallpox pandemic of 1870e1874. Proc Roy Soc Med 1933;27(2):177e92. Rowley W. In: Barfield J, sold by, Harris J, editors. Cow-pox inoculation no security against smallpox infection. London: Printed, for the author; 1805. Rusnock AA. Catching cowpox: the early spread of smallpox vaccination, 1789e1900. Bull Hist Med 2009;83(1):17e36. Rusnock AA. Historical context and the roots of Jenner’s discovery. Human Vaccs Immunother 2016;12(8):2025e8. Schrick L, Tausch SH, Dabrowski PW, Damaso CR, et al. An early American smallpox vaccine based on horsepox. N Engl J Med 2017;377(15):15e6. Smith KA. Edward Jenner and the small pox vaccine. Front Immunol 2011;2:21. https://doi.org/ 10.3389/fimmu.2011.00021. Thornton RJ. Vaccinae vindicia or defense of vaccination containing a refutation of the cases and reasonings on the same in Dr Rowley’s and Dr Moseley’s late extraordinary pamphlets against vaccination. London: Symonds; 1806. Underwood EA. Dr Charles Creighton MA (1847e1927), scholar, historian and epidemiologist. Proc Roy Soc Med 1947;91:869e76. Weiss RA, Esparza J. The prevention and eradication of smallpox: a commentary on Sloane (1755) “an account of inoculation”. Phil Trans R Soc B 2015;370. https://doi.org/10.1098/ rstb.2014.0378. Wikipedia. John Birch (Surgeon). https://en.wikipedia.org/wiki/john-birch-surgeon. Wikipedia. Stuart, John Ferdinand Smyth. https://en.wikipedia.org/wiki/John-Ferdinand-SmythStuart. Wikipedia. Statue of Edward Jenner. https://en.wikipedia.org/wiki/Statue-of-Edward-JennerLondon. Williams JTB, Nussbaum AM. Reverend Rowland Hill and a role for religious leaders in vaccine promotion. Am J Publ Health 2019;109(5):697e8.

Further reading Jenner E. An Inquiry into the causes and effects of the Variolae Vaccinae, a disease discovered in some of the. western counties of England, particularly Gloucestershire, and known by the name of cow pox. 1798. London. S. Low.

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Chapter 7

The introduction of vaccination to America The news of the novel new vaccination procedure developed by Edward Jenner spread rapidly. However, cowpox was a relatively rare disease, even in England. As a result, vaccination enthusiasts were obliged to develop methods of storing and transporting the infectious material. One of the first methods employed was developed by Dr. George Pearson, a physician working at the Vaccine Pock Institute in London. One of the functions of the Institute was to produce and distribute smallpox vaccine to practitioners across Britain and the rest of the world. In an era where refrigeration was unknown, various shipping methods were tried. Using techniques pioneered by inoculators, vaccinators placed short lengths of thread across open cowpox pustules. These absorbed the lymph fluid (and the virus) and were then simply dried. The dried threads were placed in glass vials and sent by Jenner and Pearson, across Britain, as well as to colleagues in Europe and America.

First deliveries John Clinch It is unclear just when the first vaccinations were performed in North America. In June 1798, Edward Jenner sent a copy of his new book on vaccination to an old friend and classmate, Dr. John Clinch (1749e1819) an Anglican missionary working in Trinity Harbour on the south coast of Newfoundland. (Both had studied medicine under John Hunter.) It is suggested by some historians that Jenner would also have, at the same time, sent some threads of smallpox vaccine to Clinch (Esparza, 2020). Clinch wrote: The threads you sent me produced the desired effect, which proved a happy circumstance for this harbour. After inoculating my own family, I availed myself of the opportunity, whilst the smallpox was making its ravages at St. John’s, of visiting that place. Encouraged by your representation, and in order to establish the fact of the cowpox being an absolute preventive of the smallpox, I put my nephew Joseph Hart to the most rigid test by inoculating him with activovariolous matter and exposing him to a contagious atmosphere, but without its A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00019-X Copyright © 2023 Elsevier Inc. All rights reserved.

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104 A History of Vaccines and their Opponents producing in either instance the smallest effect on the system. This single case excited the astonishment of every person without whose knowledge it came; and most of those who had not previously gone through the smallpox were eager to shield themselves against that dreadful malady by adopting the Vaccine Inoculation. Davies JW. A historical note on the Reverend John Clinch, first Canadian vaccinator. CMAJ (Can Med Assoc J) 1970;102:957e61.

Unfortunately, the date of this letter was unrecorded. It may have been as early as late 1798 or as late as January 1800. Edward Jenner’s brother, George was also a medical missionary working at Harbor Grace, close to Trinity Harbour, and it appears that Edward may have sent the first shipment to Clinch by way of his brother George. Clinch subsequently received an “additional” shipment of cowpox threads from Edward Jenner in July 1800. Clinch also received a piece of advice at the same time; “Lest the threads sent to you by George should not take effect, I have enclosed a bit more, newly impregnated with the cowpox. Use it like a smallpox thread but small as it is, divide it into portions that you may multiply your chance of infecting. Wet it before insertion or rather moisten it.” This thread worked, so that once one person had been successfully vaccinated, material from their scabs could then be used to vaccinate others. By the end of 1801, Clinch had vaccinated his own children and about 700 others in his practice (Rusnock, 2016; McIntyre and Houston, 1999). Subsequently, smallpox vaccination was enthusiastically employed across the entire island of Newfoundland. Some vaccine was also sent in 1800 to Halifax, Nova Scotia. Vaccine impregnated threads also began to arrive in the United States either sent by Dr. George Pearson or by Jenner himself (Fig. 7.1). Some worked, some didn’t. Thus, in 1799, Dr. Valentine Seaman in New York City

Waterhouse first sample Waterhouse The Milton Federal Vaccine second Experiment Act Jenner’s Report sample I 1795

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I 1805

I 1810

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War of 1812 Seaman vaccinated Clinchs the poor The Cow-pox second Act sample

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Vaccine Act Repealed

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FIGURE 7.1 A timeline showing the sequence of the early events following the introduction of vaccination into the United States.

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vaccinated his own children with cowpox threads sent to him by Jennerd unfortunately, the virus had not survived the transatlantic voyage and the vaccine may not have worked. Notwithstanding this, Seaman became a friend of Jenner and an enthusiastic vaccinator. In 1802, he developed a program to provide free vaccination to the poor of New York City (Wikipedia, Seaman). In the winter of 1799, Dr. John Chichester successfully vaccinated one person in Charleston, South Carolina, and then subsequently tested him by variolation.

Benjamin Waterhouse Dr. Benjamin Waterhouse (1754e1846) was an eminent physician in Cambridge, Massachusetts. Born in Rhode Island, he studied medicine in Edinburgh and Leiden where he received his degrees in medicine. While studying in the Netherlands, he shared a room with another student, John Adams, the future US president. Waterhouse returned to the United States in 1782 and joined the faculty of the newly created Harvard Medical School where he became a Professor of Theory and Practice of Physic. Waterhouse received a copy of Jenner’s vaccination booklet early in 1799 in addition to one of Woodville’s reports on the efficacy of vaccination (Blake, 1987). After reading them, Waterhouse was an immediate convert and became a highly enthusiastic vaccinator. In March 1799, he even had an article published in a Boston newspaper, The Columbian Sentinel, giving a short account of the new method. He corresponded with Jenner and made several attempts to obtain Jenner’s vaccine. It was not until July 4, 1800 that a British ship, the Foxcroft, arrived in Boston Harbor carrying a vial of cowpox-infused threads for Waterhouse from a Dr. John Haygarth in Bath, England, a colleague of Jenner. Waterhouse first vaccinated his 5-year-old son, Daniel, and a household servant, Samuel Carter on July 8, 1800. Their responses were mild, as Jenner had predicted. Waterhouse went on to vaccinate three more of his children, Benjamin aged 3 and Mary and Elizabeth aged 1 and 7, respectively, a nursery maid, and three domestic servants, other members of his family and friends. Two months later, he arranged for Daniel to be sent to the smallpox hospital in Brookline, and variolated with fresh material from a smallpox patient. Daniel was also kept in bed alongside a smallpox patient for 12 days and remained healthy demonstrating that he was immuneda well-controlled although somewhat unethical experiment! After overcoming initial reluctance from the medical profession, both Seaman and Waterhouse became enthusiastic proponents and encouraged public vaccination. As the only reliable source of cowpox vaccine in the United States, Waterhouse decided to set up a franchise and restricted vaccine use to those who would share their profits with him. These were mainly country practitioners across New England. He kept the vaccination business in Boston to himself. He was bitterly denounced for this. Several Boston

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physicians, as a result, sent to London for their own supplies of vaccine. Likewise, some physicians who had contracts with Waterhouse gave the vaccine away, and as a result, his efforts at establishing a monopoly soon collapsed. Another enthusiastic early vaccinator in Boston was Dr. James Jackson. Born in Newburyport in 1777, he received his AB from Harvard in 1796. He subsequently worked for a period in St Thomas’s hospital in London where he was introduced to and became deeply engaged in the practice of vaccination. When he returned to Boston in 1800, Jackson opened his own medical practice and enthusiastically encouraged vaccination. (As a result, he made $150 in fees from vaccination alone during his first month in practice!) (Worth about $3500 today.) He had received an active batch of vaccine from his colleagues in London that effectively doomed Waterhouse’s monopoly attempts (Blake, 1987). Jackson was also involved in the founding of the Massachusetts General Hospital and eventually became the first professor of clinical medicine at the Harvard Medical School and its Dean in 1820. The chronic shortage of vaccine and the difficulties in obtaining new supplies caused some physicians to make fatal errors. For example, in October 1800, Dr. Elisha Story vaccinated several individuals, including his own daughter in Marblehead, Massachusetts, with material from the arm of a sailor who had been vaccinated in London. Unfortunately, it turned out to contain smallpox and triggered an outbreak of the disease with 68 fatalities (Behbehani, 1983). In addition, Waterhouse himself had vaccinated the son of Dr. John Drury of Marblehead. Drury in turn had taken material from his son’s arm and used it to vaccinate an additional 40 people in Marblehead. Thirtynine of them developed smallpox. These outbreaks, not unreasonably, triggered serious opposition to the process of vaccination. Waterhouse may also have made a mistake in that he vaccinated some patients with cowpox but then challenged them 4e5 days later with variola. As a result, the lymph collected from their lesions would have contained both viruses and thus effectively spread smallpox (Woodward, 1932). (A similar mistake had been made by Dr. Woodville in London (Chapter 6).) Undeterred, Benjamin Waterhouse received a new consignment of vaccine from London in March 1801 and set up a public trial of the procedure. Together with six other physicians, Waterhouse vaccinated 19 boys on August 16. They were then sent into isolation for 20 days at Noddle’s Island, a smallpox isolation Hospital off Boston. They suffered no adverse events and so 12 of the boys were subsequently challenged by variolation. All the boys remained healthy, and each received a certificate pronouncing them to be a living testament to the “never failing power of the mild preventative, the Cow pox” (Wendt, 2015). Waterhouse found himself and vaccination opposed by many in the medical profession who accused him of profiteering. In 1814, Waterhouse was forced to resign from his Professorship at Harvard since he opposed a plan to

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establish a medical school in Boston, and he attempted to establish a rival medical school of his own! He served in the United States Navy during the War of 1812. He died in 1846 in Cambridge at the age of 92. In 1801, once he had received a new consignment of vaccine, Waterhouse wrote a pamphlet entitled “A Prospect of Extinguishing the Smallpox” and sent copies to his former roommate, President John Adams. Adams did not respond, so on December 1, 1800, Waterhouse wrote to Thomas Jefferson, the newly elected President. For this, Jenner earned a nice thank-you letter from Jefferson. As a result, Thomas Jefferson wanted to try vaccination, so he requested cowpox lymph from Waterhouse, but the first two attempts to ship it to him failed! Jefferson in response designed a flask where the inner container contained the lymph-soaked threads surrounded by a container of cool water. This method worked, although Waterhouse continued to ship the lymph using dried threads in conventional glass vials as well (Rusnock, 2016). Once he became president, Thomas Jefferson at Monticello had his entire family including his slaves vaccinated, about 60 persons in all, and moreover became an enthusiastic backer of vaccination. Woodhouse sent vaccine to Jefferson. Jefferson, in turn, ensured that supplies of the vaccine were sent to other cities in Virginia as well as to Philadelphia, New York, and Washington (Blake, 1987). Philadelphia became a vaccination hub sending the vaccines to many communities and ensuring that both slaves and Native Americans received vaccine. Thomas Jefferson was so enthusiastic about vaccination that he provided Meriwether Lewis and William Clark with vaccine material to distribute to Native Americans whom they met during the course of their transcontinental expedition. Unfortunately, by the time Lewis and Clark had reached their winter encampment in today’s North Dakota their vaccine was no longer viable. In 1802, upon receiving an active batch of vaccine, Dr. Valentine Seaman set out to vaccinate the poor in New York City by establishing the “Institution for the Inoculation of the Kine Pox.” The next year Benjamin Rush and his colleague Dr. John Coxe set up a similar institution in Philadelphia (Kauffman, 1967). In March 1802, Dr. James Smith set up a vaccination clinic in Baltimore. These three institutions also served as a source of reliable vaccine material for other physicians. Vaccination rapidly replaced variolation in North America. Once the cowpox vaccine was delivered to a new location it was generally maintained by arm-to-arm transfer. Thus, the vaccinator would puncture the lesion of the first patient with a lancet and then insert the material obtained into the arm of the individual to be vaccinated. This process provided some ammunition to anti-vaxxers since it violated people’s beliefs in bodily integrity. For this reason, those with little power such as orphans and the poor were common sources of vaccine lymph (Rusnock, 2016).

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Supply problems Natural cow pox did not occur in American cattle. As a result, the United States was entirely dependent upon the arrival of erratic supplies from Jenner and his colleagues. Physicians were also obliged to rely on arm-to-arm transfer to a great extent. Although charitable vaccine institutions were established in the major cities, they still had problems getting supplies. One result from this was that vaccination became expensive. For example, in 1816, New York physicians charged $5e$10 for vaccination and $5 for a house visit (Charges, 1816). Thus, vaccination was largely restricted to the most prosperous members of society. The war of 1812, cut off supplies further and more shortages developed as a result.

Early opposition and exploitation There was some opposition to cowpox vaccination in the United States, but as in Britain it was relatively muted. Waterhouse, for example, in 1813, complained in a letter to President Madison that he had had a controversy with the Medical Society on the subject of Vaccinations. “While Mr. Jefferson was kindly assisting my efforts in spreading the blessings of the kine-pox inoculation, Dr. Eustis exerted himself to discourage it, by declaring that it was a British whim, that would soon be laughed out of credit” (Waterhouse, 1813). By 1809, the success of Jenner’s vaccination method had been widely reported and received with enthusiasm. As a result, the town of Milton in Massachusetts, now an affluent Boston suburb, arranged for all its inhabitants to receive Jenner’s vaccine. That July, over 300 individuals were vaccinated. Not content however with this achievement, a committee from the Council decided to prove that the method worked and set up a public demonstration. On October 10, 1809, 12 previously vaccinated children were inoculated with fresh material from a case of smallpox! This was witnessed by 18 town members. The children were confined to a home. None developed any evidence of smallpox infection and they were released 15 days later. The town formally declared that “He (meaning smallpox) is slain.” The councilmen published a detailed account of the experiment and sent it to every town in Massachusetts. As a result, in March 1810, the State Legislature passed the Cow Pox Act (an act to diffuse the benefit of Inoculation for the Cow-Pox). This directed every community within the Commonwealth to provide for the vaccination of their inhabitants. For good measure they also published the report from Milton at the same time! (Cowpox Act, 1810). The Cow Pox Act gave local health boards the authority to require vaccination of all those over 21. It also required reporting of cases to the health board. This was effectively the first vaccine mandate in the United States! Given that Massachusetts was still primarily rural, the act was sporadically enforced through fines or quarantine during local smallpox outbreaks. Given

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the obvious threat posed by smallpox as well as the apparent safety of vaccination, there was a great demand for vaccination. It was very much considered to be a “blessing” by the media and most individuals. Over time, it was clear to many that the procedure worked and only the unvaccinated developed the disease. Between 1811 and 1837, there were only 39 deaths due to smallpox reported in Massachusetts. In 1838, the Cow Pox Act was repealed. A group of physicians from the Massachusetts Medical Society presented to the legislative judiciary committee complaining that previous laws passed in 1792 and 1797 were “useless, vexatious and burdensome.” That personal rights were interfered with, individuals and the public subjected to unnecessary expense, deprived of the comforts of home by removal to public hospitals, and that physicians were compelled to report these cases to the proper authorities and thus subject their patients to the provisions of severe and thus unnecessary laws. This petition was signed by 20 prominent persons of whom 13 were physicians. As a result, in its next session, the Legislature repealed practically all laws for the control of smallpox. Immediate transfer to a hospital was no longer required, isolation was no longer compulsory, flags no longer needed to be displayed, travelers turned back, nor physicians required to report cases. The system of fines was also abolished. Beginning in 1802, smallpox cases had declined significantly in the northeastern United States, largely as a result of vaccination. However, as the disease became less common, so too did vaccination. As a result, the disease reappeared in the 1840s. In 1839 and 1840, physicians were again required to report smallpox cases and fines for neglect reimposed in Massachusetts. Smallpox cases also increased, resulting in 1032 deaths over the next 17 years compared to 39 in the previous 36 years. This could not be allowed to continue, and new, more drastic laws were reintroduced in 1855. However, it is recorded that there were still those who considered vaccination to be “fallacious and equivocal.” Many persons were hesitant since these early vaccines were relatively crude, and could cause severe scarring and other adverse events. Sanitation was unknown and wound infections common. Other states subsequently passed similar legislation. In 1820, smallpox broke out in the village of North Hero in Vermont on Lake Champlain. The villagers voted to institute a tax to pay for the vaccination of all the town’s residents. One of the residents, a Mr. Hazen, refused to pay the tax. In response, the town constable seized Hazen’s cow, and sold it to raise his share of the vaccine tax. As usual, a legal battle ensued, but finally the Vermont Supreme Court upheld the cow confiscation (Colgrove, 2007).

The first federal vaccination legislation As a result of the ongoing problems with the supply of reliable vaccine material, President James Madison “enthusiastically” signed “An Act to

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Encourage Vaccination” on February 22, 1813. This was the first federal law regulating vaccine policy, production, distribution, and safety. This was in response to the shortage of the real vaccine as a consequence of the outbreak of the War of 1812 with the British. In effect, it was the first federal consumer protection law. The Act had two major provisions. That April, President Madison appointed a Federal Agent, Dr. James Smith of Baltimore who was charged with preserving the genuine vaccine. (As a result of the chronic shortages, fraudulent versions were circulating.) Dr. Smith was an eminent physician and a vaccination enthusiast (Smith, 1818). He was especially keen on providing the vaccine to the poor and impoverished (Lanzarotta and Ramos, 2018). His Vaccine Institute in Baltimore became, for a time, the primary national source of smallpox vaccine. Second, the agent had authority to distribute the vaccine to any US citizen and do so postage-free (packages under 0.5 ounces). The Act was fairly meaningless however since congress repeatedly refused to allocate funds for that purpose. Smith had to spend much of his time fund-raising. He too was bedeviled by a shortage of vaccine. Once he was appointed the National Vaccine agent, Smith promised to provide the military with free vaccine through the war of 1812 and did so for several years afterward. For example, in 1816 the Surgeon-General requested enough vaccine for 23 forts and regiments from Boston to New Orleans (Le Barron to Smith, 1816). This cost Smith a lot of money and he eventually had to request payment from the Army. Vaccination had been made compulsory by the US Army in 1812. Smith was fired in April and the Vaccination Act was repealed in May 1822 as a result of a smallpox outbreak that had occurred in Tarboro, North Carolina, 2 months previously in which 60 persons became ill and 10 died. It seems that in November 1821, Dr. Smith had accidentally shipped smallpox rather than cowpox scabs (labeled “variol”) and no accompanying letter, to a Dr. John Ward. When Ward administered this material to his patients it triggered the epidemic. Dr. Smith acknowledged his error but was dismissed anyway. Smith died in 1841 (Lanzarotta and Ramos, 2018). In May 1832, Congress passed another act to encourage vaccination. It was entitled, “An Act to provide the means of extending the benefits of vaccination, as a preventive of the small-pox, to the Indian tribes, and thereby, as far as possible, to save them from the destructive ravages of that disease.” The Army was to appoint physicians to go to the Indian villages and offer them vaccination. In addition, vaccine material would be supplied to Indian Agents, and they were encouraged to promote vaccination. Congress appropriated $12,000 for this purpose.

Vaccine farms When Edward Jenner first developed vaccination, he transmitted the virus by taking the material from a scab on the arm of a vaccinated person and placed it

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in a small cut in the arm of the person to be vaccinated. This arm-to-arm transfer method was in use for many years afterward. It had however significant disadvantages. The supply was erratic, the quality uneven, and other infectious diseases such as syphilis, leprosy, or erysipelas could be accidentally transmitted between individuals. In addition, over time, vaccines from different sources were probably mixed using cowpox from different countries and possibly even smallpox isolates passed through animals as well as humans. Many of the strains circulating in the US came from Britain and are assumed to be derived from Jenner’s original material. (Cowpox does not appear to occur naturally in the United States. The first recorded case of cowpox in a human in the United States resulted from a laboratory accident (Reardon, 2011).) Eventually, however, beginning around 1860, smallpox vaccine began to be made by deliberately infecting cattle. Thus, during the Civil War, cowpox was often harvested directly from calves and dried on small carved ivory points that were then used to scratch the patient’s skin. The animals, mainly calves but occasionally donkeys and horses, were tied down on a specially designed vaccinating table, their bellies were shaved and then cleaned thoroughly. About 100e120 small cuts, each about an inch long, were made in their skin and a drop of vaccinia lymph was rubbed into each of them. About 6 days later, the local response resulted in the development of vesicles loaded with virus-laden fluid called lymph as well as extensive scab formation. The calf was killed, the vesicles scraped and the mixture of skin, lymph and blood; “lymph pulp” collected, ground up, and suspended in a diluent with glycerol to act as an antibacterial agent. This “animal vaccine” had a higher yield and ensured that a consistent supply of the vaccine was available while human disease transmission was minimized. Despite some opposition from anti-vivisectionists, the method was rapidly adopted worldwide, and arm-to-arm vaccination was eventually prohibited (Esparza et al., 2020). This animal method was introduced into the United States in 1870 by yet another Boston physician, Henry Austin Martin. Many “vaccine farms” were rapidly established by physicians who saw an opportunity for profit by producing “animal vaccine.” It was often unclear just where their vaccine scabs originated. If they needed to be replenished, they were mainly imported from Europe. However, they were imported from multiple sources in different countries at different times and many would have been unlikely to be “pure stocks.” Some companies simply purchased a vial of vaccine from one of their competitors. As a result, the vaccines produced in the United States appear to have been very diverse. Modern analysis suggests that they probably contained viruses of both cow and horse origin and even recombinants between the two. As the science of microbiology developed, the vaccine farms eventually expanded their activities into making other biologicals such as tetanus and diphtheria antitoxins as well as vaccines. This production was initially unregulated, but a series of unfortunate accidents eventually forced congress to

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pass The Biologics Control Act in 1902 to regulate vaccine production. One such accident occurred in Camden, New Jersey.

The Camden incident One of the prime reasons for vaccine refusal at the beginning of the 20th century was the fear of vaccine contamination. It was reported, correctly, that many vaccines were contaminated with pus or bacteria. For example, in late 1901, nine schoolchildren in Camden, died as a result of tetanus acquired through a contaminated batch of smallpox vaccine. The first tetanus case in Camden occurred in November 1901 and another 10 quickly followed. Eventually there were 40 tetanus cases reported. The Board of Health in Camden analyzed all the batches of smallpox vaccine used in these children and claimed that none contained the tetanus bacillus. They also pointed out that the disease occurred more than 4 weeks after inoculation and implied that the disease was caused by the children picking their scabs with dirty fingers! (JAMA, 1901). However, a formal investigation identified a batch of contaminated vaccine as the source (Lilienfeld, 2008). In the early 19th century, vaccination still carried significant health risks. Once applied, the inoculated virus grew in the nearby skin cells. After 3e5 days, a papule formed at the inoculation site (CDC). It then became vesicular (that is fluid accumulates inside it like a blister) between days 5e8. The fluid filled with cells to form pus (pustular) reaching its greatest size at 8e10 days as the immune system (T cells) attacked the virus infected cells. The pustule then started to heal by drying from the center out and forming a scab. The scab fell off 14e21 days after vaccination leaving an obvious pitted scar. Small satellite lesions sometimes developed close to the central lesion and grew and healed in the same way. The CDC lists the hazards of modern vaccinia vaccines as injection site reactions such as redness, itch, pain, and swelling. They also list constitutional symptoms such as headache, fatigue, muscle aches, chills, malaise, nausea, and a mild fever. These could be so severe that an individual might have had to take time off work and hence lose earnings. Vaccination not only caused sore arms but often much more serious complications. For example, it was also linked to cases of septicemia. Many physicians and pharmacies responded by advertising fresh, pure, and clean vaccines. These concerns were widely shared. They could even develop into conspiracy theories when, for example, a Memphis paper suggested in 1917 that there was a nation-wide German plot to kill soldiers by poisoning their “vaccine serum” with tetanus germs. The plot was reportedly uncovered after five deaths had occurred (Hausman et al., 2014). These contamination concerns were by no means unfounded. Early vaccine producers faced considerable challenges in producing pure lymph from calves or antiserum from horses.

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The Biologics Control Act of 1902 On July 1, 1902, President Theodore Roosevelt signed the Biologics Control Act into Law. The Act was largely triggered by the two vaccine-associated tetanus outbreaks in Camden and St. Louis in 1901 (Chapter 16). The act mandated annual licensing of establishments that manufactured or sold vaccines, serums, antitoxins, and similar products such as blood components. It required accurate labeling of the product and its source. It established a board to oversee its implementation and regulated interstate traffic in these products. Laboratories could be subjected to unannounced inspections. The Hygienic Laboratory of the US Public Health and Marine Hospital Service was charged with its enforcement. This was the first federal drug control Law passed since 1848. It established antitoxin standards. The law was followed in 1906 by the Pure Food and Drug Act.

Triumph In 1947, three cases of smallpox occurred in New York City in patients recently arrived from Mexico. In response the authorities recommended that everyone who had not been vaccinated within the previous 10 years should be revaccinated. People came to the clinics and lined up for their vaccination. The demand was such that the city’s vaccine supply ran out! The Times reported “hundreds of eager men, women, and children queued up at Bellevue hospital at dawn, although vaccinations were not scheduled to begin until 10 a.m. At some stations the crowds did not take kindly to the news that the doctors had run out of vaccine and the police had a little difficulty dispersing a crowd of several hundred” outside one vaccine station. According to the city between 5 and 6 million people were vaccinated within a few days; however, calculations based on newspaper accounts suggested that the number was closer to 2.5 million. Either way, science won, again! (Sepkowiz, 2004). Despite opposition from anti-vaccinators, smallpox was eliminated from the United States by 1949.

References Behbehani AM. The smallpox story: life and death of an old disease. Microbiol Rev 1983;47(4):455e509. Blake JB. Benjamin Waterhouse and the introduction of vaccination. Rev Infect Dis 1987;9(5):1044e52. Colgrove J. Immunity for the people: The challenge of achieving high vaccinationcoverage in american history. Public Health Chronicles 2007;122:248e57. Davies JW. A historical note on the Reverend John Clinch, first Canadian vaccinator. CMAJ (Can Med Assoc J) 1970;102:957e61. Esparza J. Three different paths to introduce the smallpox vaccine in early 19th century United States. Vaccine 2020;38:2741e5.

114 A History of Vaccines and their Opponents Esparza J, Lederman S, Nitsche A, Damaso CR. Early smallpox vaccine manufacturing in the United States: introduction of the “animal vaccine” in 1870, establishment of “vaccine farms” and the beginnings of the vaccine industry. Vaccine 2020;38:4773e9. Hausman BL, Ghebremichael M, Hayek P, Mack E. ‘Poisonous, filthy, loathsome, damnable stuff’: the rhetorical ecology of vaccination concern. Yale J Biol Med 2014;87(4):403e16. Kauffman M. The American anti-vaccinationists and their arguments. Bull Hist Med 1967;41(5):463e78. Lanzarotta MA, Ramos MA. Mistrust in medicine: the rise and fall of America’s first vaccine institute. Am J Publ Health 2018;108(6):741e7. Le Barron F. Surgeon US Army to Dr. James Smith (Nov 5, 1816). Appended to James Smith report of the vaccine institution to congress. National archives: Senate Documents Box 16AK5; 1821. List of medical and surgical charges established by the associated physicians of the city of New York. In: Microformed on early American imprints fiche 38213 (Readex); 1816. Lilienfeld DF. The first pharmacepidemiologic investigations: National drug safety policy in the United States. Perspect Biol Med 2008;51(2):188e98. McIntyre JWR, Houston CS. Smallpox and its control in Canada. Can Med Assn J 1999;161(12):1543e7. Reardon S. First U.S. cowpox infection: acquired from lab contamination. Science 2011. https:// doi.org/10.1126/article29233. Rusnock AA. Historical context and the roots of Jenner’s discovery. Human Vaccines Immunother 2016;12(8):2025e8. Sepkowitz KA. The 1947 smallpox vaccination campaign in New York City revisited. Emerg Infect Dis 2004;10(5):960e1. Smith James of Baltimore to Thomas Jefferson. 28 March 1818. https://founders.archives.gov/ documents/Jefferson/03-12-02-0472. The Cowpox Act with the order of the legislature and a communication relevant to the subject from the selectmen of the town of Milton. Boston: Joshua Belcher Printer; 1810. The Tetanus Cases in Camden, NJ. JAMA 1901;XXXVIII(23):1539e40. Waterhouse Benjamin. To James Madison from Benjamin Waterhouse 29 April 1813. https:// founders.archives.gov/documents/Madison/03-06-02-0249. Wendt D. 12 kids who helped a doubting public accept the smallpox vaccine. 2015. https:// americanhistory.si.edu/blog/12-kids-who-helped-doubting-public-accept-smallpox-vaccine. Wikipedia. Valentine Seaman. https://en.wikipedia.org/wiki/Valentine-Seaman. Woodward SB. The story of smallpox in Massachusetts. Mass Historical Society; 1932. https:// www.massmed.org/About/MMS-leadership-history/The-story-of-smallpox.

Chapter 8

Making vaccination compulsory in Britain and Europe Throughout the 19th century, vaccination was the only effective preventive measure available against any infectious disease. It also clearly had the potential for eradicating smallpox from Britain. As a result, it was also one of very few diseases where the government chose to intervene in an intrusive and direct manner. The only other infectious diseases that have prompted similar Government intervention are venereal diseases. It is no coincidence that in association with passing multiple Vaccination Acts, successive British governments passed a series of Contagious Diseases Acts in 1864, 1866, and 1869 requiring the medical examination of women deemed to be prostitutes in certain naval ports and Garrison towns. These Acts were repealed in 1889 (Williams, 1994). No other infectious diseases have triggered such an extreme degree of governmental compulsion. When infectious disease epidemics are the major cause of childhood mortality in any country, they present a significant threat to society and are an important cause of intense fear, especially among the parents of young children. As a result, parents and most others have seized any opportunities to have their children vaccinated. Since that time, however, fear of infectious diseases has abated and with it has come an increased hesitancy to use vaccines. In effect, each parent has conducted a mental risk/benefit analysis. As its benefits become less obvious, so too is a reduced acceptance of any risk associated with the vaccination process. This reduced acceptance is readily seen with the progressive introduction of vaccine mandates by governmental authorities throughout the 19th century. Beginning with the greatest problem, compulsory vaccination against smallpox made its appearance following significant epidemics. Once a smallpox epidemic had waned, so too did the fear of the disease and the urgency to vaccinate ultimately resulted in an increase in opposition to these procedures (Wikipedia, Vaccination Act). As a result, many believe that the benefits of compulsory vaccination are outweighed by its associated ethical problems (Salmon et al., 2006). This is however a quantitative matter. Compulsory vaccination should, most obviously, not be directed against trivial diseases. A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00003-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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116 A History of Vaccines and their Opponents Major smallpox epidemic

VA I 1840

VA

I 1850

VA I 1860

Vaccination VA Royal Commission

VA I 1870

I 1880

I 1890

VA I 1900

1910

The Conciencious Leceister Vaccination Increased Demonstration Objection mandated penalties Free vaccination permitted for the poor Conciencious Vaccination Inoculation Objection officers banned clarified appointed

FIGURE 8.1 Timeline of the Vaccination Acts (VA) passed by successive British parliaments during the course of the 19th century.

Smallpox was never trivial. Despite the hazards of smallpox vaccination, mandates were effective in maintaining herd immunity, saving innumerable lives, and eventually eliminating the disease completely despite the protests of those who opposed compulsion. However, a clear sequence pattern emerged in most countries that imposed mandates, namely compulsion, opposition, and repeal (Fig. 8.1). While smallpox vaccines were very effective, especially in significantly reducing mortality among children, they were by no means completely safe. Vaccinators used scarification devices or lancets that made multiple parallel incisions. There was no understanding of the importance of sterilizing instruments and the same lancet was often used to vaccinate multiple children, one after another, resulting at times, in severe local infections. Thus, one of the prime concerns about these early legal mandates was the lack of “purity” of the early vaccines. Children were also often required to return to the vaccinator 8 days later to have the fresh lymph collected from their blisters or vesicles. This was something many parents objected to. In addition, many of these vaccinated children, especially those living in extreme poverty in workhouses, were under-nourished and often very dirty, given the lack of washing facilities. As a result, most parents had heard stories about, or knew someone who had been harmed by vaccination. For many parents, therefore, the procedure appeared to be much more dangerous than the distant threat of smallpox. As a result, resistance to compulsory vaccination began to grow immediately governments tried to compel the process. This was compounded by the intrusive ways by which some physicians tried to bully parents into having their children vaccinated against their wishes (Institute for Government, 2020).

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Compulsory vaccination laws The 1840 Act As described in previous chapters, vaccination was introduced in Britain around 1800 and was adopted with enthusiasm by many. The use of smallpox pus for variolation persisted however until the late 1830s as physicians who had made it a lucrative business were reluctant to give it up. In the 1837e40 epidemic of smallpox in Britain, 42,000 individuals died of the disease. In response, in 1840, the parliament in London was persuaded to pass “An Act to extend the practice of Vaccination ‘in England and Wales.” This act made variolation illegal and punished offenders with up to a month’s imprisonment. It also required the Poor Law guardians to vaccinate their impoverished charges for free through their own “Poor Law” medical officers. (The Poor Law, enacted in 1834, established a national poverty relief system that ensured that the very poor were housed in workhouses, clothed, and fed. Children who entered the workhouses would receive some schooling. In return for this care, paupers were obliged to work for several hours daily.) Workhouses were therefore associated with poverty and destitution. Rather than be seen visiting the poorhouse, people simply avoided vaccination completely. As a result, relatively few took advantage of this free offer. However, the management of vaccination was left in the hands of the Poor Law guardians until 1858 when the responsibility was partially transferred to a General Board of Health.

The 1853 Act Dr. Edward C. Seaton (1815e80) was a member of the Epidemiological Society and the author of the Handbook of Vaccination (Seaton, 1885). A committee of the Society conducted studies on the efficacy and prevalence of vaccination. They drew up a report that Seton presented to parliament in 1852. Its contents were sufficiently positive that it convinced members of parliament that vaccination was highly effective (even “infallible”), and so persuaded them to pass, without any opposition, the 1853 Compulsory Vaccination Act (Williams, 1994; Rolleston, 1933). Thus, 13 years after the 1840 Act, the law was drastically reinforced by establishing compulsory vaccination in England and Wales. This required that “every child whose health permits, shall be vaccinated within three, or in case of an orphanage, within four months of birth, by the public vaccinator of the district or by some other medical practitioner.” The 1853 Act also required that parents be made aware of this mandate at the time they registered their child’s birth. It required that every practitioner who vaccinated a child must then notify the local registrar of births, marriages, and deaths, certifying that he had done so. The registrars provided new parents with blank vaccination certificates that had to be signed by a qualified medical professional and returned within a specified time. Once vaccinated, the child was to be brought to the

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Public Vaccinator 8 days later to be evaluated and to determine if the vaccination had been successful. There was no assurance that vaccinators would be qualified or even if vaccination would be efficient or safe (Williams, 1994). If parents or guardians failed to have their children vaccinated, they would be fined one pound (about $130 at present). Public vaccinators were required to keep detailed records of all children in a city. They were required to record those who were vaccinated and those who weren’t, and they had to submit their records to the Poor Law Guardians every Thursday. In effect, therefore, this was the first effort in England and Wales to register newborn children as well! It is relevant to note that around same time they made vaccination compulsory, and the Parliament also passed the Contagious Diseases Act that introduced a system of compulsory disease screening, isolation, and treatment of prostitutes in Army garrison towns (Porter and Porter, 1988). The 1853 Act did not apply to Scotland which only got its first Vaccine Act 10 years later, in 1864. Unlike England, this did not involve the Poor Law Guardians. In Scotland, parish authorities paid doctors to vaccinate the very poor. Families could go to a doctor of their choice, and they were charged a small fee for vaccination (Wolfe and Sharp, 2002). The 1853 Compulsory Vaccine Act provoked an immediate outcry. John Gibbs, the Founder of the Anti-Vaccination League, wrote in a pamphlet: The Compulsory Vaccination Act, while dishonoring science, invades in the most odious, tyrannical, and, speaking as a Briton, unexampled manner, the liberty of the subject, and the sanctity of the home; Unspeakably degrades the free-born Briton not only in depriving him of liberty of choice in a personal matter, but even denying him the possession of reason.

The 1853 Act was, however, relatively ineffective since it was unclear who was responsible for enforcing it. Five years later, in 1858, another Public Health Act was passed in an effort to improve the functioning of the system by replacing the Poor Law Guardians with appointed Boards of Health and making the Guardians specifically responsible for its enforcement. Additional key requirements of the act were an improvement in the quality of the lymph used in these vaccines, and in the training of vaccinators (Porter and Porter, 1988). The General Board of Health argued that since it was compulsory, vaccines should be of only the highest quality and greater efforts should be made to assure their effectiveness.

The 1867 Act Regular inspections of the vaccination process continued to reveal ongoing problems and deficiencies. The 1853 Act was still difficult to enforce. As a result, the Government tried again. The Vaccination Act of 1867 consolidated all the existing laws related to vaccination and tightened up the regulations. Provision was made for revaccination. The powers of compulsion were

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increased so that rather than paying a single fine, offenders were obliged to pay continuous and cumulative penalties if they failed to have their children under 14 vaccinated. They could be fined repeatedly with the sentence increased each time. The Poor Law Guardians still controlled local vaccination districts but were empowered to appoint vaccination officers. Parents had to have their child vaccinated within 3 months of registration and the law reinforced the ban against variolation. Physicians were compelled to fill in the vaccination certificates efficiently. Anyone who failed to do so could be imprisoned for up to 1 month. Despite this series of compulsory Vaccination Acts, a major smallpox pandemic developed across Europe in 1870e74 that resulted in 44,000 cases and over 23,000 deaths in Britain alone, and somewhat reduced confidence in vaccination (Fig. 6.2). Following this epidemic, however, the numbers of smallpox cases went into a rapid decline and by the 1890s when vaccination was widespread, annual deaths dropped to just a few hundred (Rolleston, 1933). In 1884, new outbreaks of smallpox broke out in several English cities including Liverpool, Sunderland, and Birmingham as well as London where there were 1400 cases. It must be remembered that while opposition to vaccination was loud at this time, most of the public wanted their children to be vaccinated, especially if there was smallpox in the neighborhood. Smallpox was a fearsome, disfiguring disease.

The 1871 Act The 1871 Vaccination Act continued the tightening-up process. Poor Law Boards of Guardians were now required to appoint vaccination officers to enforce the law. They could take offenders to court, fine them up to one pound plus court costs (which were generally greater than the fine itself). If the offender could not, or would not, pay the fines, then the family’s goods could be seized and sold to generate the funds. If that didn’t work, then one parent, usually the father, could be imprisoned for up to 2 weeks. The process could then be repeated indefinitely! (Durbach, 2004). When the 1871 Vaccination Act was passed in England, some saw it as a brazen attempt to make money from babies. Vaccinators could choose to use lymph from another vaccinated individual (for free) rather than pay for the cow pox lymph provided by the National Vaccine Establishment. Thus, a vaccinated baby could be brought back 8 days later, their “lymph” collected and used to vaccinate other children. From 1871, a fine of £1 could be levied on those parents who refused to allow this arm-to-arm procedure. This upset parents who feared rightly that other infections could be transferred along with vaccinia. Parents could go to prison and Anti-vaccination Leagues would often reimburse parents for the fines involved. That same year, the smallpox pandemic broke out in Europe, spread to London, and began to spread across the country. It was at this time that the

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potential for arm-to-arm vaccination to spread syphilis was first recognized (Porter and Porter, 1988). This was a major blow to vaccinationists because syphilis was both disfiguring and under normal circumstances considered highly immoral. As a result, there was increased pressure on Parliament to switch to the mandatory use of calf lymph for vaccination. Unfortunately, change was slow and calf lymph was not used consistently until the 1890s. Arm-to-arm vaccination was finally made illegal by the 1898 Vaccine Act.

The 1898 Vaccine Act While the prevalence of smallpox across Britain was drastically reduced by the widespread vaccination of infants, opposition to mandatory vaccination grew at the same time. As a result of this growing pressure from anti-vaccination societies, the Government felt obliged to establish a Royal Commission on Vaccination to investigate their grievances and claims. The Commission, established in 1889, consisted of a large majority of distinguished physicians, most of whom were vaccination enthusiasts. However, the commission did not rush to judgment. It sat for 7 years and heard hundreds of witnesses before issuing its final report in 1896. The majority report, as expected, strongly supported vaccination and recognized its effectiveness in preventing smallpox. A minority report signed by two anti-vaccinationists came to an opposite conclusion. While waiting for the Royal Commission’s report, many communities across Britain suspended prosecutions for noncompliance and as a result there was a significant decrease in vaccination coverage. In response to the report of the Royal Commission as well as other social pressures, the compulsory component of the Vaccination Acts was relaxed by providing for a conscientious objection to vaccination. The 1898 Act stipulated that parents asking for a certificate of exemption had to satisfy two magistrates or one police stipendary (a magistrate paid a salary by the Government), that their objections were genuine and that their conscientious objections were sincere. However, the exemption certificate had to be obtained before the child was 4 months of-age. Because Parliament had not defined conscientious objection, or the ways in which it could be ascertained, there was initially considerable confusion. Some magistrates, especially if conservative, simply denied all applications. Some anti-vaccinationist magistrates, on the other hand, allowed all applications. As a result, anti-vaccinationist parents were directed to a magistrate known to favor exemptions. Many magistrates took their responsibilities seriously but had great difficulty in distinguishing between conscientious opposition and mere neglect. As a result, very few exemptions were granted, and in effect, magistrates rarely permitted such exemptions. These were not easy to obtain, especially in cities where the magistrates were in favor of compulsory vaccination. Consequently, in 1907, a new law was passed that simply permitted objecting parents to declare a belief that vaccination could be prejudicial to the health of the child and send it to the

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Vaccination Officer. By this time, the threat of smallpox had diminished greatly. By 1900, the whole concept of compulsory vaccination was so unpopular in Britain that it became a political issue and was an election manifesto commitment of the newly formed Independent Labor Party (Mortimer, 2011). It is however of interest to note that British vaccine legislation throughout the nineteenth century had never been a party-political issue. The Vaccination Laws were passed by Whig and Tory, Conservative and Liberal Governments in equal measure.

Benefits of mandates Despite the opposition they provoked, the positive effects of vaccine mandates were very obvious. It is abundantly clear that the decline in smallpox cases across Britain during the late 19th century was primarily due to vaccination. Smallpox deaths in the population as a whole dropped by about 25% in the years following the mandates. In children, the death rate dropped by 50%. The disappearance of epidemic smallpox from Britain in the years after 1903 both reduced vaccine compliance and encouraged the anti-vaccinationists. During the 1920s, analysis showed that smallpox vaccination, in addition to the well documented risks of secondary bacterial contamination and eczema vaccinatum, carried with it a small risk of severe encephalitis. It was also apparent that should smallpox break out again in the UK, then, rather than indiscriminate mass vaccination, emergency “ring” vaccination surrounding the affected area would likely be more efficient. By 1934, smallpox was considered eradicated in Britain. Compulsory smallpox vaccination was discontinued in the UK in 1948 with the founding of the National Health Service. Registrars no longer had to log successful vaccinations and conscientious objections. There was a small outbreak in Glasgow in 1950 but smallpox was eradicated globally in 1978. It can well be argued that opposition to vaccination in the UK was triggered by mistakes in policy. Thus, compulsory measures can backfire if imposed in a culturally insensitive manner or too ruthlessly. The use of penalties to enforce compliance is one such example. However, at its core, hesitancy is about knowledge and trust. The case for vaccination was wholly unconvincing when nobody had an idea as to how it worked or believed that the disease was caused by miasmas rather than by contagion. This understanding should involve society as a whole and ensure that there is an overall willingness to trust authorities and experts with the health of their children. As late as 1935, smallpox was still listed among the diseases of uncertain etiology. The smallpox virus was first observed under the electron microscope in 1947. Variola minor was only distinguished from variola major in the laboratory in 1961.

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Ireland The application of British Law to Ireland followed a similar pattern to that in England and Wales. Thus, the Vaccination (Ireland) Act of 1863 first made vaccination of children under 3 month of age compulsory. For the first time, it also required the registration of births. This was amended in 1868 and 1879 in an effort by the authorities to enforce the compulsory vaccination regulations and make them consistent with the English Laws. As in England, the Poor Law Guardians were responsible for its enforcement. The 1863 Act was relatively well accepted in most of the country and vaccination uptake rates were high. The Catholic Church raised no objections, neither did Nationalist politicians. However, when Parliament passed the 1898 law permitting contentious objection to vaccination in England and Wales, the law did not apply to Ireland! As a result, the Irish Anti-Vaccination League was founded later that year. In most of Ireland, this elicited little response and public sentiment appears to have largely been pro-vaccination. However, sentiment was different in the Northeast (modern Northern Ireland). Here there was a desire for British Law to apply fully. Pockets of opposition also developed in parts of Dublin, Enniscorthy, and Nenagh. In the city of Belfast, there was significant opposition and as a result it had a relatively low uptake rate. As a port city it suffered repeated smallpox outbreaks in 1864e65, 1870e73, and 1877e78. There was a notable case of such opposition in 1881 when Thomas Strain steadfastly refused to have his children vaccinated (Miller, 2021). Supported by the League Against Compulsory Vaccination, Strain refused to permit their vaccination for months. He appeared in court five times. He was fined continuously but continued to pay the fines until eventually the Poor Law Board of Guardians were forced to desist. The Irish playwright George Bernard Shaw was a fervent opponent of vaccination (Chapter 9). In addition to writing letters to newspapers and the British Medical Journal, he wrote to The Irish Anti-Vaccination League conference in Waterford in 1912 describing the use of calf lymph in children as “dirty and dangerous and nothing short of attempted murder.” The last smallpox case in Ireland occurred in a man who had just returned to Dublin from Glasgow in 1907 (Houghton and Kelleher, 2002). Smallpox vaccination ceased in 1972. Opposition to vaccination in Ireland persisted at a low level until Independence but the absence of the disease effectively rendered the arguments of the anti-vaccinationists moot (Wallace, 2021).

Mandates in Europe As vaccination became more common, the prevalence of smallpox gradually declined across Europe. Some countries were careful to keep detailed statistics. They noted that smallpox cases declined as vaccination coverage increased. In addition, such cases of smallpox that did occur were in the

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unvaccinated. This data was so persuasive that many governments made their own decisions. Variolation was progressively banned. Vaccination was made compulsory in Bavaria in 1807, Denmark in 1810, Norway in 1811, Bohemia and Russia in 1812, Baden in 1815, Sweden in 1816, Wurtemburg, Hesse, and other German states in 1818, and Hannover in 1821. Britain was relatively slow (1853) while France was much later in 1902. The French law mandated vaccination of infants under 1 year of age and revaccination at ages 11 and 21. This law was strictly enforced so that as a result, there were only 26 cases of smallpox in France during the First World War. Had the death rate been the same as in the Franco-Prussian War of 1870, the French army would have expected more than 200,000 deaths from smallpox! (Chapter 6) (Rolleston, 1933). Elsewhere in Europe, Sweden was the first country to use vaccination to totally eliminate smallpox by 1895 (Hopkins, 1988). Events in the Netherlands followed a similar course of compulsion followed by opposition and repeal. Thus, in response to the smallpox pandemic of 1871, the Dutch government required that all school children be vaccinated, resulting in widespread opposition. The Bond ter Bestrijding van Vaccinedwang (The Association to oppose Compulsory Vaccination) was consequently established in 1881. As in Britain, exemptions to the vaccination policy were introduced in the early 20th century (Blume, 2006). In 1880, an international conference of anti-vaccination societies from around the world was held in Brussels, Belgium. This resulted in the formation of the “International League of Anti-vaccinators.” Its founder was a Belgian ophthalmologist Dr. Herbert Boens. They held subsequent congresses in Cologne in 1881 and in Charleroi in 1885. The League appears to have faded from view after that. However, in France, the Ligue Nationale pour la Liberte´ des Vaccinations, was formed in 1954 to oppose tuberculosis vaccinations (This vaccine uses an attenuated strain of Mycobacterium bovis called Bacille Calmette Gue´rin. It is not used in the United States.) (Wiki Ligue Nationale). Much more recently, some European countries have imposed more vaccine mandates. For example, France made 11 childhood vaccines mandatory in 2017. Fines and even prison sentences can be imposed for noncompliance (Inst Gov, 2020).

Typhoid vaccines As described above, beginning with the 1898 Vaccination Act, the Liberal Party in Britain moved away from intervention in medical matters. Thus, the 1907 Vaccination Act effectively dismantled the compulsory vaccination networks established by previous governments. This change in British attitudes persisted for many years and had a direct impact on the uptake on the next vaccines to be developed. These were directed against the bacterium, Salmonella typhi, the cause of typhoid fever (Hardy, 2000).

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Vaccines against typhoid fever were developed simultaneously by Almroth Wright in Britain and Richard Pfeiffer and Wilhelm Kolle in Germany in 1896. Typhoid was at that time endemic in both Europe and the USA and was an especially severe problem in tropical countries such as India and South Africa. It was largely controlled by providing new clean water supplies and effective sewage systems. However, it remained a problem in the military, especially during the colonial wars of that period. Almroth Wright developed his typhoid vaccine around the time antivaccination fervor was reaching a peak in the UK. However, Wright was autocratic and pushy. (His colleagues privately called him “Almost Right.”) His vaccine contained killed S. typhi but was not standardized. He worked with the British army to use it in troops stationed in India and South Africa. Unfortunately, Wright didn’t keep good records of his trials and at the time it was not possible to distinguish between S. typhi and S. paratyphi the cause of a clinically similar disease. As a result, it was unclear whether his vaccine actually offered significant protection. Wright hadn’t determined the minimum protective dose of his vaccine. Because it was very crude and contained large amounts of bacterial endotoxin, it caused severe reactions that discouraged volunteers from taking the second dose of the vaccine. For example, it caused severe localized pain, faintness and collapse, inappetence, and a fever lasting 12e24 hours. Vaccinated soldiers were in obvious distress and Winston Churchill, then a war correspondent, described them on a voyage to South Africa thus: Inoculation for enteric fever proceeds daily. The doctors lecture in the saloon. One injection of serum protects; a second secures the subject from attack. Wonderful statistics are quoted in support of the experiment. Nearly everyone is convinced. The operations take place forthwith, and the next day sees haggard forms crawling about the deck in extreme discomfort and high fever. The day after, however, all have recovered and rise gloriously immune. Others like myself, remembering that we stand only on the threshold of pathology, remain unconvinced, resolved to trust to “health and the laws of health”. Churchill WS. London to Ladysmith via Pretoria. London: Longmans, Green; 1900.

However, William Leishman continued to work on Almroth Wright’s vaccine and progressively improved it. He standardized its contents and the method by which the bacteria were killed. He regulated the dose so that severe adverse events were avoided. He also demonstrated that this improved vaccine was very effective and thereby increased its acceptability. The British army gradually adopted the new, improved, typhoid vaccine beginning in 1906 but always on a voluntary basis. It was especially popular among troops based in India where nearly all the soldiers were immunized and as a result typhoid fever cases dropped dramatically. It was used in some English hospitals for the nursing staff. It was used by many missionaries.

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However, the word vaccination was still associated with smallpox, so uptake of the vaccine among the British civilian population was very low even when localized typhoid outbreaks occurred. In effect, authority’s acceptance of the vaccine reflected middle class values while the resistance of the population to vaccination reflected attitudes of the working classes. In many cases, this resistance also reflected a desire to avoid loss of earnings that might result from having to take time off as a result of adverse events. Anti-typhoid vaccines, indeed, all vaccinations, were opposed by anti-vaxxers based on first, the liberty of the individual and second, a belief in the efficacy of hygienic procedures. The First World War broke out in August 1914. The British medical establishment and eminent physicians like Sir William Osler and Almroth Wright proposed compulsory typhoid vaccination of the troops. The antivaxxers responded immediately. They emphasized the liberty of the individual and their view of civilization. They promoted the right of the individual citizen-soldier to consent rather than submit to medical information. Given the prior anti-vaccination battles, there was a belief that civilian standards of liberty also extended to the military (Hardy, 2000). As the army expanded rapidly with hundreds of thousands of patriotic volunteers, it is estimated that only 25%e30% of these volunteers had received a single shot of typhoid vaccine. Anti-vaccinationists produced pamphlets to persuade the newly recruited soldiers that vaccinations were harmful. They maintained that conditions on the front line in France were not as bad as presented and that the fear of typhoid outbreaks was exaggerated. They suggested that the vaccine was ineffective. However, the first cases of typhoid appeared among the troops in France in October 1914. The Army Medical Corps grew seriously concerneddsomething had to be done! Despite pressure from the army medical establishment, the British government still resisted making typhoid vaccination compulsory for their troops. The situation changed in early 1915 when the army, for the first time, produced an effective pamphlet outlining the clear benefits of inoculation. In addition, the eminent physician, Sir William Osler wrote a letter to the Times suggesting that failure to be vaccinated against typhoid was unpatriotic. He called the anti-vaccinationists “misguided cranks who are playing into the enemy’s hands” (Osler, 1915). The medical profession piled on. This patriotism campaign was accompanied by the obvious fact that the war would drag on and that hygienic conditions in the trenches were very poor. It resulted in a complete change of attitude toward typhoid vaccination. The antivaccinationists continued their fight, but the tide had turned. Facts, once again, beat opinions. By the end of 1915, it is estimated that about 90% of British troops had received all their typhoid shots. During the war, there are estimated to have been about 7000 British cases, 125,000 French cases, and 112,400 German cases of typhoid among their troops (Hardy, 2000).

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References Blume S. Anti-vaccination movements and their interpretations. Soc Sci Med 2006;62:628e42. Churchill WS. London to Ladysmith via Pretoria. London: Longmans, Green; 1900. Durbach N. Bodily matters: the anti-vaccination movement in England, 1853e1907. Duke University Press; 2004, ISBN 978-0-8223-3412-5. Hardy A. “Straight back to barbarism”: antityphoid inoculation and the Great War. 1914. Bull Hist Med 2000;74(2):265e90. Hopkins DR. Smallpox: ten years gone. Am J Publ Health 1988;78(12):1589e96. Houghton F, Kelleher K. Smallpox in Ireland- an historical note with possible (and unwelcome) relevance for the future. Ir Geogr 2002;35(1):90e4. https://doi.org/10.1018/0075077020 9555796. Institute for Government. Vaccine mandates. 2020. https://www.instituteforgovernment.org.uk/ explainers/vaccine-mandates. Ligue Nationale pour la Liberte´ des Vaccinations. (National League for Liberty in Vaccination). https://en.Wikipedia.org/wiki/National-League-for-Liberty-in-Vaccination. Miller I. Smallpox and Victorian anti-vaxxers. 2021. https://epidemic-belfast.com/8-smallpox-andvictorian-anti-vaxxers/. Mortimer PP. The diphtheria vaccine debacle of 1940 that ushered in comprehensive childhood immunization in the United Kingdom. Epidemiol Infect 2011;139:487e93. https://doi.org/ 10.1017/s095026881000302X. Osler W. In: Times; January 15, 1915. p. 9. Col d. Porter D, Porter R. The politics of prevention: anti-vaccinationism and public health in nineteenth century England. Med Hist 1988;32:231e52. Rolleston JD. The smallpox pandemic of 1870e1874. Proc Roy Soc Med 1933;27(2):177e92. Salmon DA, Teret SP, MacIntyre CR, Salisbury D, Burgess MA, Halsey NA. Compulsory vaccination and conscientious or philosophical exemptions: past, present, and future. Lancet 2006;367:436e42. Seaton EC. Dictionary of national biography, 1885e1900. Seaton: Edward Cator; 1885. https://en. wikisource.org/wiki/Dictionary-of-NationalBiography. Vaccination Act. https://en.wikipedia.org/wiki/vaccination-act. Wallace C. Antivaccination activism in 20th century Ireland. 2021. https://www.irishcentral.com/ roots/history/anti-smallpox-vaccination. Wolfe RM, Sharp LK. Anti-vaccinationists past and present. Br Med J 2002;325:430e2. Williams N. The implementation of compulsory health legislation: infant smallpox vaccination in England and Wales, 1840e1890. J Hist Geogr 1994;20(4):396e412.

Chapter 9

Vaccine mandates in the United States In the United States, the preservation of Public Health has historically been the responsibility of state and local governments. The authority of each state to enact laws regarding Public Health derives from the state’s general police powers. Thus, states can impose quarantine and isolation, and they can enact mandatory isolation and vaccination laws. These powers were confirmed and delineated by the US Supreme Court in their ruling in the case of Jacobson v Massachusetts in 1905. Compulsory smallpox vaccination in the United States has been imposed in three ways. First, all immigrants entering the country were required to show evidence of vaccination. Second, there were temporary mandates established in communities suffering from a local smallpox outbreak. Third, there were mandates applied to children enrolling in school (Hausman, 2020). As medicine evolved during the 19th century, and especially as the germ theory took hold, there was a progressive increase in the role of state governments in regulating public health. This progressed through the provision of clean water supplies, the proper removal of garbage, and the establishment of efficient sewer systems. Thus, the ongoing emphasis on vaccination and the corresponding resistance to compulsory vaccination must be considered in relation to other simultaneous public health measures including the provision of safe and clean water and food.

State-mandated vaccination Historically, mandated vaccination in the United States can be divided into three phases. The first phase involved widespread mandatory vaccination against smallpox through the 19th century (Fig. 9.1). As smallpox declined in importance, these mandates were progressively repealed, and the country went through a phase from about 1910 to the late 1950s when there were few new mandates and the medical profession relied primarily on persuasion to have children vaccinated. However, as diverse new vaccines were introduced, the pendulum swung again, and new mandates were progressively reintroduced. This second wave of mandates was however characterized, at least initially, by broad personal exemptions that sought to reconcile vaccination with personal A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00007-3 Copyright © 2023 Elsevier Inc. All rights reserved.

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128 A History of Vaccines and their Opponents US Mandate timeline 1819-2021

Mass School Vaccine Mandate 1855 San Antonio Mandate 1830 Massachusetts mandate 1809 1800

1825

1850

Urbana Vaccine Mandate 1867 1875

Jacobson v Massachusetts 1905 Biologics Control Act 1902

Childhood Immunization Program 1977

Prince v Mass 1944 Zucht v King 1922

1900

1925

1950

COVID-19 Mandates All 2021 states require vaccination 1980 1975

2000

2025

FIGURE 9.1 Timeline of major vaccine mandated events in the United States over the past 200 years.

freedoms (Conis and Cuo, 2021). Thus, the pattern seen in Britain was also followed in the American states, namely, compulsion triggering opposition and eventual repeal. However, compulsion subsequently reappeared as new vaccines directed against childhood diseases were developed and introduced.

Phase 1: 1810e1920. Mandatory smallpox vaccination Massachusetts For most of the 19th century, in the United States, public health was regarded as strictly a local issue and the states were solely responsible for drawing up and enforcing vaccine regulations. During this period, Massachusetts tended to be the leader in such matters, perhaps as a result of its puritan legacy of highquality education. For example, as described in the previous chapter, the Massachusetts Legislature on March 6, 1810, passed a law titled “An act to diffuse the benefits of Inoculation for the Cow-pox” (Chicago Tribune, 2021). They accepted that vaccination was very much safer than inoculation and presumably felt confident that they could mandate it without significant adverse consequences. For the next 30 years, Massachusetts continued to lead the way. In 1827, all Boston children had to provide proof of smallpox vaccination in order to attend school. Unfortunately, after the repeal of this mandatory vaccination law in 1839, smallpox case numbers in Massachusetts began to increase significantly.

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In response to this increase in smallpox cases, the Massachusetts Legislature enacted a statewide vaccine requirement. In May 1855, the Governor approved “An Act to Secure General Vaccination.” This law was much more drastic than the 1810 Cow Pox Law. It was increasingly recognized that smallpox was much more likely to be transmitted between individuals in crowded institutions. As a result, the managers of manufacturing companies, superintendents of almshouses, state schools, lunatic hospitals, masters of houses of correction, jailers, prison helpers, and the heads of all other institutions supported in whole or in part by the state were ordered to immediately cause to be vaccinated all inmates and all entrants (Woodward, 1932). Boards of Health were given authority at any time to vaccinate all the inhabitants of any town! “All parents and guardians of youth shall cause the children under their care to be vaccinated before they reach the age of 2 years.” Any parents or guardians who had neglected to vaccinate their children or wards by age 2, unless they possessed a certificate from a physician certifying that the child was unfit, were fined $5 yearly until the child was vaccinated (about $156 in today’s dollars). “The school committee of the several towns and cities shall not allow any child to be admitted to or be connected with the public schools who has not been duly vaccinated.” The enforcement of this act was somewhat erratic, and a Massachusetts State Board of Health was not established until 1869. Since most of the population remained unvaccinated, when smallpox returned in the 1870s, it soon resulted in epidemics. Yearly deaths from smallpox in Massachusetts averaged about 180 until a major epidemic developed in 1872e73 in which 1697 people died. About 1040 of these deaths occurred in Boston. These losses provided the stimulus for increased vaccination rates and increased enforcement of the 1855 law. As a result, with the exception of an epidemic in 1901e02, the annual death rate from smallpox in that state never again exceeded 100. The 1855 vaccination law was repealed in 1908 despite the opposition of the Massachusetts Medical Society (Woodward, 1932).

Texas Texas was part of Mexico until it declared independence in 1836. Prior to that time, Mexican Laws had prevailed. Thus, in response to ongoing smallpox epidemics in San Antonio, the provincial government of Coahuila y Tejas decreed in 1830 that all children in the city were to be vaccinated. That same year the provincial government also provided financial aid to smallpox victims.

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Ohio On July 8, 1867, the Urbana, Ohio, board of health passed a draft sanitary law requiring notification of any infectious disease and that “The Heads of families must see that all the members of their families have been vaccinated. This must not be delayed.” If they couldn’t pay the physician’s fee, the Health Officer would do so for free (Urbana Union, 1867).

Mandatory smallpox vaccination During the late 19th century, public education and health improved in parallel. Thus, the enactment of compulsory school attendance coincided with the need for mandatory smallpox vaccination. The growth in the size and number of public schools brought large numbers of susceptible children into close contact within classrooms. This, it was recognized, would obviously facilitate the spread of smallpox as well as other infectious diseases. As a result, compulsory school attendance laws naturally led to compulsory vaccination (Malone and Hinman, 2003). Recognizing that schools were prime sites of smallpox transmission, by the end of the 19th century, 13 states required that schoolchildren be vaccinated, and 11 states also had adult vaccination mandates. California passed its first required mandatory vaccination law for school enrollment in 1889. This law included provision for a medical exemption.

Mandate enforcement While states and local governments could issue vaccination mandates, it was often a difficult matter to enforce these laws. In theory, a person had to produce a certificate of vaccination to travel by train, attend school or public events, or even to work. Given that there was significant opposition to these mandates, it is unsurprising therefore that forgery of vaccination certificates was common. This was especially a problem during the smallpox epidemics in the large eastern cities at the beginning of the 20th century. There was an extensive trade in worthless vaccination certificates signed by sympathetic doctors for a price. The Anti-vaccination Leagues would provide lists of sympathetic doctors who would either provide a certificate of medical exemption or simply a completed vaccination certificate. Some parents would simply forge their own certificates (Roos, 2021). The problem of vaccination certificate forgery grew to such an extent that the authorities were forced to rely on another method of vaccination verificationdthe presence of a vaccination scar. Thus, when an individual was vaccinated, an inflammatory lesion and vesicle would develop at the inoculation site. A scab eventually formed and when the scab fell off it would leave a characteristic scar about 1 cm in diameter.

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Given the problem of forged certificates, health officials enforcing vaccination orders eventually began to simply ignore the vaccination certificates and ask to see the scar. These were a very convenient physical form of certification and were not readily forged. As early as 1864, during a smallpox epidemic in Memphis, Tennessee, at the end of the Civil War, the Union Brigadier in Command, Ralph Buckland ordered his physicians to inspect everyone and vaccinate those who did not have “well marked scars.” During another smallpox epidemic in Tennessee in 1882e83, a Memphis newspaper reported. “At Chattanooga, when a doctor and a policeman enter a house together the folks inside know that they have to show a scar, be vaccinated, or answer to the law. There is no nonsense in that way of stamping out disease and saving life” (Taylor, 2021). Almost 20 years later, in 1903, the State of Maine issued a decree that “no person shall be allowed to work in a lumber camp who cannot show a good vaccination scar.” Even in later years, for example during a 1921 outbreak in Kansas City, showing a scar was a prerequisite to admission to lodges and other meetings (Roos, 2021). Public school administrators often required students to show a “plain scar” if they could not provide a certificate of vaccination. Even eminent physicians such as Dr. James Hyde of the Rush Medical College in Chicago wrote an editorial urging public health officials to use the presence of a vaccination scar as a passport to participation in civic life. As a result, in schools, factories, offices, and even on immigrant ships, and trains from Canada, individuals who couldn’t show a reasonably fresh vaccination scar would be vaccinated on the spot! It was widely reported however that some young ladies resisted vaccination since it would blemish their otherwise perfect skin. During the 1901e03 smallpox epidemic in the large northeastern cities such as New York and Boston, many communities actively resisted or sought to evade the smallpox police. As a result, the authorities resorted to force! Thus, hundreds of police officers and doctors would converge on a city block at night. These were usually in low income, immigrant neighborhoods. Under the command of the Bureau of Contagious diseases, vaccination teams entered each home, wakened, and then vaccinated everyone, and removed any smallpox cases to a quarantine hospital on North Brother Island in the East river. Parents often fought fiercely to prevent the removal of their children. If they had been alerted to the forthcoming raid, they grabbed their children and fled into the night. The vaccination fight continued. Homeless shelters, factory workers, and even the New York police themselves were subjected to surprise vaccination raids. It is estimated that the focus of the New York Health Department on these vulnerable populations resulted in them administering 810,000 vaccinations in 1902 alone (Marvar, 2019).

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Phase 2: 1910 to 1940e60: Voluntary vaccination However, as new mandates were enacted popular opposition to them also increased while the progressive decline in smallpox cases removed much of the incentive to be vaccinated. The experience of California exemplifies this. Thus in 1899 an anti-vaccination society was founded in Los Angeles. Students at Berkeley went on strike when the University mandated vaccination. Anti-vaccination groups were formed in other cities as well. Jacobson v Massachusetts had been decided by the Supreme Court in 1905 and so permitted mandatory vaccination. That same year, the sympathetic legislature in California approved a bill to ban mandatory vaccination for school enrollment. Governor George Pardee, a physician vetoed it! The fight continued; the legislature generated 12 anti-mandate bills over the next 10 years, but none was successful. Eventually, in 1911, the California legislature replaced its 1889 vaccination act with one that waived required vaccination for everyone who was “conscientiously opposed”. In effect, it adopted the language from the British 1907 Vaccination Act. This time, Governor Hiram Johnson signed it. The anti-vaxxers had triumphed for now. In 1921, California repealed its vaccination law completely (Conis, 2020). The new law expressly prohibited local school or health authorities from adopting any rules or regulations on the subject of vaccination (Conis and Cuo, 2021). The medical profession in California were not happy with the repeal of the smallpox vaccination law. One obvious reason was that smallpox cases began to climb in the state from just over 500 cases annually between 1912 and 1916 to more than 4000 in 1929. Dr. Kellogg of the University of California is quoted as saying that repeal had given “the people of California . the privilege of enjoying all the smallpox they wanted” (Eberson, 1929). Opposition to obligatory vaccine mandates grew as states started to enforce them and as the prevalence of smallpox declined. Anti-vaxxers flooded states with pamphlets and brochures, took states to court, and fought in state legislatures to prevent vaccination. Their prime arguments were that vaccines were ineffective and unsafe, while mandating their use was an affront to liberty and freedom. These early anti-vaccinationist campaigns were often successful. For example, Utah also suffered from a smallpox epidemic in 1899e1901. This was accompanied by a rancorous debate between the state’s physicians, religious leaders, and educators about the imposition of mandates on schools. The physicians lost. The state legislature passed a law in January 1901 despite the Governor’s veto attempt, prohibiting the exclusion of unvaccinated children from schools. The act remained in effect until 1933 (Cater, 2016). In 1903, Minnesota made compulsory vaccination unlawful in most circumstances. After enacting vaccine mandates, they were subsequently repealed in California, Illinois, Indiana, West Virginia, and Wisconsin (Kaufmann, 1967). Anti-vaccinationists also fought strenuously to overcome smallpox vaccine mandate laws in Massachusetts, Pennsylvania, and Rhode Island.

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Thus, the transition from smallpox to other vaccines such as diphtheria also coincided with a switch from attempted coercion to persuasion. This was not unreasonable since smallpox vaccination, while very effective, had little scientific evidence to explain how and why it worked. The newest vaccines however carried with them an understanding of the mechanisms involved in immunity. They could be trusted. In the decades after Jacobson v Massachusetts there was considerable legislative activity across the United States regarding vaccination. At least four states repealed existing vaccination laws; two other states made their laws less restrictive. However, anti-vaccination measures were defeated in three states. By the middle of the 20th century, infectious diseases had declined in importance in the developed world. Chronic diseases, especially heart disease and cancer became the leading causes of morbidity and mortality. There were few infectious disease outbreaks that presented an imminent threat and required emergency responses and mass vaccination. While society debated whether compulsory vaccination was effective and ethical, the impact and relevance of the anti-vaccination societies gradually waned. Some argued from experience that people were too concerned about their personal liberties to submit to vaccine compulsion. Others pointed out that there would always be a minority who actively resisted vaccination. Others argued that compulsory vaccination worked every time (Colgrove, 2007). In general, the Public Health authorities opted for persuasion even when there was a very obvious threat from an infectious disease. It is also important to note that new discoveries regarding how vaccines worked, and the science of immunology were developing around this time. There was much more confidence in vaccines, their safety, and effectiveness than at any time previously. The frequency of severe adverse events declined. As smallpox faded, it was replaced as a major health concern by diphtheria. New developments resulted in the availability of diphtheria vaccines and as a result, a debate ensued among medical professionals as to whether a diphtheria vaccine mandate should be imposed for school entry. Few states did so, wary of stimulating a backlash. Doctors differed. Many, with the experience of the anti-vaccination campaigns behind them opted for persuasion. Moreover, diphtheria is a disease of infants and there was a concern that parents would delay vaccination of their children until they were about to be enrolled in school. This could be too late. In many cases, public health officials turned to aggressive marketing to overcome vaccine hesitancy. Advertisements in the press and popular magazines, and posters were common. Many were paid for by insurance companies. Charities set up health clinics that encouraged vaccination. This approach worked but had limitations. Price was an issue for many and so they had recourse to free clinics. Many still needed the active encouragement of a nurse or a doctor. As pointed out in Chapter 14, the scares about socialism and communism in American society during the 1920s and 1930s led to significant

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opposition to governmental intrusion into health affairs. Public health was a hard sell, and doctors resented governments telling them how to treat patients. They also resented governmental interference in determining their fees and the costs of vaccinations. Notwithstanding this, diphtheria vaccination was widely accepted by many parents so that, for example, two thirds of parents in New York City had had their children immunized against diphtheria by the late 1930s.

Phase 3: 1960epresent: New vaccine mandates For much of the 20th century, as medical advances occurred in rapid succession, there was growing admiration and trust in the medical profession. Life expectancy increased rapidly. These new advances worked. As a result, over much of that period there was little resistance to vaccination. Up to 90% of parents surveyed in a 1978 poll said that they would have their children vaccinated even if this was not required by law. Unfortunately, vaccination rates began to lag in the late 1970s not because of opposition, but because of complacency. Vaccines were the victims of their own success. The better they worked, the lesser the threat, and the greater the perception that they were no longer needed. Parents never underwent the same worries of earlier generations when they were terrified of polio or whooping cough. As a result, states began to gradually reimpose vaccination mandates (Amark, 2022). The only vaccine available from its discovery in 1795 until the end of the 19th century was that directed against smallpox. Only in the 1880s did the discoveries of Louis Pasteur and other early immunologists demonstrate that the body’s immune response could be harnessed to protect us against other important infectious diseases as well. The first such vaccines to be developed such as those against rabies and typhoid were relatively crude and had manifold adverse effects. However, over the years, vaccines have been progressively improved and their safety profile steadily enhanced. It took some time however for many of them to be approved for use. For example, pertussis (whooping cough) vaccine was first produced in 1914, but it was not until 1948 that the CDC formally recommended its use in children. The combination vaccine containing diphtheria, pertussis, and tetanus (DPT) was not formally recommended by the CDC until 1948. Likewise, measles vaccine was developed in 1963, mumps in 1967, and rubella in 1969. The CDC recommended their use in children, infants, and teens as a combined vaccine (MMR) in 1971. These delays reflected an abundance of caution on the part of the CDC and the FDA with respect to their safety. However, collectively, once mandated for children entering schools, they largely eliminated the threat of these childhood diseases in older children (CDC, 2016). They did not however improve vaccine coverage in infants and preschoolers and many private insurers did not cover the costs of routine vaccinations.

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Vaccination mandates, however, did not go away. As more diverse vaccines were developed, states returned to the practice of mandating vaccination for schoolchildren. Most of these new mandates permitted religious and personal exemptions. Thus, in 1939, North Carolina mandated diphtheria immunization while New Mexico did the same in 1943. Hawaii mandated diphtheria vaccination in 1945 with only a medical exemption but in 1951 added a religious exemption. Michigan went even further in 1949 requiring that patients be vaccinated against diphtheria, pertussis, tetanus, and smallpox. The participation of millions in the Second World War also ensured that they received mandatory vaccination on enlistment in the military. It was an accepted part of military life. People still remembered the huge numbers of deaths in troops due to influenza in the First World War. It didn’t happen a second time. The development of polio vaccines in the 1950s was welcomed enthusiastically by parents and the initial problems resulted more from a shortage of vaccines rather than a shortage of arms to be vaccinated. Initially, the vaccine had to be rationed. This was done through the National Foundation for Infantile Paralysis (The March of Dimes). The Federal Government of the 1950s wanted nothing to do with vaccine distribution, but they did provide funds for states to provide free vaccination to poor children. The Kennedy administration accepted that federal involvement in childhood vaccination should occur, and in 1962, Congress passed the Vaccination Assistance Act. The act provided funds for states to support the delivery of diphtheria, pertussis, tetanus, and polio vaccines (Colgrove, 2007). In 1971, with no cases of smallpox having occurred in the United States in 22 years, but with 6e8 deaths per year due to vaccination complications, the United States Public Health Service formally ended routine smallpox vaccination. The growing belief that government intervention was required if high levels of immunity were to be achieved resulted in an increased number of states adding polio vaccination to their diphtheria and smallpox mandates. Ohio was the first in 1959 and permitted personal exemptions. More states joined in, usually also permitting religious exemptions. New Hampshire was an outlier since it only allowed medical exemptions. In addition to Ohio; Kansas, Michigan, Missouri, and California, all allowed personal exemptions. New Mexico, Virginia, and Kentucky also allowed religious or spiritual exemptions. In 1977, the Federal Government established the Childhood Immunization Initiative. This was aimed at increasing the vaccination rates against the major childhood diseases. As a result, many states, using the CDC prevention schedule as a guide, updated their laws to mandate vaccination against the seven childhood diseases; diphtheria, pertussis, tetanus, polio, measles, mumps, and rubella. By 1968, half of the states required some vaccination prior to entry. By 1974, 40 states required vaccinations prior to school entry.

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The last to do so were Idaho, Iowa, and Wyoming. By 1981, all 50 states had laws related to the vaccination of children. These laws however vary between states. All require vaccination against polio, diphtheria, tetanus, pertussis, measles, and rubella. Most states require vaccination against chickenpox, hepatitis B, and pneumococcal pneumonia. Newer childhood vaccines such as those against hepatitis A, and seasonal influenza are required in only a limited number of states. Only DC, Hawaii, Rhode Island, and Virginia require human papilloma virus vaccination which protects against cervical cancer, but has been somewhat controversial, especially in conservative states since it is transmitted sexually and it is argued by some that it therefore promotes sexual promiscuity (Chapter 19). Meningococcal vaccines are recommended for teens and children over the age of 11 or 12 and are required by 33 states.

Polio vaccine mandates As case numbers increased during the first half of the 20th century, polio provoked tremendous fear especially since its victims were primarily young children. The development of effective vaccines thus provided great relief, and they were widely accepted immediately. As a result, the authorities generally relied on persuasion for polio vaccine use but a minority of states passed laws mandating polio vaccine for school entry. The senior managers of the National Foundation for Infantile Paralysis opposed a proposed New York Law in 1965 saying that “We are very much opposed to coercion especially since the city had achieved high rates of vaccine coverage without the use of legal compulsion” (Colgrove and Bayer, 2005). While initially received with enthusiasm, eventually there was a progressive decline in polio vaccine usage, especially in impoverished rural areas. As a result, many states imposed polio vaccination mandates in the late 1950s and early 1960s as effective and safe vaccines became increasingly available. Generally, these new mandates were accepted only after much negotiation and allowances for personal belief exemptions. For example, Michigan introduced a mandate in 1958 following a polio outbreak that year. However, the bill only passed in 1960 once an exemption was allowed for those with “religious or other” objections. In Ohio, in 1959, a vaccination bill was held up by politicians opposed to the loss of “the right to freedom of choice.” It eventually permitted parents to opt their children out by submitting a written statement objecting to immunization. In 1961, a polio vaccination mandate bill was introduced in California. It required polio vaccination for school enrollment but originally permitted exemptions based on “religious beliefs.” But alternative health adherents persuaded the legislature to remove the word “religious.” Thus, in their 1961 Bill, California used a broad personal belief exemption clause that could be applied to any vaccine laws.

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Measles vaccine mandates Another wave of mandate laws was triggered in response to declining measles vaccination rates in children. As discussed in Chapter 18, measles vaccines were first made available in the United States in 1963. However, a change in attitudes occurred in the late 1960s when the CDC was leading a nationwide campaign to eradicate measles. In 1968, just half the states had laws that required measles vaccination for school entry. School vaccination laws were often modified during the 1960s as public health officials became increasingly frustrated with recurrent outbreaks of measles despite the availability of a safe and effective vaccine. Many parents grossly underestimated the potential seriousness of measles. By 1981, all 50 states had made vaccination against measles and other vaccine preventable diseases mandatory for school entry. The CDC believed that the hesitant simply required a small additional stimulus to get a parent’s attention and get the job done (Colgrove and Bayer, 2005).

Current state mandates Every US state as well as the District of Columbia now has a law requiring children entering school to provide documentation that they have met the state vaccination requirements (Cole and Swendiman, 2014). The number of recommended pediatric vaccines increased from 7 to 14 between 1990 and 2006. This expansion of vaccine mandates initially provoked little controversy. After all, these mandates result in a safe environment in schools where the chances of your child getting measles, mumps, rubella, polio, or whooping cough are reduced to an absolute minimum. Routine child vaccination has been estimated by the CDC to have prevented 936,000 premature deaths and 419 million illnesses in American children born between 1994 and 2018. The laws have however attracted challenges that generally focused on the nature of exceptions. While mandates were initially largely supported by the US population, over the final years of the 20th century and the first decades of the 21st, misinformation and a growing distrust of government has spread, and these laws are being increasingly challenged. Anti-vaccinationists and their political supporters increasingly pushed back against mandated vaccination. Compulsory vaccination did result in children receiving many more injections, a factor that has resulted in some resistance. Likewise, it has also resulted in increasing anxiety regarding the safety of vaccines. One anti-vaccination approach has been to push for limits on compulsory vaccination. Thus, while these laws might be partially repealed, they also pushed for limitations of their powers and the increased availability of exemptions, especially medical exemptions and wherever possible nonmedical exemptions as well. One concern expressed by many parents is the sheer number of vaccine doses administered to children under 2 years of age. These can involve giving

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the infant from 24 to 26 different injections. Some parents worry that this will overload the immune system. However, the immune system has evolved to handle multiple different antigens at one time. For example, streptococci contain 20e50 different antigens. Rhinoviruses up to 10 antigens. Exposure to germs and environmental antigens can easily expose a child to over 100 antigens daily. Vaccines fall well within these ranges and do not overload the immune system (Chapter 1).

Covid vaccine mandates Effective vaccines against the coronavirus, COVID-19, became widely available in early 2021. In July 2021, the Biden administration mandated COVID-19 vaccination for all federal workers and contractors, with masking and regular testing as an alternative option. The Department of Veterans affairs issued mandates for all frontline healthcare workers; and President Biden ordered mandatory vaccination in the military. Coronavirus vaccination became a highly political issue, and as a result, some states have issued mandates in some form or another, whereas others have banned such mandates (Congressional Research Services, 2022). California and New York City and State required that all government workers get vaccinated or else submit to weekly testing. Mandates are also required for healthcare workers working in hospitals and nursing homes to be vaccinated against diseases such as measles, mumps, and rubella in addition to seasonal influenza in some cases. Institutions of Higher Education may require hepatitis B and meningococcal disease vaccination. By 2022, all students attending Los Angeles Public Schools were required to be fully vaccinated against SARS Coronavirus 2, the cause of COVID-19 (Wiki, COVID-19).

Canada The Committee against Compulsory Vaccination was formed in Ontario in November 1983 in response to a 1982 Actd“An Act to protect the Health of Pupils in Schools.” This act authorized medical officers of health to exclude from school, children who failed to demonstrate that they had met all immunization requirements. The Committee was however successful in amending the Act which allowed a conscience-based exemption and sincerely held beliefs in addition to religious exemptions. Despite widespread publicity, the committee does not appear to enjoy the same level of popular support enjoyed by the Anti-smallpox Vaccination Leagues. Their meetings are poorly attended, and their publications not widely circulated (Arnup, 1992). Thus in 1985, the committee claimed to have 375 members. Ontario and New Brunswick are currently the only provinces that require regular vaccinations for children enrolling in public schools and they both accept medical and religious exceptions.

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Exceptions As described in the Chapter 11, in 1905 the US Supreme Court upheld the authority of the states to enact laws that mandated vaccination. In 1922, they went further and decided that states have the authority to enforce vaccine mandates for public school enrollment. As a result, all 50 states have vaccine mandates for public schools for polio, diphtheria, tetanus, and pertussis, as well as measles and rubella. However, they all allow for medical exemptions and many permit religious and personal belief exemptions (Conis, 2020). In the 20th century and following the Supreme Court rulings, much of the legal struggle around vaccine mandates focused on these exemptions. Lawsuits were often brought by adherents of “alternative medicine.” In most cases, the courts rejected them. Nevertheless, vaccine mandates were no longer absolute or inflexible. All states, plus DC, permit medical exceptions which allow children with certain medical conditions that will negatively affect vaccination or generate unacceptable adverse events to avoid the process. As discussed in later chapters, many states also allow philosophical or religious objections. Thus, as the 20th century passed, much of the heat was taken out of the vaccine wars by the availability of exemptions in addition to the changes in medical practice. As the ability of physicians to actually cure disease increased, so too did the respect for the medical profession. Advances like the polio vaccine did not trigger significant pushback in developed Western countries. Suspicion of physicians declined. (One notable exception was the Tuskegee Syphilis study conducted by the US Public Health Service where black patients were denied treatment for syphilis even after such a treatment was available.) School admission vaccinations were first made compulsory in Texas in 1971, Oregon in 1973, Utah and North Dakota in 1975, Oklahoma in 1976, and in Vermont in 1979. The Texas law mandated protection against smallpox, diphtheria, tetanus, polio, rubeola, and rubella. Almost all had personal belief exemptions either present in the original law or added later. For example, the original Texas Law provided that exemptions could be obtained for religious or medical reasons. However, religious exemptions may be set aside during an emergency or epidemic. In 2003, organized vaccine opponents lobbied Texas lawmakers to add a personal belief exemption. North Dakota allowed “a right to refuse.” Vermont permitted exemptions based on “moral convictions.” Arizona simply added them to those “who do not consent.” Arkansas had permitted a religious exemption but in 2003 a court obliged them to add philosophical beliefs as well. More vaccines were added to the required list, such as varicella, meningitis, and hepatitis B as time passed (Desilver, 2021). In 2015, California enacted a new vaccination law (Assembly Bill 1940) that no longer permitted nonmedical exemptions for schoolchildren. Governor Jerry Brown signed the Bill despite strenuous protests from protesters, especially those who believe that some vaccines cause autism. Maine also removed the nonmedical exemptions, that same year, 2015. Two other states West

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Virginia and Mississippi have had similar laws in place since the 1970s. In 2021, Connecticut banned religious exemptions for school vaccine mandates, but they are still in place for workplace vaccination requirements.

Military mandates The military has always had broad authority to protect the health of their personnel, both military and civilian (Cole and Swendiman, 2014). The requirement for smallpox inoculation in the Continental Army ordered by George Washington was discussed in Chapter 5. Since that time, the American military have been subjected to multiple vaccine mandates depending upon the immediate threats to their health and safety. For example, at the beginning of yet another war with the British in 1812, vaccination was deemed a prudent precaution. As a result, on May 26, 1812, the US Army mandated smallpox vaccination. Vaccination: orders the immediate, of troops, May 26, 1812 From War Department General Orders: The Surgeons and Surgeon’s Mates of the Peace Establishment and additional Military Force of 1808 at the several Posts and Stations will immediately procure matter and vaccinate the troops. By Command of the Secretary of War.

Many at that time would have remembered the positive effects of George Washington’s inoculation order and been aware that the British Amy had begun vaccinating its troops in 1800. In subsequent years, the army mandated the use of other vaccines depending upon the specific disease and the threat that it posed. It is interesting however to note that neither army in the Civil War sought to apply any vaccination mandates to its troopsdvaccinia was of course, the only one that would have been available. In 1816, the US Navy appointed a surgeon to visit its ports and vaccinate all seamen, both merchant and naval. They did not however enforce this for several years since smallpox was not seen as a great problem at the time. This changed in the 1830s and 1840s when smallpox caused severe disease outbreaks on some vessels. As a result, on December 1, 1848, the Secretary of the Navy, John G. Mason made vaccination mandatory for recruits at the time of enlistment (Sobocinski, 2021). During the Spanish-American War in 1898 fought largely in Cuba, 243 soldiers were killed in action or died of wounds, but 1580 died of typhoid fever. As a result, the US army commissioned the development of a typhoid fever vaccine. In June 1911, the War Department mandated the use of their typhoid vaccine for “all troops entering federal service” as well as for all

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service personnel under 45 years of age (Smith et al., 2011). The US Navy did the same in 1912 (BMJ, 1912) (Fig. 9.2). As America mobilized to fight the Germans and Japanese in 1941, the US army decided that it would be a good idea if all its troops were immunized against yellow fever. After all, nobody knew where the fighting might eventually extend to. The vaccine was provided by the Rockefeller Foundation without charge. The attenuated 17D vaccine at that time needed to be “stabilized” by the addition of normal human serum to prolong its shelf-life. Unfortunately, seven vaccine lots were contaminated with serum from donors carrying hepatitis B virus although this was unknown at the time. Some batches were much more infectious than others. Thus, a batch in one camp caused 1004 cases of hepatitis among 5000 troops. Overall, more than 300,000 troops were infected; there were 50,000 clinical cases, and 29,000 cases of jaundice developed. For a short time, it was believed that the vaccine itself may have caused yellow fever. Once the problem was recognized the

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5.00 4.00 3.00 2.00 1.00 0

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FIGURE 9.2 The occurrence of typhoid and paratyphoid fevers in the US Army from 1900 to 1925. Note that typhoid vaccination was mandated in 1911 but was available to troops since the Spanish-American War (1898). The Philippine war was fought from 1899 to 1902. The rate given is the number of cases per 1000 troops. Note that during the First World War, the number of cases rose to reach 875 in 1918, but the army was so large at that time that the overall incidence rate remained low. Data from Surgeon General Annual reports.

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contaminated batches were promptly withdrawn and the use of the vaccine containing human serum was discontinued. This was the largest vaccinerelated disease epidemic in US history. The great losses suffered by US troops as a result of the influenza pandemic of 1918 ensured that by the end of the Second World War, an effective influenza vaccine was developed and used. Thus, during 1946 and 1947, influenza vaccination was mandated for all army enlistees. Unfortunately, it did not reduce the incidence of the disease because of the ability of the virus to genetically alter its surface antigens (antigenic drift). As a result, the mandate was rescinded in 1949. During the Vietnam War, the terrain and climate meant that soldiers had to be vaccinated against many infectious diseases, most notably measles and polio that were prevalent in south-East Asia. Other mandated vaccines included cholera, influenza, meningococcus, plague, smallpox, tetanus diphtheria, typhoid, typhus, and even yellow fever. During the Gulf War, concern regarding Saddam Hussein’s capacity for biological warfare resulted in mandatory vaccination against two biowarfare agents, anthrax (Bacillus anthracis) and smallpox. (These are discussed further in Chapter 22.) The anthrax vaccine was especially controversial, not for safety reasons but for doubts about its efficacy. In August 2021, the Secretary of Defense mandated coronavirus vaccination for all members of the US armed forces. Unlike the anthrax vaccine, the COVID-19 vaccines had received full FDA approval making legal claims against their use difficult. By October 2021, over 96% of service members had received at least one dose of the COVID-19 vaccine. There were however a significant number of vaccine refusals, especially in the Air Force and the Army National Guard. It is estimated that nearly 8500 service members were dismissed as a result, and numerous lawsuits resulted (Elslinger and Paradis, 2021). The opposition to mandating COVID-19 vaccination for military personnel grew to such an extent, that the mandate was withdrawn in December 2022. This resulted from pressure from the Republican members of Congress who refused to support a Military Appropriations Bill unless mandatory vaccination was rescinded. As of 2020, mandatory vaccinations for American military personnel include hepatitis B, measles, mumps, rubella (MMR), tetanus, diphtheria and pertussis (DTaP), polio, meningococcus, and influenza (Elliott and Chambers, 2022).

References Amark Foundation. A brief history: mandated vaccinations (and exemptions) in US states, public schools, and the military. 2022. https://amarkfoundation.org/a¼brief-history-mandatedvaccinations-and-exemptions. Anomymous. Br Med J 1912;1:299.

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Arnup K. “Victims of vaccination?”: opposition to compulsory immunization in Ontario, 1900e90. Can Bull Med Hist 1992;9(2):159e76. https://doi.org/10.3138/cbmh.9.2.159. Cater B. The religious politics of smallpox vaccination, 1899e1901. Utah Hist Q 2016;84(1):6e25. Center for Disease Control and Prevention. Requirements and laws. State vaccine requirements. 2016. https://www.cdc.gov/vaccines/imz-managers/laws/index.html. Chicago Tribune. History of vaccine mandates in the US. October 21, 2021. https://www. chicagotribune.com/coronavirus/sns-stacker-vaccine-mandates. Cole JP, Swendiman KS. Mandatory vaccinations: precedent and current laws. Congressional Research Service; 2014. https://www.crs.govRS21414. Colgrove J. Immunity for the people: the challenge of achieving high vaccine coverage in American history. Public Health Rep 2007;122:248e57. Colgrove J, Bayer R. Manifold restraints: liberty, public health, and the legacy of Jacobson v Massachusetts. Am J Public Health 2005;95(4):571e6. Congressional Research Service. State and Federal authority to mandate COVID-19 vaccination. 2022. https://crsreports.congress.govR46745. Conis E. The history of the personal belief exemption. Pediatrics 2020;145(4):e20192551. Conis E, Cuo J. Historical origins of the personal belief exemption to vaccination mandates: the view from California. J Hist Med Allied Sci 2021;76(2):167e90. https://doi.org/10.1093/ jhmas/jrab003. COVID-19 vaccination mandates in the United States. https://en.wikipedia.org/wiki/COVID-19vaccination-mandates-in-theUnitedStates. Desilver D. States have mandated vaccinations since long before COVID-19. 2021. https://www. pewresearch.org/fact-tank/2021/10/08/stateshave-mandated-vaccinations. Eberson F. Smallpox and vaccination. Cal West Med 1929;30:401e4. Elliott BP, Chambers S. A historical analysis of vaccine mandates in the United States military and its application to the COVID-19 vaccine mandate. Vaccine 2022. https://doi.org/10.1016/ j.vaccine.2022.08.017. Elslinger E, Paradis M. Federalism and coronavirus vaccination mandates for military personnel. Lawfare 2021. https://lawfareblog.com//federalism-and-coronavirus-vaccination. Hausman T. Variolation vs, vaccination: 18th century developments in smallpox inoculation. Beehive 2020. Mass Historical Society, https://www.masshist.org/beehiveblog/2020/05/ variolation-vs-vaccination. Kaufmann M. The American anti-vaccinationists and their arguments. Bull Hist Med 1967;41(5):463e78. Malone KM, Hinman AR. Vaccination mandates: the public health imperative and individual rights. In: Goodman RA, et al., editors. Law in public health practice. New York: Oxford University Press; 2003. p. 262e84. Marvar A. How New York separated immigrant families in the smallpox outbreak of 1901. 2019. https://www.smithsonianmag.com/history/how-new-york-separated-immigrant-families-small pox-outbreak-1901-180971211/. Roos S. The first ‘Vaccine passports’ were scars from smallpox vaccinations. 2021. https://www. history.com/news/vaccine-passports-smallpox-scars. Smith PJ, Wood D, Darden PM. Highlights of historical events leading to national surveillance of vaccination coverage in the United States. Public Health Rep 2011;126(Suppl. 2):3e12. https://doi.org/10.1177/00333549111260S202.

144 A History of Vaccines and their Opponents Sobocinski AB. Immunization and the fight against disease: a short history of vaccines in the US navy. The Sextant; 2021. https://usnhistory.navylive.dodlive.mil/recent/article/2687034/ immunization-and-the-fight-against-disease. Taylor JE. The U.S. had “vaccine passports” beforedand they worked. 2021. https://time.com/ 5952532/vaccine-passport-history. Urbana Union. Board of health resolution. July 10, 1867. Woodward SB. The story of smallpox in Massachusetts. Mass Historical Society; 1932. https:// www.massmed.org/About/MMS-leadership-history/The-story-of-smallpox.

Further reading Bayne-Jones S. Preventive medicine in the United States army, 1607e1939. Washington DC: Office of the Surgeon General, Department of the Army; 1968.

Chapter 10

Anti-inoculation and anti-vaccination riots Protests against what is seen as overreach by the public health authorities are not new. These anti-vaccine protests have turned violent at times. They have not generally affected the broader use of vaccines, and in many cases tend to reflect specific local issues. The first riots were directed at the practice of inoculation. Inoculated patients developed severe arm lesions that shed large quantities of the smallpox virus. As a result, these individuals were highly contagious for several days after inoculation and could act as smallpox superspreaders. Not unreasonably, other citizens were concerned and made these concerns known to the authorities, often in the form of violent protests.

Anti-inoculation riots The 1730 Marblehead riot In May 1730, news reached the fishing town of Marblehead, located close to Salem that smallpox had broken out in Boston. The townspeople resolved to do something about it and voted to build a fence with a gate across the road into town. They stationed four men at the gate who had orders to exclude all strangers coming from Boston. They maintained the watch for 2 months. For good measure, free African-Americans, Native Americans, and slaves were also subjected to a nine o’clock curfew (possibly as a racist precaution against social disorder). Unfortunately, the barrier failed to keep the smallpox out. A young woman called Hannah Walters developed the disease. In response, the town minister, Edward Holyoke, together with some of his parishioners advocated strongly for people to be inoculated. However, many in the town were skeptical. Being religiously conservative, they generally believed that God alone should decide who lived and died. In addition, inoculation was not free and could only be afforded by the wealthy. As a result, they held a town meeting on October 12, 1730, and voted to ban inoculation unless everyone could be inoculated. Unfortunately, Richard Dana, a Justice of the Peace, was overheard declaring that he would have his family inoculated if his wife had not been pregnant. Rumors began to spread that Dana, and a merchant, Stephen Minot, intended to ignore the ban. As a result of their fear that inoculation would spread the disease, a crowd of about 20 men accosted the A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00006-1 Copyright © 2023 Elsevier Inc. All rights reserved.

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potential inoculees. They denied that anyone had been inoculated, but later that night, about 200 people surrounded Dana’s house. They threatened to tear down the homes of Dana and Minot. The militia were of no help. The sheriff locked up some protesters in a makeshift jail and the riot subsided. A few folk were charged with rioting, but in the end, only one member of the mob was convicted. Things settled down, but the smallpox raged through Marblehead until the summer of 1731 affecting almost every family in the town.

1774dMarblehead again! In June 1773, smallpox broke out once again in Marblehead. As a result, the town considered building an isolated smallpox hospital on one of the small islands in the harbor. While the proposal failed, the town permitted four private citizens to build a private inoculation hospital on Catta Island (now called Children’s Island). They purchased the island and in September 1773 began to build the hospital called Castlepox or Essex hospital. Within a few months, doctors had begun to inoculate groups of patients in the hospital. As might be expected, a few died and as a result the townspeople were infuriated. They began rioting over several days. They burned a small boat that took supplies to the hospital, and they broke the windows of the proprietor’s homes. The Boston Tea party had occurred in December 1773 and anti-British (and antiinoculation) sentiment was high. In January 1774, four Marbleheaders were caught stealing contaminated clothing from the hospital. It was assumed that they planned to spread the epidemic to the town and so discredit the hospital. The next day, they were tarred and feathered, placed in a cart and paraded through all the main streets of Marblehead. They were then taken to prison in Salem. Despite this, 22 cases of smallpox developed in the town and the townspeople threatened to lynch the hospital proprietors. The owners eventually agreed to close the hospital but on the night of January 25, 1774, about 20 heavily disguised townsfolk, sneaked onto the island, and burnt the hospital to the ground (Wehrman, 2009). Town officials arrested two suspects from Marblehead on February 25 and locked them up in Salem jail where they were charged with arson and attempted murder. In response, a large number of Marbleheaders marched to Salem, surrounded the jail, broke open the doors, overpowered the jailers, freed the prisoners, and carried them home. In response, the Salem sheriff gathered 500 citizens and marched them to Marblehead to recapture his prisoners. However, they were then confronted by 1000 Marbleheaders! At that point, the Hospital proprietors decided to drop the prosecution. As a result, the sheriff disbanded his posse, and they all went home (Wehrman, 2009).

1768e1769: The Norfolk riots While many believed inoculation to be an effective means of controlling smallpox, other members of the community regarded it as a reckless procedure

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because inoculated patients were infectious and could spread the disease to others. This debate between Pro- and Anti-inoculationists was the cause of two riots in Norfolk, Virginia, in 1768 and 1769. Interestingly, as at the present time, these two schools of thought were also divided along political lines. “Patriots” were generally opposed to inoculation while “loyalists” supported it. The trouble in Norfolk appears to have started with a report that some inoculated patients in Yorktown had left quarantine early and thus triggered the epidemic. In June 1868, a number of eminent Norfolk citizens decided to invite a skilled inoculator, Dr. John Dalgleish, to town in order to inoculate their families. Smallpox was prevalent in the colony at the time and was especially severe in Williamsburg. In view of the expected public opposition, these citizens arranged for their families to travel to Dr. Archibald Campbell’s plantation, about three miles out of town, where Dr. Dalgleish would vaccinate them, and they would then be quarantined. Word got out however and “the people” requested a magistrate to restrain the Campbell party. The magistrate refused to do so, but some of the crowd then adjourned to local taverns and began drinking. It is relevant to note that the leading anti-inoculationist, Maximilian Calvert, was an active “patriot” in Norfolk. Conversely Dr. Campbell and the pro-inoculationist James Parker were active loyalists. (Campbell was the only pro-inoculationist in town. All the other physicians were anti-inoculationist patriots.) Following negotiations, the inoculationists agreed to delay the procedure until June. However, one week later, a group of men attacked and destroyed the doors and windows of the Campbell plantation. The loyalist families were inoculated on June 25. The patriots requested that the inoculated families be removed from the Campbell plantation to the public pesthouse. This was to be done quietly but a mob gathered. The drunken mob drove the families to the pesthouse while later breaking the windows of their homes. Two days later, Campbell’s house was burned to the ground. None of the mob were ever brought to trial. The controversy flared up again in April 1769 when bills were brought by the anti-inoculationists against Dr. Dalgleish. However, inoculation was not illegal in Virginia at that time, so the case collapsed. In the spring of 1769, a ship with smallpox cases aboard arrived in Norfolk. Three apprentices and three Negro slaves belonging to Cornelius Calvert, the Mayor of Norfolk, were taken to the pesthouse. Dr. Dalgleish inoculated the three Negroes at Calvert’s request. Whereupon Maximilian Calvert, Cornelius’ brother the Borough Justice, had Dalgleish arrested and imprisoned. A few weeks later, a mob attacked the home of Cornelius Calvert. They then attacked Campbell’s house. They also decided to attack James Parker’s house, but Parker had been forewarned, and he and his friends mounted an armed guard, so the crowd dispersed vowing future violence (Henderson, 1965). These cases ended up in the courts where they went back and forth with disputes over

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jurisdiction for many years. Campbell and Parker’s legal representative was a lawyer called Thomas Jefferson (Najera, 2021). As described in Chapter 5, Virginia first attempted to prohibit inoculation but repealed that law at George Washington’s request in 1777.

Anti-vaccination riots Vaccination using cowpox was a very much safer operation than variolation. The virus was not transmitted, so there was little opposition to the presence of vaccinated individuals in a community. There was however considerable opposition to mandated vaccination. Thus, on occasion, if insensitively or forcibly imposed, civil unrest could break out.

The Montreal vaccine riots of 1885 In Montreal, the largest and most prosperous Canadian city at that time, a major smallpox epidemic broke out in 1885. Smallpox had not affected the city in a major way for almost 100 years and the citizens were quite unprepared (and lacked immunity). The disease appears to have arrived by rail from Chicago that March. The infected individual was a railroad conductor called George Longley who arrived at Bonaventure Station with a fever and covered in pocks. Longley was a Protestant, so he was automatically taken to the Protestant, Montreal General Hospital; he was diagnosed as having smallpox, but the resident physician refused to admit him! As a result, he was obliged to go to the Catholic hospital, the Hotel-Dieu. Here the nuns treated him courteously and admitted him. Longley survived, but his contaminated sheets infected a worker in the laundry room of the hospital. She died on April 2, 1885 and was soon followed by her sister. Smallpox spread through the hospital, so the health department decided to release all patients who did not appear to be sick. Big mistake! The authorities assumed that most of the inhabitants of Montreal had been vaccinated and that the disease had been effectively eradicated. However, the French Canadians living in the city were unhappy under British/Protestant rule. They did not trust the British. They were very suspicious of vaccination and were encouraged in this belief by anti-vaccination campaigners. They tended to live in the poorest parts of towndthe East end, in shabby overcrowded tenements. Anti-vaccination advocates called the vaccinators, “charlatans who were seeking to poison their children.” Anti-vaccinationists pulled down quarantine warning signs. As a result, the disease spread across the city. Bodies were soon being carried in a continuous stream to the cemetery. Attempts to force vaccination on the unwilling citizens were resisted (Berman, 2021). Several cases of erysipelas (a Staphylococcal skin infection) developed after vaccination suggesting that a bad batch of vaccine had been employed.

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As a result, the vaccination program had to be suspended from May to August 1885. Unfortunately, the epidemic worsened over the summer so that by the end of September there were estimated to be about 4000 cases in the city. In late September, the sanitary police began to force people into isolation. On September 28, the Montreal Board of Health announced that vaccination was to be made compulsory. On that same day, the city council cut the vaccination appropriation from $5000 to $2000. Three French-Canadian Aldermen announced that the city was on the eve of a riot. They were correct. At 7 p.m. on the evening of September 28, 1885, a mob estimated at 2000e3000 attacked the east end branch office of the Board of Health Building, smashing its windows and completely wrecking it. They then attacked the Central Police Station. The chief of police was stabbed and stoned but survived. They smashed the windows. The police fired over the heads of the crowd only to be received with jeers and laughter. The crowd was dispersed by baton-wielding police, but the mob dispersed and attacked other buildings. They attacked the Health Office in Montre´al City hall injuring some inside with thrown stones. The residence of the Health Officer, Dr. Laborge, was also attacked. Once the police arrived, the mob were driven away but continued to riot so that streetlamps and police station windows were smashed. Pharmacies that sold vaccines were attacked. The next day 1400 troops were brought in to restore order. The sanitary police were issued with revolvers. Much of the mob’s anger was also driven by nationalist fervor and antiEnglish sentiment, since a rebellion among the French-Canadian Metis in Manitoba under the leadership of Louis Riel had been crushed that summer and Riel had been sentenced to death that September. The smallpox epidemic finally ended in November. It had killed more than 5864 people (about 2% of the population) and infected another 13,000. Ninety percent of the victims were French-Canadian. Most were children under 10 years of age. Dr. Alexander M. Ross (1832e97) was a physician and the Editor of The Antivaccinator. (Ross, Wikipedia). He was very much opposed to vaccination, insisting instead on strict sanitation and quarantine. In 1885, Ross founded the Canadian Anti-Vaccination League. He considered that compulsory vaccination was an abuse of human rights. Ross also publicly asserted that vaccination was “useless and dangerous.” “Rather than protecting patients from smallpox it actually produces it’s like.” Ross claimed that vaccination was “a fearful engine of destruction and death to children.” As the 1885 epidemic progressed, Ross circulated many pamphlets that urged refusal, derided the vaccinated “as driven like dumb animals,” and insisted categorically that “vaccination does not prevent smallpox in any cases.” (Interestingly, in 1885, Ross left Montreal and took a train into Ontario. Quarantine inspectors examined him and found a recent vaccination scar on his arm! The newspapers of the day made much of this although Ross denied having been vaccinated. The Kansas State Board of health in 1885 claimed that Ross had also had his children vaccinated.) Ontario passed a Vaccination Act in 1887 requiring that all parents have their children

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vaccinated by 3 months of age and revaccinated every 7 years (Berman, 2021). The Anti-vaccination League of Canada was founded in 1900 in response to the Ontario Vaccination act (Arnup, 1992).

The Milwaukee riots of 1894 One ongoing problem with vaccination in the United States was the debate on whether to make it compulsory. Sometimes, the debate could get violent. For example, Milwaukee was typical of many American cities in the 19th century since it suffered from recurrent smallpox epidemics. A major such epidemic broke out in the city in late 1894. This was a time, as discussed elsewhere, when smallpox cases were diminishing but had not been eliminated while antivaccination sentiment had grown significantly in some segments of the healthcare industry. While most physicians supported vaccination, some thought that it provided inadequate protection while the anti-vaccinationists alleged that it was more harmful than the disease itself (Leavitt, 1976). The epidemic started gradually (Stefanik, 1970). The first case, in the 6year-old daughter of a Polish family, was diagnosed and the child immediately moved to the City’s Isolation Hospital. By that night, there were six smallpox patients in the Hospital. On June 9, the first death was reported, an old man from the Soldiers Home. Alarm began to spread. The Milwaukee Public Health Commissioner tried to reassure the public. By June 2, there had been only 18 cases of smallpox and only two deaths. However, the authorities began to suspect that not all cases were being reported. Vaccination was available to those that wanted it, but such was the suspicion of the medical authorities that relatively few Polish and German immigrants chose to be vaccinated. The riots continued throughout the month of August as the mob protested the Health Department rules. For example, there was another riotous night in the South Side on August 9 involving 4000 rioters when five policemen were seriously injured in addition to several other citizens (New York Times, August 10, 1894). The epidemic ended in early 1895 after 894 cases and 244 deaths. These riots did not appear to primarily involve mandatory vaccination. The rioters were more concerned about quarantine and conditions in the local smallpox hospital. It is of interest to note that when smallpox broke out again in Milwaukee in 1925, the Public Health Department took a much more conciliatory stand, relying on public education and fear of the disease to promote voluntary vaccination. This cooperative approach worked well, and vaccination was both widespread and effective.

The Laredo smallpox riots, 1899 Smallpox broke out in the Texas border town of Laredo in October 1898. By the end of January 1899, more than 100 cases of smallpox had been reported.

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The State of Texas Medical Officer, Dr. Walter T. Blunt, began taking measures to control the epidemic. These included house-to-house vaccination and fumigation. Any contaminated material that could not be fumigated was ordered to be burnt. He established a quarantined field hospital (the pesthouse). The control efforts focused largely on the poorer areas of the city located along Zacate Creek. Nevertheless, the epidemic worsened. On March 16, Blunt arrived from Austin to take charge of the control efforts. Residents began to resist the forced vaccinations and fumigations. Blunt called in the Texas Rangers to help the medical teams (Cue´llar, 1995). The Texas Rangers had long had bad relations with the Mexican American community in South Texas. Where the Rangers met resistance, they broke down doors, removed the occupants by force, and moved those suspected of having smallpox to the pesthouse. Protesters gathered and in addition to shouting abuse, the mob hurled rocks and stones at both Rangers and health officials. The Rangers shot back. One ranger was hit on the head by a rock and one protester was shot in the leg (Webb, 1965). Having been warned about an order placed for 2000 rounds of buckshot, the next day, the Rangers searched the neighborhood for the hidden ammunition. A gun battle erupted with one Ranger wounded and a suspect killed. An angry crowd of about 100 gathered around the body. Abuse and taunts were thrown. Someone in the crowd shot at the Rangers. They returned fire killing one more person and wounding seven. The next morning, March 21, the Rangers called in the Cavalry. The Tenth US Cavalry moved in, patrolled the streets, arrested troublemakers, and as a result the situation quieted rapidly. The epidemic continued through March but improved in April to such an extent that the quarantine was lifted on May 1, 1899 (Cue´llar, 1995).

Some British riots The Seven Wise Men of Keighley Following the great smallpox pandemic of 1871e74, it was felt in British Government and medical circles that the law of 1853 had not been sufficiently enforced. As a result, steps were taken to enforce the law more vigorously and increase the penalties for noncompliance. During the 1870s, however, several Boards of Poor Law Guardians were reluctant to enforce the law, especially in communities where there was significant opposition to vaccination. As a result, some Guardians chose civil disobedience. For example, in 1876, seven of the Poor Law Guardians in the Yorkshire town of Keighley refused to implement the law. They had been elected a year previously on an antivaccination platform. They were arrested by the police, but this provoked a large mob to gather in the streets of the town. The Times claimed that the aim of the crowd was to rescue the offenders. They were taken by the police to the railway station bound for prison in York (Durbach, 2004). However, their carriage was surrounded by the mob, who released the horses and dragged the

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carriage with the prisoners inside, “back into town”! The Times went on to report that several of the police offices “were maltreated and had their clothes torn from their backs.” Eventually, the police were forced to let the Guardians return home after promising to turn themselves in once the commotion had subsided. Keighley remained in a state of unrest for the remainder of that day. The seven Guardians surrendered to the police the next morning and were escorted to the train station by a number of well-known anti-vaccinators. A large crowd had gathered at the station who cheered them loudly as they left. They were imprisoned in the debtor’s prison in York castle for a month before being released on bail. They appeared in court several months later where they refused to renounce their anti-vaccinationist views but did promise not to obstruct the compulsory vaccination program. They oversaw the distribution of poor relief, but they had refused to enforce the vaccination acts that mandated vaccination by 3 months of age. These Guardians became national heroes. The “Seven Wise Men of Keighley” played a key role in fueling the anti-vaccination sentiment of the 1870s in England.

The Charlbury anti-vaccination riots Charlbury is a small town located about 12 miles to the northwest of Oxford (Charlbury, 1897). Like every other English town at the time, vaccination of infants was routine, and the town’s vaccination officer ensured that all were vaccinated, and if not, was empowered to issue fines to offending parents. In late 1896, 10 parents refused to have their children vaccinated and also refused to pay the fine of 13/6d. As a result, in early 1897, the police turned up at their homes, seized their furniture with the intention of selling it at auction. On February 3, the police brought in an auctioneer from Oxford to conduct the sale. The news spread through the town, bills were posted advertising “A meeting to protest against Modern Slavery,” and a large crowd of protesters gathered at the location where the first auction was to be held. Led by Arthur Phelps, the President of the National Anti-Vaccination League and a brass band, the crowd gathered. As the auction began, the band began to play “Rule Britannia” as loudly as they could, completely drowning out the auctioneer! Giving up, the auctioneer then moved to the next locations on his route where the procedure was repeated. At various houses he tried to auction off various items seized from the offender’s homes but was drowned out by the brass band, the singing protesters, and banging on metal sheets. The crowd also proceeded to throw rice, flour, eggs, and mud at the auctioneer. One bag of flour got him on the head, much to the crowd’s amusement. Eventually, the auctioneer made his way back to the local police station and fled out the back door back to Oxford. None of the articles had been sold and so were returned to their owners. That evening, the protesters continued to party where they lit a bonfire and burnt effigies of the auctioneer and of one man who had attempted to bid at the

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auction. At the Oxford Assizes that summer, 19 men were charged with riotous assembly and conspiracy to defeat the course of justice. They pleaded guilty but were bound over to keep the peace (probation) (Charlbury, 1897).

The vaccine rebellion, Brazil, 1904 At the beginning of the 20th century, Rio de Janeiro, then the capital of Brazil, was an overcrowded, impoverished, and disease-ridden city (Vaccine Revolt, Wikipedia). As a result, in October 1904, the Brazilian Congress approved a Mandatory Vaccination Law. This authorized sanitary brigade workers accompanied by the police to enter homes and apply the vaccine by force. This caused great outrage. The press reported the risks of the vaccine. There were rumors spread that the vaccine would require women to undress. While most of the objections centered on the individual’s ability to control what entered their body, there was still some debate at that time regarding the efficacy of smallpox vaccination. On November 5, the opposition parties created the Liga Contra a Vacina Obrigato´ria. The group originally consisted of politicians, some journalists, members of the military, joined by trade unionists. One member, on leaving a meeting argued with a police officer and was promptly arrested. Witnesses besieged the police station to which the men were taken and began to fight with cavalry officers brought in to control the growing mob. The vaccination law was to take effect on November 11. From November 10 to 14, Rio descended into violence and chaos. Shops were looted, trams were burned and overturned, barricades were set up, while the mobs attacked federal troops with rocks, sticks, knives, and guns. Rioters cut the water and gas mains. The revolt reached a peak on November 14 when cadets from the Military College of Praia Vermelha mutinied and tried to overthrow the government. They attempted to march on the Presidential palace but were arrested. The government suspended mandatory vaccination and declared a state of siege. By November 16, all municipal transportation had come to a halt. Eventually, the rebels were driven out, and there was significant brutal fighting, but by November 18, the rebellion was effectively suppressed. The forced vaccination program was suspended for the time being. Smallpox continued to affect the city and an especially severe epidemic occurred in 1908. As a result, mandatory revaccination was reintroduced the following year.

Coronavirus vaccine protests The global Coronavirus pandemic that broke out in China in November 2019 (COVID-19) prompted the rapid development of several effective vaccines. Several such vaccines were approved in late 2020 and governments around the world hastened to get them into use. There was a special urgency about healthcare workers since hospitals, especially intensive care facilities, were

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being overrun by seriously ill patients. Staff were grossly overworked, and the problem was compounded when the healthcare workers themselves began to sicken as well. As a result, many governments enacted healthcare vaccine mandates. As in other vaccine situations, most workers were happy to be vaccinated. However, a small proportion of this, and other groups, were opposed. Their prime concerns were the personal liberty, and bodily integrity issues. But there were others who felt that the new vaccines had been hurried onto the market with insufficient safety testing and a lack of concern for potential long-term adverse events. Opposition to vaccine mandates also happened to coincide with the deep political divisions affecting Western countries. By July 2021, a small number of private businesses enforced mandates for both employees and customers. Thus, some restaurants required proof of vaccination. Airlines required proof of vaccination. Many private colleges and universities did the same. Some states such as New York and counties such as Los Angeles county mandated vaccines. Some school districts did the same. In September 2021, President Joe Biden announced that the federal government would mandate vaccination for certain entities of the Federal government. In response to the growth of Governmental mandates in the United States and elsewhere large numbers of protests occurred worldwide. The vast majority were peaceful, but a few were highly disruptive and turned violent, European cities such as Paris, London, Madrid, Vienna, Brussels, and Rome, also saw large numbers gather to protest. Ottawa and Melbourne also saw significant protests that resulted in scuffles with the police. The protests varied in their size, the motivations behind them, and the type of protest mounted. The economic disruption caused by COVID-19-related layoffs, a predilection for believing conspiracy theories suggesting that COVID-19 was a hoax, and resentment over what is seen by many over a government plot to control people. In many countries, far-right groups and extreme right-wing politicians were very much involved in the protests, since there is a close correlation between holding populist political views and being opposed to mandatory vaccines and vaccination (Protests, Wikipedia).

References Arnup K. “The victims of vaccination”: opposition to compulsory immunization in Ontario, 1900e90. Can Bull med Hist 1992;9:159e76. Berman JM. When antivaccine sentiment turned violent: the Montreal vaccine riot of 1885. CMAJ (Can Med Assoc J) 2021;193:e490e2. https://doi.org/10.1053/cmaj.202820/tab-relatedcontent. Charlbury, Riots. https://www.darkoxfordshire.co.uk/explore/charlbury-anti-vaccination-riots. Cuellar CE. Laredo smallpox riot. 1995. https://tshaonline.org/about/people/carlos-cullar. Durbach N. Bodily matters: the anti-vaccination movement in England, 1853e1907. Duke University Press; 2004.

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Henderson P. Smallpox and patriotism: the Norfolk riots, 1768e1769. Va Mag Hist Biogr 1965;73(4):413e24. Leavitt JW. Politics and public health: smallpox in Milwaukee, 1894e1895. Bull Hist Med 1976;50:553e68. Najera R.F. Thomas Jefferson and the Virginia inoculation riots. History of Vaccines, 2021; https:// historyofvaccines.org/blog/american-presidents-and-vaccines-thomas-jefferson-and-the-virgin ia-inoculation-riots New York Times. Two smallpox riots in milwaukee. Aug 10 1894. Protests, Wikipedia. Protests against responses to the COVID-19 Pandemic. www.wikipedia.org/ wiki)Protests-against-responses-to-the-COVID-19 pandemic Ross, AM. https://en.wikipedia.org/wiki/Alexander-Milton-Ross. Stefanik RL. The smallpox riots of 1894. Historical messenger. 1970. https://www.marquette.edu/ cgi-bin/cuap.db-cgi?uid¼default&ID¼5982&view-search&mh¼1. Vaccine Revolt, Wikipedia. https://en.wikipedia.org/wiki/Vaccine-revolt. Webb WP. The Texas rangers: a century of frontier defense. Austin: University of Texas Press; 1965. Wehrman AM. The siege of castle pox. New Engl Quarterly 2009;82(3):385e429.

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Chapter 11

The Supreme Court weighs in Over the course of the 19th century, widespread vaccination had resulted in a progressive decline in the number of smallpox cases occurring in the United States and other developed countries. This in turn resulted in a decline in the fear factor and the motivation to vaccinate. Nevertheless, the disease had not been eliminated and the virus could often find sufficient unvaccinated individuals in which to grow and spread. As a result, periodic epidemics continued to occur in the large cities of North America.

Smallpox in Boston In May 1901, smallpox broke out once again in Boston and Cambridge. Between then and 1903, there were 1596 smallpox cases and 270 deaths as a result. Of these cases, 754 individuals had scars suggesting prior vaccination and 82 of these patients died (11%). Among those patients who had no evidence of prior vaccination there were 188 deaths (22%). The city had previously passed a law in 1855 requiring that children had to be vaccinated in order to attend school, and it appeared to be effective in that only 3% of smallpox cases occurred in school-aged children. Immunity conferred by smallpox vaccination does not however last indefinitely. This probably accounts for the relatively large numbers of cases that occurred in previously vaccinated individuals. Many citizens may not have been revaccinated after they received their first dose as young children (Albert et al., 2001). By the fall of 1901, the Boston Board of Health under its Chair, Samuel Durgin, as well as the neighboring Cambridge Board, had both established quarantine hospitals and had initiated a program of voluntary vaccination. They established free vaccination stations and physicians visited commercial businesses to vaccinate their employees. At that time, vaccination employed a glycerinated liquid vaccine inoculated with a bone or ivory “point.” The historical method of using vaccine obtained from humans for arm-to-arm transfer was, by that time, recognized as a way of transmitting other infections. As a result, commercial vaccine lymph was generally produced in the skin of calves maintained for the purpose on commercial “vaccine farms.” However, its production was still unregulated, and as a result, the quality of the vaccine lymph was highly variable. Vaccination still carried with it significant risks including generalized vaccinia if the patient was immunosuppressed, local ulceration or abscess formation, cellulitis, and well as possible sepsis and even tetanus. A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00016-4 Copyright © 2023 Elsevier Inc. All rights reserved.

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By December 1901, over 400,000 Bostonians had been vaccinated, but the disease persisted. In that year, there had been 773 cases and 97 deaths (Parmet et al., 2005). As a result, the Board of Health initiated compulsory vaccination beginning in January 1902. Any inhabitant that had not been successfully vaccinated since January 1, 1897 was required to be vaccinated or revaccinated. The Board initiated an aggressive program of house-to-house vaccination. The vaccinators were instructed to vaccinate all who were willing and not too ill. They were told. “Do not use force. Clean the skin first. Make two scarifications but do not make the patient bleed. Rub the lymph well into the wound and let it dry. Warn the patient against rupturing any vesicle that forms or otherwise injuring the site.” Accompanied by guards, the vaccinators descended on the railroad yards and forcibly vaccinated all the employees they could find. As the epidemic persisted, there was a growing belief that the disease was persisting in and being spread among the homeless. There was a sense that the homeless and destitute were escaping vaccination. As a result, in November 1901, the Board of Health ordered “virus squads” to find and vaccinate men living in cheap rooming houses. A reporter for the Boston Globe described the mayhem that resulted. “Every imaginable threat from civil suits to cold-blooded murder was made by the writhing, cursing, struggling tramps who were operated upon, and a lot of them had to be held down on their cots, one big policeman sitting on their legs, and another on their heads, while the third held the arms, bared for the doctors.” One “fighting tramp” who “went down in a heap on the floor” from the blow of a policeman’s club received both vaccination and suturing of his scalp. In hearings on compulsory vaccination, opponents alleged that in Massachusetts, Boards of Health “in many cases had acted with autocratic power and forcibly assaulted persons to vaccinate them.”

Anti-vaccination sentiment As expected, the Anti-compulsory Vaccination League severely criticized the Board of Health for its actions. The Board members, in turn, considered Boston to be practically a “hotbed of the anti-vaccine heresy.” Their opponents always questioned both its safety and efficacy. Anti-vaccination organizations selectively focused on the adverse effects of vaccination. They cited alleged cases of death and deformity. They called compulsory vaccination “the greatest crime of the age.” They claimed that it “slaughters tens of thousands of innocent children.” They also considered compulsory vaccination to be a violation of their civil liberties. As a result of their agitation, in January 1902, legislation was introduced in the Massachusetts Legislature repealing the state’s compulsory vaccination

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laws. The opponents of vaccination testified on behalf of the repeal legislation. On the other side, arguing for vaccination included prominent physicians, educators, and business leaders. Professors from Harvard and the President of the Massachusetts Medical Society also opposed repeal. The proposed antivaccination bill failed to pass. This failure led subsequently to the US Supreme Court.

The Pfeiffer affair The anti-vaccination campaigners persisted in their efforts. Samuel Durgin, the chairman of the Boston Board of Health, grew frustrated. He decided to call their bluff by issuing a challenge. Were any of them sufficiently confident in their theories that they were willing to expose themselves to smallpox? He made an announcement in the Boston Globe wondering whether there were any adult anti-vaccinationists who would like an opportunity to demonstrate “the sincerity of what they profess.” He declared that he was willing to make the necessary arrangements for them to be exposed to smallpox without vaccination. He probably didn’t expect anyone to take him up on his offer, but 60-year-old, Dr. Immanuel Pfeiffer did so. Pfeiffer believed that diet, exercise, and hygiene were sufficient to ward off the disease. He claimed that people in good health were not at risk. Pfeiffer asked for permission to visit the smallpox hospital on Gallops Island in Boston Harbor. Durgin gave him permission even although he knew that Pfeiffer had not been recently vaccinated (Klein, 2021). On January 23, 1902, Pfeiffer traveled by steamer to Gallops Island. He was given a tour of the hospital and made a point of inhaling the breath of some of the sickest patients. After returning to the city, Pfeiffer traveled on trains and attended several meetings. Durgin had arranged to have him followed, but 11 days later Pfeiffer vanished! The search began. It appears that a sick Pfeiffer had gone to his family’s farm in Bedford. On February 8, the Public Health officials descended on the farm and charged up the stairs to find Pfeiffer seriously ill with smallpox! The Health officials posted guards and isolated the farm including Pfeiffer and his family for 5 weeks. Eventually he recovered. The press savaged Pfeiffer. “Pfeiffer has smallpox. Anti-vaccionationist may not live!” said the Boston Herald. The Herald called him “the victim of his own folly and professional vanity.” The Philadelphia Medical Journal called his illness “poetic justice.” Durgin’s ploy had worked. The day after Pfeiffer’s illness hit the newspapers, 130 Board of Health doctors descended on under-vaccinated parts of the city and vaccinated 12,000 individuals. They met with very little objection. Pfeiffer had helped enormously. Any holdouts were simply asked. “Did you read about the man who wouldn’t get vaccinated and is now dying of smallpox?” Durgin was also criticized for endangering the public and letting unvaccinated Pfeiffer visit the hospital, but he did not regret his decision. However,

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the Pfeiffer episode was yet another trigger for the Jacobson versus Massachusetts case that went ultimately to the Supreme Court. The epidemic ended in March 1903. Sporadic cases followed and the last case of smallpox in Boston occurred in 1932. The establishment of vaccine mandates in both the UK and the US led inevitably to pushback. Much of this pushback was of a legal nature but a series of case decisions by American courts established that vaccination mandates were lawful and could be enforced. The most significant of these cases was Jacobson v Massachusetts that was argued in December 1904 and decided in February 1905.

Jacobson v Massachusetts In the midst of the 1901e02 smallpox epidemic, on January 1, 1897, the Cambridge City Board of Health mandated that everyone in the city who had not been vaccinated within the previous 5 years should be vaccinated or revaccinated. Anyone over 21 who refused vaccination was fined $5 or 15 days in jail (Worth about $150 today). The mandate provided an exception for children with a doctor’s certificate. The Anti-Compulsory Vaccination League took the city to court. The plaintiff in this case was a Swedish Pastor, Hemming Jacobson, had been born in Yllestad, Sweden, in 1856. He had migrated to the United States in 1870. He served as the founder and pastor of the Augustana Lutheran Church in Cambridge. His home country, Sweden, had made strenuous efforts to control smallpox by requiring mandatory vaccination. Thus, when Jacobson was a child, he had been vaccinated against smallpox. He claimed that it had caused him “great and extreme suffering that he would have to endure for the rest of his life.” He also reported that one of his sons had also suffered severe adverse effects after being vaccinated as a child. As a result, Jacobson and his wife strongly resisted the mandatory vaccination order imposed by the Cambridge Board of Health. When, on March 15, 1902, the chairman of the Cambridge Board, Dr. Edwin Spencer knocked on his door, Jacobson refused the vaccine for both him and his son claiming that it was an invasion of their liberty. As a result, he was fined $5, and the court ordered him held in custody until the fine was paid. (They were not “forced” to receive the vaccine.) Jacobson maintained that the state was restricting his liberty. On July 17, 1902, another criminal complaint was issued against Jacobson and three other vaccine activists including a city clerk called Albert Pear. They were each fined $5 by the Middlesex County District Court and appealed first to the state trial court and then to the Massachusetts Supreme court. Jacobson was represented by two eminent lawyers, Henry Ballard of Vermont and James Pickering. Pickering was associated with the Anti-vaccination League and was a neighbor of Immanuel Pfeiffer. It is likely that Jacobson’s persistence in the courts stemmed from the ardent support of Pickering and the anti-vaccination movement. Jacobson

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wanted to produce evidence that the vaccines were both dangerous and ineffective. The judges rejected that argument and sided with the authority of Public Health officials. After losing his case in the Massachusetts Supreme Court, Jacobson appealed to the US Supreme Court (Justia, 1905). In his brief to the Supreme Court, Jacobson asserted that the state was restricting one aspect of his liberty by forcing him to get vaccinated. He asserted that this was contrary to his rights under the 14th Amendment to the Constitution. This Amendment prohibits the states from depriving “any person of life, liberty, or property, without due process of law.” Was the right to refuse vaccination among those protected personal liberties? Jacobson also argued that the law was “arbitrary or oppressive.” Jacobson also claimed that smallpox vaccination did not work and could cause further disease. We have on our statute book a law that compels ... a man to offer up his body to pollution and filth and disease; that compels him to submit to a barbarous ceremonial of blood poisoning, and virtually to say to a sick calf, Thou art my savior: in thee do I trust ..” Brief of the Defense, Commonwealth v Jacobson, 183 Mass. 242 (1903)

Jacobson’s lawyers ended their brief by asking “Can the free citizen of Massachusetts, who is not yet a pagan, nor an idolator, be compelled to undergo this rite, and participate in this new, - no, revived-form of worship of the sacred cow?” The State countered by arguing; first, that they were justified in restricting individual liberty. Under the pressure of great dangers to the safety of the general public. They also argued that mandatory vaccination in the face of an epidemic is neither arbitrary nor oppressive but a measure for achieving the goal of eradicating smallpox. Jacobson lost the case. The justices voted 7 to 2 in favor of Massachusetts. Justice John Marshall Harlan delivered its decision on February 20, 1905. The Court firmly rejected Jacobson’s claim that the 14th Amendment gave him the right to refuse vaccination and upheld the right of the city of Cambridge, Massachusetts, to mandate vaccination against smallpox. Primary holding: In Harlan’s opinion, the justices declared that the state legislature could, at times, suspend personal liberties and require vaccination if in their opinion, it was the best way to protect the public health and safety from a dangerous communicable disease. The states had the authority to enact “Health laws of every description to guard the common good in whatever way the citizens, through their elected representatives, thought appropriate.” An individual objector could not stand in the way of this. They also found that the legislature could exempt children if it treated all adults equally. Harlan observed that state public health laws could not be arbitrary or oppressive. They noted that the rising prevalence of smallpox in the city meant that the rule was clearly relevant to maintaining public health. Harlan further noted

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that the majority of medical opinion held by most reputable doctors for many years was that the vaccine was effective and that the benefits vastly outweighed the risks of injury. Harlan stated his vision of the role of the individual. “The liberty secured by the Constitution of the United States to every person within its jurisdiction does not import an absolute right in each person to be, at all times and in all circumstances, wholly freed from constraint. There are manifold restraints to which every person is necessarily subject for the common good. On any other basis organized society could not exist with safety to its members. Society based on the rule that each one is a law unto himself would soon be confronted with disorder and anarchy.” Harlan went on to state that the compulsory vaccination law was consistent with what the Massachusetts constitution had laid out as a “fundamental principle of the social compact that the whole people covenants with each citizen and each citizen with the whole people.” In effect, Jacobson v Massachusetts was consistent with a broad pattern of the 19th-century laws and regulations. Freedom of the individual must sometimes be subordinated to the common welfare. The community has a right to protect itself against disease. Harlan wrote that the punishment of a fine or imprisonment on those who refused vaccination was acceptable, but importantly, declared that individuals must not be forcibly vaccinated. He warned against the state targeting specific individuals or populations. He also noted that under some conditions, such as the state of the person’s health, vaccination of some individuals would be cruel and inhumane and as such, an overreach of government power. In effect, Harlan created a medical exemption for some individuals, but Harlan specifically denied that Jacobson deserved exemption. The court also asserted that the police could enforce it. One paradoxical effect of this ruling was the further growth of the antivaccine movement in the United States (Jacobson, Wiki). The Antivaccination League of America was founded in Philadelphia in 1907. It sought to promote the principle that “health is nature’s greatest safeguard against disease and thus no state has the right to demand of anyone the impairment of his or her health.” This case also established the terms by which Public Health ethics were established in the United States. It has served as the precedent in the numerous cases that have been brought challenging mandatory vaccination laws including vaccination against COVID-19. In hundreds of legal decisions, the ruling has been cited in reference to the authority of the states to constrain individual behavior. These cases have ranged from fluoridation of municipal water supplies to abortion and the right to die. Notoriously, it was invoked by the Supreme Court in the 1927 case of Buck v Bell. That decision upheld a Virginia forced sterilization law. Obviously that decision was highly problematic. The case involved key constitutional issues that reflect the tensions between individual rights and the common welfare (Mariner et al., 2005).

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Zucht v King In a subsequent case, Zucht v King et al. in 1922, the Supreme Court reaffirmed their 1905 decision and ruled unanimously that a school district had the power to exclude unvaccinated students from both public and private schools (Justia, 1922). The city of San Antonio, Texas, in 1914, had enacted an ordinance that prohibited any child from attending a public school or another place of education without first presenting a valid certificate of vaccination against smallpox. As a result, a Texas student, Rosalyn Zucht aged 9, who refused to receive the vaccine, was prevented from attending both public and private schools. Zucht’s parents sued the members of the school board (King et al.) complaining that there was no current smallpox emergency requiring such vaccination and that, as a result, she was deprived of liberty without due process as a result of compulsory vaccination. The Texas State courts denied her claims and as a result they appealed to the US Supreme Court. Her lawyers argued that the school district’s ordnance requiring proof of vaccination denied the student “equal protection under the laws” as guaranteed by the 14th Amendment. The opinion of the court was brief and to the point. Justice Brandeis wrote the opinion and the decision in November 1922 was unanimous. The court noted that in the previous case of Jacobson v Massachusetts, the Court “had settled that it is within the police power of a state to provide for compulsory vaccination.” The court found no reason to question the fairness with which the San Antonio ordinance had been applied and indeed found that the ordinance reflected the discretion needed by the authorities to protect the public health. The court noted that the plaintiff had asserted an equal protection violation but had not articulated any discrimination that would prove such a claim (Flanagan-Klygis, 2003).

Prince v Massachusetts In 1944, the Supreme Court further ruled that the Government has broad authority to regulate the actions and treatment of children. “Neither rights of religion nor rights of parenthood, are beyond limitation” (Justia, 1944). Parental authority is not absolute and can be restricted if necessary for the child’s welfare. Thus, for example, states may require school attendance or regulate child labor. This specific case involved a young child being forced by her guardians to sell magazines on the street and thus violated child labor laws. While this case did not specifically involve vaccination mandates, the court did cite Jacobson v Massachusetts as an example of governmental authority. Because they did so, Prince v Massachusetts has also been cited by courts upholding the constitutionality of vaccine mandates. “The right to practice religion freely does not include liberty to expose the community or the child to communicable disease nor the latter to ill-health or death.”

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O’brien v Cunard Prior to the Supreme Court’s Jacobson v Massachusetts decision, two interesting lawsuits regarding vaccination and associated damage had been decided in Boston in 1890. In the first, Mary E. O’Brian sailed from Cobh (Queenstown) in Ireland to Boston in 1889 as an immigrant to the United States. They sailed on a steamship, the “Catalonia” operated by the Cunard Shipping Company. She alleged that prior to arrival, the shipping company vaccinated her against her will. She and her family had traveled Third Class with about 400 other passengers. Shortly before they disembarked from the vessel on July 15, she and about 200 other women were vaccinated by the ship’s doctor. As a result, O’Brien claimed that she suffered from “blood poisoning, sores and humors.” She alleged that the vaccine had been contaminated. She testified that she had told the doctor that she had already been vaccinated and “did not care to have it done again.” However, when the ship’s doctor examined her arm, he could not identify a vaccination scar. The doctor, James Giffin, pointed out that by law, she had to be vaccinated if she wanted a landing certificate and promptly vaccinated her. As a result, O’Brien claimed that she had been assaulted as well as injected “with impure virus” and sued Cunard for $10,000 (Today worth $1.7 million) (Casey, 2022). The defense pointed out that the US Quarantine Authorities required the vaccination of all immigrants. If it was not performed by the ship’s doctor, it would have had to be performed by the port physicians before any individual was permitted to land. They denied that their vaccine was contaminated. The court ruled in favor of Cunard and O’Brien’s attorney immediately appealed. The new case accused Cunard of assault and medical negligence. Experts were brought in to testify. Most physicians simply averred that this was a normal reaction to vaccination they called “vaccine disease.” One suggested that Mary may have had an autoimmune skin disease, called pemphigus. Federal law required ships such as the Catalonia to have a physician. State law required steerage passengers to have certificates of vaccination. Again, the court sided with Cunard.

Maricopa County v Harmon In 1987, the Arizona Court of appeals rejected the claim that an individual’s right to education trumped the state’s need to protect students from infectious diseasesdin this case measles. Given the relative slowness of measles diagnosis at that time, the court ruled it prudent that the state should require vaccination where there is a reasonably perceived risk of disease. The court did not require that epidemics should exist before compelling vaccination.

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Vaccine compulsion From October 1990 to June 1991, a measles outbreak swept through Philadelphia resulting in over 1400 cases. Nine children died. The outbreak began when an infected teenager, recently returned from Spain, attended a rock concert. Within days, over 100 additional cases had developed. A CDC investigation showed that six of the children who had died were associated with two fundamentalist Christian churches, five from Faith Tabernacle Congregation, their church-run school, in North Philadelphia, and one from First Century Gospel Church in Juniata Park. Both were faith-healing congregations that refused both vaccination and medical care. If their members fell ill, then the congregation prayed for them. Sick children were not taken to hospital to be treated for measles pneumonia. One church member is quoted as saying, “If I go to God and ask him to heal my body, I can’t go to a doctor for medicine. You either trust God or you trust man.” In the absence of medical treatment, the children’s fatality rate was unusually high (Their case fatality rate was 1.2% compared to an expected rate of 0.3% in the United States as a whole.) (Rogers and Atkinson, 1993). The city therefore obtained an order from a Family Court Judge permitting them to examine the children in their homes and if necessary, send them to a hospital for medical care. They also obtained a court order to vaccinate children against their parent’s will! Three families appealed this ruling saying that “their religious abhorrence of medical treatment outweighed concerns about protecting three boys and two girls from a measles epidemic.” On appeal, the State Superior court judge said, “Society does put limitations on religious rights.” The State Supreme Court declined to block the order (LA Times, 1991). Nine children were eventually made wards-of-the-state, vaccinated in the presence of their parents and some grandparents, and immediately returned to their parents. This was despite the existence of a religious exemption for vaccination in the state of Pennsylvania. The pastor of the Faith Tabernacle Church asked the American Civil Liberties Union to take their case to court to fight the compulsory vaccination order. The ACLU declined with the comment from the Philadelphia director that “There is certainly a free exercise of religion claim by the parents.” “But there is also a competing claim that parents don’t have the right to martyr their children” (Offit, 2017).

References Albert MR, Ostheimer KG, Breman JC. The last smallpox epidemic in Boston and the vaccination controversy, 1901e1903. N Engl J Med 2001;344:375e9. https://doi.org/10.1056/NEJM200 102013440511. Casey M. A 19th century Irish anti-vax case. 2022. https://www.irishecho.com/2022/5/a-19thcentury-irish-anti-vax-case.

166 A History of Vaccines and their Opponents Flanagan-Klygis E. School vaccination laws. Virtual mentor 2003;5(11):386e8. https://doi.org/ 10.1001/virtualmentor.2003.5.11.pfor1-0311. Jacobson v. Massachusetts. https://en.wikipedia.org/wiki/Jacobson-v-Massachusetts. Justia J.v. Massachusetts, 197, U.S. 11 (1905). Justia Pv Massachusetts, 321, U.S. 158 (1944). Justia, Zv King. 260, U.S. 174 (1922). Klein CA. 1901 Smallpox epidemic, a charismatic quack, and the rise of anti-vax propaganda in Boston. Globe magazine; 2021. LA Times. Children vaccinated after court order is upheld. AP; March 9, 1991. Mariner WK, Annas GJ, Glantz LH. Jacobson v Massachusetts: it’s not your great-great-grandfather’s public health law. Am J Public health 2005;95(4):581e90. https://doi.org/10.2105/ AJPH.2004.055160. Offit PA. When parents force the Government’s hand on vaccines. Daily Beast; 2017. https://www. thedailybeast.com/When-parents-force-the-governments-hand. Parmet WE, Goodman RA, Farber A. Individual rights versus the Public’s health e 100 years after Jacobson v Massachusetts. N Engl J Med 2005;352(7):652e4. Rogers DV, Atkinson WL. High attack rates and case fatality during a measles outbreak in groups with religious exemption to vaccination. Pediatr Infect Dis 1993;12:288e92.

Chapter 12

The rise of anti-vaccine societies in Britain Early resistance to Jenner’s smallpox vaccination did not result from the efforts of an organized movement but was generated by relatively few jealous, engaged, and enraged individuals. This was especially the case when vaccination was entirely voluntary, and an individual could decide for themselves and their families whether or not to undergo the procedure. Thus, as described previously, some individuals had religious objections to vaccination and believed that it was inappropriately thwarting God’s will. Others were aware of the potential for severe adverse events, especially in an era when hygiene was unknown and as a result had a not unwarranted distrust of medicine as practiced at that time. These individuals generally remained quiet and were left in peace. All that changed once vaccination mandates were imposed (Fig. 12.1). Smallpox persisted in British towns. In the epidemic that occurred in 1838e40 almost 42,000 persons died. About half of these deaths occurred in London and 24 large towns. It accounted for about 10% of overall deaths but Anti-compulsory Vaccination National League Anti-compulsory 1867 Vaccination League Anti-vaccination 1874 London League Society 1853 1880 1850 1860 1870 First Second Vaccination Vaccination Act Act 1867 1853

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National Anti-vaccination League 1896 1890

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Tebb visits Royal New York Commission on 1879 Vaccination Mass Leicester Protest 1885

1910 Abolition of Compulsory Vaccination 1907

FIGURE 12.1 Timeline showing the progressive changes in British anti-vaccination societies over the 19th century. The arrows denote progressive changes largely reflected by alterations in the name of the league as a result of changes in leadership. A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00018-8 Copyright © 2023 Elsevier Inc. All rights reserved.

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up to 80% of deaths in children under 5 (Fig. 6.2). As a result, the Government decided that some action was necessary (Williams, 1994). Once the efficacy of smallpox vaccination had been proven, successive British Governments felt obliged to ensure that everybody was vaccinated with the praiseworthy goal of eliminating the disease from the country. As a result, over the course of the 19th century, the British Parliament passed a series of laws mandating vaccination. Each of these laws tended to be progressively more draconian. Each subsequent law was largely designed to eliminate loopholes, maximize enforcement, and increase the penalties for those who refused vaccination. Each such law triggered progressively greater opposition from increasingly organized anti-vaccination associations. The first Vaccination Act passed in 1840 provided free vaccination for the poor and outlawed inoculation. It did not mandate vaccination but simply encouraged it. As noted previously, it was of limited effectiveness since the vaccines were provided for free by the Poor Law Guardians and as a result were directed primarily at the most impoverished citizens and orphans. It did not elicit significant opposition, but a stigma was associated with the procedure and the middle- and upperclasses stayed away from the workhouses where it was performed.

The Anti-Vaccination League of 1853 The Vaccination act of 1853 marked a new milestone in the history of vaccines since it required that all children born after August 1, 1853 be vaccinated against smallpox before reaching the age of 3 months. Parents who failed to do this were liable to a fine or imprisonment. It worked. By the 1860s, about twothirds of children had been vaccinated and smallpox cases had begun to decline. However, the Act was highly controversial and triggered significant opposition (Larsson, 2021)! The first Anti-Vaccination League was founded in London that same year by Richard Butler Gibbs of Finsbury, together with his brother George and his cousin John Gibbs, a hydropathic healer and vegetarian. John Gibbs believed that the problem was not just the “beastly” origin of the bovine lymph which he objected to as a vegetarian. He was also incensed by the fact that the Medical Establishment had colluded with the Government, and in his mind had acquired state sanction for a procedure whose safety, efficacy, and scientific standing had yet to be established. John was the author of their first anti-vaccination pamphlet “Our Medical Liberties” published in 1854. In it he said, The Compulsory Vaccination Act, while dishonouring science, invades in the most odious, tyrannical, and speaking as a Briton, unexampled manner the liberty of the subject, and the sanctity of the home; unspeakably degrades the free-born Briton not only in depriving him of liberty of choice in a personal matter, but even in denying him the possession of reason ..

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It should be pointed out at this stage that the predominant medical belief at the time was that diseases such as smallpox were spread by airborne pollutiond miasmas. It was also understood that the seeds of the disease were present from birth in most individuals. The miasmas simply caused the release of these seeds. Thus, the argument that the infected individual was the source of infection for others was not widely held and could not logically therefore be used to support mandatory vaccination. It is also relevant to note that in addition to the Vaccination Acts, Parliament passed Contagious Diseases Acts in 1864, 1866, and 1869. These allowed physicians to forcibly inspect the bodies of women suspected of being prostitutes for evidence of venereal disease. If present, a woman could then be confined to a hospital for treatment without her consent. Similar Acts were passed in 1889 and 1899 permitting tuberculosis patients to be forcibly confined to hospital. Thus, Government mandated compulsory vaccination was by no means the only concern of these “liberals.” Branches of the Anti-vaccination League were gradually established across the country. They were generally led by the upper working classes, tradespeople, some clergy, lawyers, and shop owners. In addition to producing pamphlets against compulsion, they also formed support groups for those that fell afoul of the law. Thus, they helped offenders obtain legal advice and even paid their fines for non-vaccination in some cases. Many were also involved in other social causes including prohibition, vegetarianism, and nonconformist religions. The 1853 Act was a failure insofar as its compulsory aspects could not be strongly enforced. There are few records of individuals being fined for noncompliance although The Times reported in 1859 that a laborer called George Fry was fined the maximum penalty of £1, 18 shillings, and six pence plus court costs for failure to vaccinate his children (Worth almost £200 today!) (Durbach, 2005)..

The Anti-Compulsory Vaccination League of 1867 The second Vaccination Act in 1867 went much further than the first and required that all children under 14 be vaccinated with severe penalties for vaccine refusal. Fines and imprisonment were to be inflicted indefinitely until parents complied (Swales, 1992). As a direct consequence, new antivaccination groups sprang up in cities across Britain. Many were in northern cities such as Birmingham, Leeds, Bradford, Sheffield, Durham, and Manchester. The most important of these was in the town of Leicester where the Anti-Compulsory Vaccination League (ACVL) was founded in that year.

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The ACVL published a Newsletter, the National Anti-Compulsory Vaccination Reporter. Its mission statement began: I. It is the bounden duty of Parliament to protect all the rights of man. II. By Vaccination Acts, which trample upon the right of parents to protect their children from disease, parliament has reversed its function. III. As parliament, instead of guarding the liberty of the subject, has invaded this liberty by rendering good health a crime, punishable by fine or imprisonment inflicted on dutiful parents, parliament is deserving of public condemnation. William Hume-Rothery, President 1878, Anti-Compulsory Vaccination League.

Prosecuted parents formed the bulk of the membership in these AntiCompulsory Vaccination Leagues. However, some eminent intellectuals such as the sociologist Herbert Spencer, the biologist Alfred Russel Wallace, and the playwright George Bernard Shaw were also supporters. These intellectuals deplored what they saw as overreach by the medical profession. One such intellectual leader of the movement was Francis Newman, Emeritus Professor of Latin at University College London and a militant vegetarian. He believed the following that was widely reported: Against the body of the healthy man Parliament has no right of assault, whatever under pretense of the Public Health, nor anymore against the body of the healthy infant. To forbid perfect health is a tyrannical wickedness, just as much as to forbid chastity or sobriety. No lawgiver can have the right. The law is an unendurable usurpation, and creates the right of resistance.

In June 1867, the journal Human Nature began to campaign against The Vaccination Humbug (National Anti-vaccination League, Wikipedia). It asserted that many petitions had been presented to parliament against compulsory vaccination but had been ignored. It also asserted that many children had died as a result of vaccination. “To overthrow this huge piece of physiological absurdity and medical tyranny.” Richard Gibbs, who ran the Free Hospital at the same address, was quoted as saying, “I believe we have hundreds of cases here, from being poisoned with vaccination, I deem incurable.” “We strongly advise parents to go to prison rather than submit to have their helpless offspring inoculated with scrofula, syphilis, and mania.” By 1871, the ACVL had grown significantly and claimed to have 103 branches and over 10,000 members. However, after the death of Richard Gibbs that year, the ACVL languished until it was revived and reorganized under the leadership of William Hume-Rothery and his wife Mary Hume-Rothery. William and Mary Hume-Rothery founded the National Anti-Compulsory Vaccination League (NACVL) in Cheltenham in Southwest England in 1874. Mary Hume-Rothery was a social reformer and just as active as her husband in

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the affairs of the League. (Mary Hume-Rothery, Wikipedia) He was technically the leader; she was technically the secretary but probably much more capable and influential. In that capacity she edited the organization’s magazine. She attributed her anti-vaccination stance to the experience of seeing her own child vaccinated. Mary insisted that neither “the persons of women nor the cradles of infants, nor the sick-room itself” were safe from the tyranny of state-sanctioned doctors (Durbach, 2005). Mary suggested that good citizenship did not mean enforcing public health measures. It entailed respecting the bodies of one’s neighbors (Durbach, 2002). The NACVL prospered for a few years but was not a great success. The Hume-Rotherys were very much upper middle class and as a result, their organization was gradually overshadowed by the London Society whose leaders were more interested in their working-class base (Williams, 1994). After the publication of his book On Liberty in 1859 by the eminent philosopher John Stuart Mill, the principle of “First do no harm” became a common reference point for both pro-vaccinationists and the anti-vaccination community. Mill articulated the harm principle that held that the only justification for the use of coercive state power was to prevent imminent harm to other people. Thus, an individual should be free to make decisions only if their decisions are not harmful to others (Boniolo, 2016). Anti-vaccinationists espoused this principle in both the UK and the USA. Thus, it supported both side’s arguments. As pointed out above, this was an era when diseases were still believed to be caused by environmental miasmas. Consequently, the anti-vaccinationists claimed that people did not spread the disease, but that environmental miasmas did, especially under unsanitary conditions. Conversely, health officials claimed that people that refused vaccination for themselves or their children posed an unacceptable danger to other members of the community and justified state intervention. Anti-vaxxers continued to argue that mandatory vaccination was an unacceptable violation of individual liberty. During the 1870s and 1880s, large numbers of anti-vaccination tracts and books were published in England. These journals included, The Antivaccinator (founded in 1869 by Henri Pitman); The National Antivaccination Reporter founded by the Hume-Rotherys in 1874; and the Vaccination Inquirer founded by William Tebb in 1879. These journals persisted in an ideological fight with the major medical journals of the day, The Lancet (founded 1823), and the British Medical Journal (founded 1840). The fight persists to this day.

The London Society for the Abolition of compulsory Vaccination In 1880, William Tebb reorganized the Anti-compulsory Vaccination League by forming the London Society for the Abolition of Compulsory Vaccination

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(LSACV). With William Young as its secretary, its official organ was “The Vaccination Inquirer” established by Tebb in 1879. It was heavily antivaccination and anti-science. It constantly derided the Public Health Service and battled individual Medical Officers of Health. The London Society focused its activities on lobbying Parliament in the 1880s and 1890s and eventually forced the establishment of the Royal Commission on Vaccination in 1889 resulting in a truly national movement (Williams, 1994). The secretary of the London Society, William Young, stated in an 1886 pamphlet that “Thousands of children are killed annually by vaccination” (Satya-Murti, 2022). This was part of a 17-page booklet he had published against compulsory smallpox vaccination. He used anecdotes to describe a series of 24 such cases. He claimed that compulsory vaccination had maimed or murdered thousands. He even claimed that between 1881 and 1883, one child in every six was directly killed by cow-pox or vaccination. As in so many of these pamphlets his tone was strident and accusatory. Young was also prone to quote eminent physicians out of context. Thus, Sir James Paget, an enthusiastic supporter of vaccination, was quoted as saying “vaccines produce a permanent morbid (though beneficial!) condition of the blood”. (An early concept of antibodies and immunologic memory). The parentheses and explanation point were inserted by Young. In general, any deaths occurring within a few weeks of vaccination were attributed by him to vaccination. Of course, in many cases, these vaccines were administered by poorly trained vaccinators in an era where hygiene was discounted, and cases of secondary infection and sepsis certainly did occur.

The National Anti-Vaccination League of 1896 As smallpox cases declined and anti-vaccination sentiment grew, the influence of the London Society progressively overshadowed the National party and the Hume-Rotherys. As a result, it was re-structured in 1896 as the National AntiVaccination League (NAVL). Its president was Arthur Phelps, and its secretary was Lily Loat (Loat, Wikipedia). Lily worked for the League for nearly 50 years until she died in 1958. The League had published its journal Vaccination Inquirer and Health Review since 1880 and only ceased publishing new issues of its magazine in 1972. In 1951, Loat published a small book The Truth about Vaccination and Immunization that summarized the arguments of the antivaccinationists.

George Bernard Shaw In 1906, the Irish playwright George Bernard Shaw wrote a supportive letter to the NAVL equating methods of vaccination with “rubbing the contents of the dustpan into the wound” (Dukore, 2020). He had a heated correspondence with the British Medical Journal in which he declared “the old Jennerian claim that

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infant vaccination protects for life (is) obsolete.” He was correct. In 1944, he claimed in another letter to the Irish Times that “more people are now killed by vaccination than by smallpox” (Lannelli, 2016). He called the British Medical Journal “bigotedly vaccinist” in a letter to the BMJ in October 1902 (Shaw, 1902). He also asserted that “vaccination is nothing short of attempted murder” (Lannelli, 2016).

Alfred Russel Wallace The eminent biologist, Alfred Russel Wallace was also drawn into the debate over mandatory smallpox vaccination. His initial concern was that for individual liberty. “Every day the vaccination laws remain in force, parents are being punished, infants are being killed.” Wallace cited statistics from a report by the Registrar General showing that an average of 52 individuals died each year from complications resulting from vaccination. Pro-vaccinologists of course, countered with other statistics showing how the numbers of smallpox deaths dropped as a result of vaccination. It should also be pointed out that Wallace, like his contemporaries, was a believer in the miasma theory. Thus, he argued that toxic miasmas were generated by the unsanitary conditions under which the poor and impoverished lived. The solution to smallpox was not vaccination but better sanitation, housing, and nutrition. This require freeing up urban and rural space for new construction space occupied by the aristocracy, the real enemies of public health. Wallace was also a believer in natural selection and as such felt that organisms were in a state of balance with their environment. He consequently considered that vaccination might well upset that balance with bad results. He published a Pamphlet in 1898 entitled “Vaccination a delusion; its Penal Enforcement a Crime.” Wallace asserted that the Vaccination Acts were felt to “stand alone in modern legislation as a gross interference with personal liberty and the sanctity of the home; while as an attempt to cheat outraged nature, and to avoid a zymotic disease without getting rid of the foul conditions that produce and propagate it, the practice of vaccination is utterly opposed to the teachings of sanitary science” (Wallace, 1898). In 1890, Wallace gave evidence before the Vaccination Royal Commission. However, when his testimony, especially the data supporting it was examined, it was found to contain numerous errors and questionable statistics. The Lancet argued that Wallace and the other anti-vaccinationists were being selective in the data that they used and ignored large amounts of data that were inconsistent with their position. Other eminent anti-vaccinators included the Russian novelist Leo Tolstoy, and Mahatma Gandhi, the Indian independence leader. Anti-vaccination sentiment flourished across Continental Europe at this time as well. For example, in Stockholm, the three concerns, religious objections, efficacy questions and personal freedoms, resulted in resistance to

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vaccination becoming so intense that vaccination rates in the city were about 40% compared to 90% across the rest of Sweden. Unfortunately, a major smallpox epidemic struck the city in 1873e74 and resulted in a rush to vaccinate (Wolfe and Sharp, 2002). In a society with huge differences in social class, the anti-vaccination movement encompassed individuals of all classes. As in English society as a whole, the leaders tended to be upper class while the activists were middle and upper working class. They were often out of the mainstream as socialists, trade unionists, vegetarians, anti-vivisectionists, and believers in alternative medicine (Durbach, 2000).

Leicester Anti-vaccination Leagues were established in many English towns, but one stood out far above the others. The town of Leicester, located close to the geographical center of England, had grown rapidly during the first half of the 19th century. Its infrastructure had failed to keep up and as a result it had a reputation as an unhealthy town where fevers and disease were rampant. The poor sanitary state of Leicester and other growing British towns was the subject of a Royal Commission that reported on the death rate in these towns in 1844. Leicester was one of the worst. In response, the government established a central Board of Health that set about improving matters. Initially the emphasis was on the improvement of drainage, building regulations, water supplies, paving and removal of rubbish (garbage) of the worst towns (Ross, 1967). Conditions gradually improved, and the death rate began to fall. Smallpox also persisted in Leicester. Initially the numbers were low, but they began to rise progressively. Leicester was a reasonably well vaccinated town during the early 1970s. During the major epidemic of 1871e72 there were only 314 smallpox deaths in the city. A relatively low number for a city that size (Williams, 1994)! The first recorded prosecution under the 1853 Vaccination act occurred in Leicester where a William Johnson served 14 days in prison for refusing to have his child vaccinated (Howard, 2003). When he was released his supporters presented him with a silver watch! As the numbers of smallpox cases in Leicester dropped steadily through the 1870s, apathy toward vaccination progressively developed into hostility! This hostility grew, especially after the act of 1871 confirmed that compulsion was to be employed. The number of prosecutions in Leicester grew from 2 in 1869 to 1154 in 1881 and parents began to deliberately flout the 1871 act. As a consequence, the number of prosecutions increased with many parents opting for jail time rather than paying the fine. Since compulsion and prison time were proving ineffective in promoting vaccination the Local Board of Health was obliged to emphasize quarantine and isolation as their primary control measure. This “Leicester Method” was considered to be an alternative to compulsory vaccination. It appeared to work well during an outbreak of

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smallpox in 1877 when there were only six deaths. Because of this success, Leicester made isolation compulsory in a local bylaw passed in 1879. In spite of the success of the Leicester method, people who still refused to have their children vaccinated continued to be prosecuted and as a result, compulsory vaccination remained a key political issue (Williamson, 1984). The Leicester (later National) Anti-vaccination League was formed in 1869. Its Secretary was John Thomas (J.T.) Biggs (1847e1929). (Biggs, Wikipedia) Much of the impact of the Leicester anti-vaccination movement was a result of Biggs’ activities. JT Biggs was a sanitary and waterworks engineer and an active member of the Leicester Board of Guardians. He believed strongly that vaccination was an inefficient method of preventing smallpox. He also argued that many “medical men” lacked knowledge and made multiple errors in diagnosis. Biggs estimated the error rate to be 5% e10%dnot implausible considering the state of medicine at that time. He had considerable organizing abilities, and as a result of his efforts as the secretary of the Leicester Anti-vaccination League it exercised an influence out of all proportion to its size. As a Poor Law Guardian he was also in a position to impede compulsion. The vaccination issue began to influence municipal elections. The League put up candidates for election to the Board of Guardians. Anti-vaccinators made strenuous attempts to influence its outcome. The League sought victory as “the freedom for which the sons of Britain fought and bled long before our miserable local divisions rendered us a prey to the decaying laws of overbearing centralisation.” By 1883, the Board of Guardians was evenly divided. In order to win the vote ensuring the prosecution of defaulters, an elderly Chairman was dragged from his sickbed. He died soon after (Swales, 1992). The numbers of vaccinated individuals in Leicester continued to fall. In 1872, it had been 90%. By 1892, it was only 3%. In 1883, out of 2281 births, only 707 infants were vaccinated. As noted above, the great smallpox epidemic of 1870e73 had caused relatively few cases in Leicester, a fact that the antivaccinationists seized upon. The situation in Leicester was accentuated by the London Society for the Abolition of Compulsory Vaccination who wrote a steady stream of supportive letters to Leicester Newspapers. In October 1884, the Leicester Board of Guardians went to the Local Government Board in London claiming that the “Leicester method” was so successful that prosecutions should be discontinued. The Leicester method required immediate notification of suspected cases and strict quarantine and disinfection of infected premises. (While this no doubt helped, the low prevalence of smallpox in Leicester at this time was probably also a result of a high rate of vaccination in the surrounding countryside, towns, and villages.) However, their request was rejected and thus contributed to the mass protest of 1885. Biggs’ prime target was, however, the Central Government in Westminster. The Board did nothing, prosecutions continued, culminating in a massive

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popular demonstration in 1885. “The Great Leicester Demonstration” took place outside the Leicester Temperance Hall on 23 March. It was attended by an estimated 80,000e100,000 (Biggs’ estimate) (historians have estimated it closer to 20,000) demonstrators from all over the United Kingdom (Earl, 2015). They carried flags, banners, a child’s coffin, and an effigy of Jenner that was subsequently hanged. Signs read “Better a felon’s cell than a poisoned babe.” The protesters burnt copies of the Vaccination Acts in front of the Mayor and Chief Constable. Eventually the protests began to reflect a broader distrust of science and government. “Keep your children’s blood still pure.” “Stand up for Liberty.” The climax of the demonstration was a motion passed by acclaim, “The Principle of Compulsory Vaccination Acts is subversive of that personal liberty which is the birthright of every freeborn Briton.” As a result, at the next local election, the majority of Guardians elected were opponents of compulsory vaccination. They corresponded extensively with the London Board but didn’t change anyone’s minds. In 1886, the medical journal, The Lancet sent a commissioner to Leicester to report on the true state of the situation. The commissioner commended the city’s quarantine enforcement but pointed out that the method also relied on vaccination of contacts. Contacts, and those who cared for smallpox patients, were vaccinated and revaccinated. The Leicester method was not operated by the anti-vaccinationists. It was undertaken by the local medical authorities using the resources available to them. While many credited the decline in smallpox cases to improved sanitation, it was clear at the time that improved sanitation played only a minor role in some selected communities (Lloyd, 1898). In 1889, when the Leicester vaccinating officer retired, the board made no attempt to appoint a replacement. By that year there had been over 6000 prosecutions in Leicester resulting in over 3000 fines and 64 prison terms. However, the Local Government board issued a writ of mandamus ordering the Leicester Guardians to appoint a new vaccinating officer who would enforce the law. The Guardians continued to resist for a while but were eventually forced to submit (Swales, 1992). Under pressure from the Leicester Board of Guardians and their local Member of Parliament Peter Taylor, who “raised the scandal” of the ongoing prosecutions of those who refused vaccination, the government established a Royal Commission in 1889 to study vaccination grievances. (Taylor eventually became the President of the London Society for the Abolition of Compulsory Vaccination and thus was a nationally recognized figure) (Howard, 2003). The Commission was stacked with eminent physicians, most of whom were staunchly pro-vaccination. Over a period of 7 years, the commissioners interviewed many professional medical experts. Leicester as a principal center of opposition to vaccination also sent many witnesses. The principal witness from the Leicester Anti-vaccination League against compulsion was JT Biggs. He presented the members of the commission with 51 statistical tables, some

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of which were shown to be erroneous and delayed the commission’s report for 2 years. He also told the commissioners that an anti-vaccination prisoner had been seriously mistreated. He had been thrown into a “black hole” and suffered every possible degradation. He claimed that a child had caught “a sort of foot-and-mouth disease” from calf lymph vaccination. Biggs also arranged for 40 other anti-vaccination witnesses to be heard. While the Commission was meeting, and in anticipation of its findings, there was a reluctance to enforce the vaccination laws. 122 of 620 districts across Britain responded to the pressure from anti-vaccinationists by temporarily halting all prosecutions. The anti-vaccinationists were to be disappointed. The Royal Commission, in its final report in 1896, recognized the fact that vaccination certainly protected against smallpox. In a gesture to the anti-vaccinationists, they recommended that repeated penalties imposed for failure to vaccinate should be abolished. This was not sufficient for Biggs and the anti-vaccinationists. He declared that there was no need for any child to be vaccinated and thus, there was no need for anyone to insist on vaccination. Basically, the majority of the Royal Commission felt that a case had not been made that vaccination was ineffective. The Vaccination Inquirer commented. “This is a dishonest Bill, and a reckless Bill and nobody likes it: Reynolds Newspaper declared, “It is neither fish, flesh, or fowl, nor good red herring. How large is the world governed by asses” (Durbach, 2005). The government accepted this report, so that 2 years later, the 1898 Vaccination Act removed repeated penalties and included a conscientious objection clause. Those who objected to vaccinating their children could obtain an exemption certificate from two judges or a stipendiary police magistrate. Thus “conscientious objectors” were recognized by British law. The Lancet “found it hard to understand how prosecutions and complaints of tyranny continued, when certificates could be obtained for the asking.” However, as pointed out in the previous chapter, magistrates were often reluctant to issue Certificates of Exemption since the definition of conscientious objection was very vague, confusing, and almost impossible to refute. Nevertheless, by the end of 1898, 203,413 certificates of conscientious objection had been issued. An amended conscience clause was passed in 1907 making Certificates of Exemption easier to obtain and as a result the national exemption rate climbed to 25% (Durbach, 2005). The number of vaccinated infants in England and Wales was already droppingdfrom 96% in 1875 to 78% in 1889 (Howard, 2003).

William Tebb Born in Manchester, England, William Tebb (1830e1913) was a businessman and a radical activist who participated in many social organizations, including the anti-slavery campaign, anti-vivisection and even anti-premature burial campaigns. He spent some time in the United States in the 1850s and was

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active in the abolitionist movement. (Tebb, Wikipedia) He made a considerable fortune producing bleaching chemicals for paper. When he returned to England in 1869, most of his efforts and money went into supporting the antivaccination campaign. His opinions were largely formed by a mystical philosophy called Theosophy. (This was a religious movement established in the United States in the late 19th Century. It was founded by a Russian immigrant, Helena Blatavsky. It teaches that there is an ancient brotherhood of “masters” that promotes universal brotherhood and social improvement) (Theosophy, Wikipedia). Tebb became involved in organizations that sought to repeal the Vaccination Acts. Like many anti-vaccinationists he made outlandishly exaggerated claims regarding the hazards of vaccination, claiming for example, that it was responsible for 48,000 deaths in England and Wales (Tebb, 1884). He was prosecuted and fined 13 times for his refusal to vaccinate his third daughter (Government prosecutions, 1879). In 1880, he cofounded the London Society for the Abolition of Compulsory Vaccination. He established its official publication the Vaccination Inquirer. The London Society lasted until 1896 when it became the National Anti-Vaccination League. William Tebb was its first president. His opposition to compulsory vaccination was largely based on social grounds rather than religious principles although his beliefs in Theosophy probably also had an influence. Tebb revisited the United States in 1879 where he actively campaigned against vaccinations and was involved in the establishment of the Anti-vaccination League of America in New York City. Tebb, like many ardent anti-vaccinationists was a believer in sanitation. He considered that vaccines caused disease by contaminating blood that was previously “pure.” In an 1892 paper, Tebb wrote “Cancer is reported to be increasing not only in England and the continent, but in all parts of the world where vaccination is practiced.” Tebb commented, “It is allowed by physicians that cancer may be caused by impregnating the blood with impure matter.” Of course, at a time when smallpox vaccines were relatively crude and often contaminated with other bacteria, there were occasions, probably rare, when Tebb would have been correct, and vaccination may have resulted in a septicemia. Charles Creighton was also a frequent contributor to the Vaccination Inquirer where he suggested that cowpox was a form of syphilis and the whole thing was a giant con (Chapter 6).

References Boniolo G. Public obligation and individual freedom. How to fill the gap? The case of vaccinations. J Public Health Res 2016;5:732. https://doi.org/10.4081/jphr.2016.732. 58e59. Dukore BF. Bernard Shaw and the smallpox epidemic of 1901e1902. Shaw 2020;40(2):285e97. Durbach N. ‘They might as well brand us’: resistance to compulsory vaccination in Victorian England. Soc Hist Med 2000;13(1):45e62.

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Durbach N. Class, gender and the conscientious objector to vaccination. 1898e1907. J Br Stud 2002;41:58e83. Durbach N. The anti-vaccination movement in England, 1853e1907. 2005. Earl E. The Victorian antivaccination movement. Atlantic 2015 July 15. https://theatlantic.com/ health/archive/2015.07/victorian-anti-vaccinators-personal-belief-exemption/398321/. Howard CR. The Impact on public health of the 19th century anti-vaccination movement. Today Off 2003;30:22e4. Lannelli V. George Bernard Shaw on vaccines. Vaxopedia; 2016. https://Vaxopedia.org/2016/10/ 07/george-bernard-shaw-on-vaccines. Larsson P. Anti-vaccers: vaccination resistance in nineteenth century Oxfordshire. 2021. https:// uncomfortableoxford.co.uk/post/anti-vaccers-vaccine-resistance. Lloyd W. Sanitation and smallpox. Westminst Rev Nov 1898:548e60. Ross DL. Leicester and the anti-vaccination movement 1853e1889. Trans Leicester Archeol Hist Soc 1967;43:35e43. Satya-Murti S. “Killed by vaccination”: the enduring currency of a nineteenth century illogic. Hektoen International March 15, 2022. https://hekint.org/2022/03/15/killed-by-vaccinationthe-enduring-currency-of-a-nineteenth-century-illogic/. Shaw GB. Mr Bernard Shaw on vaccination. Br Med J Oct 18 1902:1283. Swales JD. The Leicester anti-vaccination movement. Lancet 1992;340:1019e21. Tebb W. Compulsory vaccination in England. With incidental references to foreign states. London: EW Allen; 1884. Wallace AR. The wonderful century: its successes and failures. London: Swan Sonnenschein; 1898. Wikipedia. J.T. Biggs. https://en.wikipedia.org/wiki/J.-T.-Biggs. Wikipedia. L. Loat. https://en.wikipedia.org/wiki/Lily-Loat. Wikipedia. Mary Hume-Rothery. https://en.wikipedia.org/wiki/Mary-Hume-Rothery. Wikipedia. National Anti-Vaccination League. https://en.wikipedia.org/wiki/National-antivaccination-league. Wikipedia. Theosophy. https://en.wikipedia.org/wiki/Theosophy. Wikipedia. W Tebb. https://en.wikipedia.org/wiki/William-Tebb. William Tebb Government prosecutions for medical heresy: a verbatim report of the case, “Regina versus Tebb” Dedicated to the Board of St. Pancras Guardians, London with an introduction and appendix of illustrative matter. London: Allen and Hall; 1879. Williams N. The implementation of compulsory health legislation: infant smallpox vaccination in England and Wales, 1840e1890. J Hist Geogr 1994;20(4):396e412. Williamson S. Anti-vaccination leagues. Arch Dis Child 1984;59:1195e6. Wolfe RM, Sharp LK. Anti-vaccinationists past and present. Br Med J 2002;325:430e2.

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Chapter 13

Anti-vaccination movements in the United States and Canada Anti-vaccination sentiment progressively increased in the United States through the 19th century. It was associated with a broader anti-science sentiment as well as the increasing power of the medical community as they established their discipline on firm scientific ground. In effect, it was a reaction against so-called experts. It was also associated with progressive growth and involvement of governments at all levels in the state of the public health. To a limited degree, it was also influenced by events in Britain. However, given the relative sizes of the two nations, the anti-vaccination leagues in the United States tended to be regional rather than national. Much of their activity therefore centered in the Northeast states (Colgrove and Samuel, 2022). In the early years of the 19th century, the prevalence of smallpox was relatively low (among the white population), and vaccination rates were relatively low also. Beginning however in the 1870s after the Civil War, smallpox reemerged and became endemic, especially in large, crowded cities. As a result, states roused themselves to enforce vaccination requirements, or pass new mandates. In response, a series of anti-vaccination societies were established whose primary role was to fight against school vaccination requirements. However, they often had other diverse goals and their emphasis differed. Many were primarily focused on the East Coast, while others were truly national or even international in scope. Some had underlying economic objectives, especially with respect to the patent medicine business. As in Britain, their growth was in large part triggered by the advent of compulsory education, and the consequent recognition that vaccination was necessary to prevent the spread of diseases, initially smallpox, in crowded school classrooms. By the end of the 19th century, school vaccination laws were becoming increasingly common. Massachusetts passed such a law in 1855, New York in 1862, and Connecticut in 1872. By 1913, 16 states had school vaccination laws in place (Tolley, 2019). The US government established a requirement in 1891 that all immigrants had to show proof of a recent, successful vaccination. This also caused interesting problems. For example, a leading English anti-vaccinationist, F. Scrimshaw left England to avoid their vaccination laws. Once on the ship he discovered, to his horror, that American immigration law required him to be A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00008-5 Copyright © 2023 Elsevier Inc. All rights reserved.

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vaccinated on board the ship! Despite his indignation, he submitted to the operation concluding that “America is closed to the unvaccinated antivaccinator.”

The Anti-Vaccination League of America The Anti-Vaccination League of America (AVLA) was founded in New York in October 1879 (Fig. 13.1). The founders were predominantly physicians that met in the United States Medical College. They had come to listen to a lecture by the prominent British anti-vaccinationist and social reformer William Tebb. The meeting was chaired by Dr Alexander Wilder (Wilder was president of the Eclectic Medical Society of New York and also served as a trustee of the New York Homeopathic Medical College) (Kaufman, 1967; Tolley, 2019). In his lecture, William Tebb explained that he was visiting New York expressly to campaign against vaccination, with the ultimate goal of abolishing compulsory vaccination. He told his audience about the tactics the anti-vaccination leagues used in Britain and about the success of his publication, The Vaccination Inquirer. He must have been a very persuasive speaker since his audience voted to establish the AVLA, with Wilder as the League’s first President. The League had about 100 members and met regularly until 1885. In December 1880, representatives from the AVLA attended the Paris conference of the International Anti-Vaccination League. Other representatives came from Belgium, France, the Netherlands, Switzerland, the United Kingdom, and the Kingdom of Wu¨rttemberg. They discussed the issues associated with smallpox vaccination and at the end of the conference issued a statement containing nine conclusions as to why vaccination should be suppressed, and all compulsory vaccination legislation should be repealed.

American Anti-vaccination Society 1885 1870

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Anti-vaccination League of America 1879

National League for Medical Freedom 1910

1900 1910 The Anti-vaccination League of America 1908

1920 The American Medical Liberty League 1918

William Tebb visits New York 1879 FIGURE 13.1 Societies.

A timeline of the establishment of the major American Anti-Vaccination

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“It is unwise, impolitic, unjust and tyrannical to enforce vaccination” (Newton 2013). AVLA representatives also attended the international conference in Cologne in 1885. Many of the leaders of this first American anti-vaccination organization were physicians, homeopaths, or members of the diverse medical sects that flourished around that time. Many were very active in other social causes such as anti-vivisection and almost all were of the white middle-class. The term vivisector was used to describe a scientist or physician who operated on living animals without regard to their discomfort or pain. Thus, they linked the painful experimental studies in animals to similar studies on children. Most were located in the Northeast although organizations emerged in other regions of the country in response to local vaccination disputes. However, the League progressively disintegrated as its members moved to a new organizationdThe Anti-vaccination Society of America.

William Tebb As described in the previous chapter, William Tebb was British businessman and ardent anti-vaccinator who had lived in the United States for a time prior to the Civil War. As a result, he had become a committed abolitionist. He frequently compared compulsory vaccination to slavery. This linkage to slavery was also recognized by other anti-vaccinationists in both Britain and America. For example, Lora C Little published the anti-vaccination newsletter The Liberator named after the newspaper published by the anti-slavery crusader, William Lloyd Garrison. Likewise, the most famous abolitionist Frederick Douglass also expressed his opposition to compulsory vaccination. On the other hand, freed slaves were not monolithic, and many sought to be vaccinated as a demonstration of their right to control their own medical care.

The Anti-Vaccination Society of America The AVSA was incorporated in New York City in December 1885. Its membership initially consisted largely of physicians, with Peter Barclay as President while Alexander Wilder, formerly of the AVLA, was a member of its executive committee. Several former members of the AVLA were also actively involved in this organization and William Tebb was made its Honorary Vicepresident. Most of its members were physicians from New York State with a few coming from other nearby States. The AVSA operated throughout the rest of the 1880s and 1890s until the 1910s. In general, the members of the AVSA opposed vaccination because they truly believed that it was dangerous. They used much of the “data” generated by the British societies and claims from people like Tebb to support their beliefs. They were not anti-science per se. However, many were homeopathic physicians who resisted the germ theory. Thus, as a steady stream of new

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scientific discoveries emerged from the laboratories of Robert Koch, Louis Pasteur, and Emil Behring in Europe, they found that their own theories of homeopathy were increasingly under threat. As a result, they asserted that people like Pasteur were charlatans, and that the germ theory was bunk! In the 1880s, seven states adopted compulsory vaccination laws in response to new smallpox outbreaks. However, the degree to which these laws were enforced was highly variable. Some sent squads of police with the vaccinators to ensure mass vaccination. Others failed to enforce the laws through budgetary constraints or an avoidance of controversy. Thus, there was much greater variation in vaccination risks across the USA when compared to the UK. Physicians were often depicted in league with policemen in antivaccination pamphlets. While the homeopaths and their colleagues persisted in their anti-scientific approach and their criticisms of the germ theory, non-physicians, especially those who believed that their children had been damaged by vaccination also began to organize. They too sought to prevent compulsory vaccination in schools by launching multiple lawsuits. Eventually, these laypersons joined the AVSA and rose to leadership positions in the organization. Among these leaders was Frank D. Blue from Terre Haut, Indiana (Miley, 2020). Blue effectively took over the propaganda arm of the AVSA and used their slogan: Compulsory Education is an equal sharing of the national stock of acquired knowledge. Compulsory vaccination is a distribution of the national stock of acquired disease.

Blue was an advocate of drugless nature cures, and phrenology as well as healing with magnets and electricity. His first periodical was called the AntiVaccination News, but this closed in 1897. Subsequently, when Blue took over the leadership of the AVSA in 1898, he began publishing a new periodical, called Vaccination. During the smallpox outbreak of 1900e02, Indiana mandated that schoolchildren must be vaccinated. Blue refused to let his son be vaccinated and launched his own lawsuit against the school principal, the teacher, and the Education Board’s mandatory vaccination policy. The first judge ruled in Blue’s favor, but the State appealed, and the case eventually dragged out for years. Blue argued that vaccination was ineffective and based on the disproven germ theory. The Indiana appeal court however ignored those claims and ruled in favor of the Board of Education. As a result, Blue appealed to the Indiana Supreme Court who in early 1900 also rejected his claims foreshadowing the results of Jacobson v Massachusetts several years later. Around 1900, the membership of the AVSA began to decline as physicians tended to leave. One reason for this was the rise in scientific knowledge, especially regarding Immunology. Vaccination was no longer a deeply mysterious subject. The Biologics Control Act of 1902 had also increased confidence in vaccine safety. By 1905, it was routine to grow many infectious

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agents in the laboratory. Diagnostic tests for infectious diseases became available. Medicine had a very much sounder scientific basis than previously imagined. Confidence in medicine, especially allopathic medicine, increased immeasurably. Many homeopaths had come to accept the germ theory. In response to this growth of medical knowledge, Blue’s anti-vaccine rhetoric became more explicitly anti-scientific. He disparaged the germ theory; he disparaged physicians. He also began to promote alternative therapies in line with his own beliefs. He claimed that you could cure smallpox with saffron tea or by soaking in bran mash! The other reasons why AVSA membership declined were the series of legal decisions that began with Jacobson v Massachusetts and supported mandatory vaccination. The AVSA never recovered from that ruling and Vaccination ceased publication in 1906 (Box 13.1).

The Anti-Vaccination League of America The decline of the AVSA however did not mean that compulsory vaccination of school children was no longer an issue. The growing authority of sciencebased medicine resulted in the progressive exclusion of other unconventional medical sects. They and their adherents fought back in the name of “medical liberty”dthe right of every American to choose their own form of medical treatment. A legislative battle in Philadelphia triggered the formation of the Anti-Vaccination League of Pennsylvania in September 1906. This League immediately began to fight against compulsory vaccination in schools and as a

BOX 13.1 Variola minor Beginning in the last decades of the 19th century, smallpox virus and the disease it caused changed. The virus had mutated, probably somewhere in West Africa. As a result, it lost much of its virulence. This new strain was called Variola minor or Alastrim. Like the classical variola major, variola minor was spread via the respiratory route or through contaminated material. However, while variola major could have a mortality rate of about 30%, the mortality caused by variola minor was close to 1%. Because this milder disease was much less debilitating than classical smallpox, patients were able to move around much more and better able to infect others. As a result, it became the dominant cause of smallpox outbreaks in developed Western countries in the first decades of the 20th century (Marsden, 1967). For example, there was a smallpox outbreak in Pennsylvania in 1906 with 15,000 cases but only 90 deaths. This mortality rate, while low by historic standards, was still very much greater than the mortality caused by vaccination at that time - 0.005% (Tolley, 2019). The disease still had the potential to cause blindness and severe scarring. Nevertheless, it was much less fearsome and for many, much less frightening than the known hazards of vaccination.

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result, the Pennsylvania legislature passed a bill banning compulsory vaccination in 1907. However, Governor Stuart vetoed it! In October 1908, a National Anti-Vaccination conference was held in Philadelphia sponsored by a wealthy Pittsburgh industrialist James Pitcairn. This resulted in reorganization of the Pennsylvania League and the establishment of yet another organization, The Anti-Vaccination League of America (AVLA). Its cofounders were Charles M Higgins, an ink manufacturer, from Brooklyn (1854e1929) and John Pitcairn Jr (Higgins, Wikipedia). They focused their campaigns on New York and Pennsylvania. Higgins was the League’s spokesman, letter writer, and pamphleteer, and the league dissolved after his death. In 1912, he published a pamphlet entitled “Open your Eyes Wide!” in which he demanded that “parents, school officers, editors, judges, legislators” rise up to oppose vaccination. During an outbreak of smallpox in New York City in 1914, he paid for an advertisement urging parents not to vaccinate their children. In 1915, he wrote another book entitled The Crime Against the School Child. In 1920, Higgins wrote yet another lengthy book entitled Horrors of Vaccination Exposed and illustrated with lots of lurid illustrations. He also initiated a petition to the President to abolish compulsory vaccination in the army and navy. John Pitcairn Jr (1841e1916) was a Scottish immigrant who had made his money in railways and oil. (Pitcairn Junior, Wikipedia). He was the co-founder of the Pittsburg Plate Glass Company. Like many other avid antivaccinationists, his opposition to the procedure stemmed from a bad experience involving his son Raymond who had developed an infection following vaccination in 1885. Pitcairn was a follower of Swedenborgianism, a Christian denomination that was based on the mystic visions of the 17th century philosopher Emanuel Swedenborg who reportedly had frequent conversations with angels and demons. The denomination was closely associated with homeopathy. As a result, Pitcairn considered vaccines morally wrong and compulsory vaccination even worse. As in so many similar situations, he considered vaccination as “putting an impure thing into the blood,” and as a result, vaccination scarred the soul. Hence, his response to his son’s postvaccination infection. His adherence to homeopathy stemmed from a belief that only very highly diluted vaccine would have left his son’s soul unscarred. Pitcairn used his considerable fortune in fighting vaccines. In 1907, he addressed the Committee on Public Health and Sanitation of the Pennsylvania General Assembly criticizing vaccination. He sponsored the National Anti-Vaccination Conference held in Philadelphia in October 1908. In 1910, he wrote an article published in the Ladies Home Journal entitled The Fallacy of Vaccination. As a result, his views received very wide distribution. In December 1911, Pitcairn was appointed to the Pennsylvania State Vaccination Commission by the then Governor, John Tener. The law mandating this commission required that it had two anti-vaccination members as well as two pro-vaccination members. Pitcairn saw his task as repealing the state’s

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compulsory vaccination law. He addressed the Assembly’s Public Health and Sanitation committee in a speech in 1907 in which he stated “We are here this evening in the cause of freedom.” As in all these cases, he focused on the dangers of vaccination as well as issues of freedom and liberty. As described above, the repeal law passed both houses of the Pennsylvania legislature but was vetoed by the Governor. It was this defeat that prompted Pitcairn to found the AVLA the next year. In some respects, Higgins and Pitcairn were mere figureheads. Most of the work was done by the League’s treasurer, DW Ensign. He was the owner of Ensign Remedies, a Patent Medicine Mail Order operation in Battle Creek Michigan. Ensign and four of his relatives acted as the staff of the League’s periodical, “The Truth Teller.” Ensign Remedies issued a mail order catalog with a very diverse listing of Patient medicines. Thus, if a patient has appendicitis, they had simply to order remedy numbers “758 a and b.” When analyzed by the Michigan Board of Health, these consisted of 100% sugar solutions (Kaufman, 1967). The Anti-Vaccination League of America never became a truly National organization as its founders had hoped. One reason was its narrow focus on vaccination at a time when broader issues of medical liberty were coming to the fore.

Lora Little Individuals who believed that they had lost children as a result of vaccination joined the anti-vaccination cause in significant numbers. For example, another prominent figure in the anti-vaccination movement was Lora Cornelia Little (1856e1931). Born in Minnesota, she married an engineer and moved to the East Coast. Ms Little had developed her anti-vaccination beliefs following the death of her seven-year-old son Kenneth from diphtheria in April 1896. She blamed his death on his pre-school vaccination performed 7 months previously in September 1895 since he immediately developed a “severe catarrh.” She claimed that the vaccine had “polluted his blood,” and so weakened his constitution that he was susceptible to first measles and then to diphtheria. Lora Little was influenced by the Swedenborgian religion and was also active in the holistic health movement. She wrote a newspaper column in the Mt Scott Herald entitled “Health in the Suburbs” in which she recommended a diet of whole grains and high in vegetables. She advertised herself as a health teacher and traveled widely giving lectures on “How to eat right, live right.” She was involved in the production of multiple periodicals, for example, she was involved with The Truth Teller, the periodical published in Battle Creek, Michigan. This was a successor to The Peril, a weekly newspaper that promoted homeopathy and was managed by the American Medical Liberty League (previously the National League for Medical Freedom). (The Peril promoted patent medicines and was forced to close by the Pure Food and Drug

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Act signed by Teddy Roosevelt in 1906.) From 1900 to 1905, she was the editor of a monthly magazine in Minneapolis called The Liberator in which she generally condemned the medicine of her time. “The aim of The Liberator was to proclaim the freedom of health from the tyranny of medical science.” She promoted the view that doctors put children at risk in order to make money. Like so many other anti-vaccinationists, she believed that infections could be prevented by a healthy diet and an active lifestyle. She was a believer in certain fringe treatments such as the water-cure and phrenology. She did not believe in any form of medication; disease was not caused by germs but by the body cleaning itself (shades of the old humoral theory!). As long as you followed the right diet, got the right exercise, and stayed clean, all your diseases and injuries would “quickly disappear.” Her prime motivation however was her opposition to compulsory medical treatment in any form. Lora Little worked in Central Pennsylvania and sought to overcome that state’s compulsory vaccination law of 1895. She actively opposed the Pennsylvania Department of Health and its Commissioner Samuel G, Dixon. She challenged him to debate her over the effectiveness of vaccination. In 1906, she published a booklet entitled Crimes of the Cowpox Ring: Some Moving Pictures Thrown at the Dead Wall of Official Science in which she described 336 cases of serious and fatal diseases which she believed were caused by vaccination. In 1918, she wrote another booklet entitled Know the Facts About Vaccination in which she, as usual, emphasized its risks while minimizing its benefits (Little, 1918). Having made a career out of opposing vaccination mandates, Ms Little finally went too far! In 1918, when the country was engaged in the First World War she was acting as the field agent of the Medical Freedom League. She wrote an article in “The Truth Teller” attacking the army system of preventive vaccination calling it, “Graft in Patriotic Guise: A Lot of Dirty Graft.” As a result, she was arrested in Bismarck, North Dakota, and charged with sedition based on section 3 of the Espionage Act, 1916. On April 22, 1918, Lora Little was charged with seeking to “willfully cause or attempt to cause insubordination, disloyalty, and mutiny and refusal of duty in the military and naval forces of the United States.” It was further alleged that her propaganda was calculated to interfere with or discourage recruiting and enlistment in the United States Army and Navy. Ms Little had actually been producing and distributing pamphlets and procuring signers to petitions which requested an order from the Commanderin-chief of the Army and Navy “forbidding compulsory vaccination of these originally vigorous and healthy young men” and “solemnly protesting these violations of our boy’s bodies for the satisfaction of any medical theory whatsoever.” She had gotten about 100 signatures. Ms Little was released under $1000 bond, but the charges were eventually dismissed, and she continued her crusade.

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State anti-vaccination efforts The first anti-vaccination leagues were established by true believers. They truly believed that the smallpox vaccine then in use was ineffective or that it was unsafe. However, as time passed, the leagues attracted all those who believed that they had been adversely affected by state or Federal Public Health legislation. American anti-vaccinationists like their British counterparts pressed for limits on compulsory vaccination (Conis, 2020). Thus, they tried to restrict or repeal vaccine mandates. Their campaigns were often mounted in response to stepped up enforcement of these laws. They had victories. Collectively, these societies aggressively fought mandates and were eventually able to persuade legislators to repeal compulsory vaccination laws in California, Illinois, Indiana, Minnesota, Utah, West Virginia, and Wisconsin.

New England The Anti-Vaccination Society of Connecticut was one of the earliest being founded in 1872. The New England Anti-Compulsory Vaccination league was founded in 1882. The Anti-vaccination League of New York City was founded in 1885. This organization subsequently reincorporated as the American AntiVaccination Society. The Anti-Vaccination Society of America was established in the Midwest in 1885. In 1911, a Thomas Boudren submitted a 16-page open letter to the Governor and Legislators in Connecticut claiming that vaccination was “an assault and a crime in the nature of rape.”

Minnesota The Minneapolis Anti-Vaccination League was founded in September 1901. For a few years it was very active, staging regular debates with the Public Health Authorities that do not appear to have changed anyone’s mind. On January 3, 1903, the Minneapolis Tribune reported that the League had elected Mr Charles E Stevens as its Secretary. On April 15 that same year the Minneapolis Journal reported that Mr Stevens had died from a “most malignant” case of smallpox. The paper was unsympathetic. Its headline was: ENEMY OF VACCINE SUCCUMBS TO SMALLPOX. They also noted “A fact in connection with the case which has called forth considerable comment that Mr. Stevens’ friends in the anti-vaccination cult, some of whom profess to believe that smallpox is not contagious, did not seem to have the hardihood to call on him or offer their services.” The League quickly faded from the headlines (Boller, 2021). Minnesota made compulsory vaccination unlawful in most circumstances in 1903.

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Louisiana Dr Moritz Schuppert was an eminent New Orleans physician who in 1879 declared that he could no longer remain silent about the hazards of vaccination (Kaufman, 1967). He said that he was aware of the deaths that it had caused and its “utter inefficiency.” He had a friend that suffered from erysipelas after vaccination. He took his friend with him when he went to vaccinate the girls in a local High School. He showed them his friend’s arm whereupon the girls refused to be vaccinated. As a result, Schuppert was dismissed as City Physician. (Erysipelas is a skin infection caused by the bacterium Streptococcus pyogenes. It results in a painful red rash with raised edges. Today it is readily treatable with antibiotics. It could develop as a result of vaccination with a contaminated lancet.) Schuppert presented a paper entitled “Antivaccination” at a meeting of the Louisiana State medical Society in 1883. In response, the Society adopted a resolution affirming its confidence in vaccination “as the surest and only practical means of preventing the spread of smallpox” (Kaufman, 1967).

Pennsylvania In 1924, Pittsburg’s Health Director began smallpox vaccination in response to a smallpox threat. The anti-vaccinationists however indicated that they much preferred sanitation procedures and put it in verse (Kaufman, 1967): Our smart Health Director named Vaux The finest of Pittsburgh’s big Docs’ “I’ll not clean the town” Said he with a frown, But fill up their blood with cowpox.

California California mandated that all children receive smallpox vaccination before entering public Schools. Following the Supreme Court decision in Jacobson v Massachusetts in 1905, the California legislature approved a bill prohibiting required vaccination for school enrollmentdbut the Governor vetoed it! The opponents of compulsory vaccination kept on lobbying while the State pushed for its enforcement. The center of the opposition to vaccination appears to have been in San Diego. Thus, at one stage 11 members of the San Diego school board boycotted a meeting that had been called to vote on the vaccine mandate. A stick of dynamite and a death threat note were left on the doorstep of the county health officer whose task was to enforce the vaccination law. In September 1908, the school officials simply defied the authorities and one principal refused to allow the authorities to examine children for evidence of

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vaccination scars. (However, he permitted them to simply ask the children if they had been vaccinated.) They estimated that there were 1401 children were unvaccinated at that time (San Diego Union, 1908). As a result, in 1911, California replaced its 1889 law for one that permitted conscientious objection. In 1929, California completely repealed its compulsory vaccination law. However, in 2015, California Law eliminated the personal belief exemption for schoolchildren.

Meanwhile in Canada Following the Montreal smallpox epidemic and riots of 1886, the Government of Ontario passed the Vaccination Act in 1887 (Arnup, 1992). This act was similar to the British Vaccination Acts requiring that parents have their children vaccinated by 3 months of age and then revaccinated every 7 years. It also empowered a municipality to make a mandatory smallpox vaccination order in the face of an outbreak. To complete the process, the Act also empowered local school boards to demonstrate proof of vaccination for schoolchildren. The opposition was slow to respond. However, in 1894, the Toronto Board of Education passed a by-law enforcing its vaccination mandate. Opponents organized and in January 1900 the Anti-Vaccination League of Canada was formed. Their objective was to repeal the compulsory vaccination act. The size of the League is subject to debate (Arnup, 1992). It likely had only a few hundred active members, but it was widely supported in the community. It struck a responsive chord and was supported by politicians, workers, and many businesses as well as members of the medical profession. In 1906, the League presented a petition with 5000 signatures demanding the repeal of the by-law. The Board responded and by a vote of ten to two removed the requirement of a vaccination certificate for school admission. This was despite the protest of the Toronto Medical officer of Health. Empowered by this victory, the League then tried to get the Provincial legislation repealed. As with other such campaigns they exaggerated the adverse effects of vaccination while minimizing its benefits. Their rhetoric was similar to other such campaigns. They produced multiple anecdotal reports of significant adverse reactions. Like other campaigns elsewhere they also emphasized the rights of the individual. They especially emphasized that while vaccination was forced upon the poor, impoverished, and recent immigrants; upper class citizens were treated much more leniently. The Public Health Authorities fought back. Dr Charles Sheard is reported to have labeled the anti-vaccinationists as “a hygienic cult, holding opinions on medical and health matters opposed to the well-grounded convictions of the physicians of the whole world.” In effect, the opposition were characterized as “ill-informed fanatics.” The Ontario Board of Health also launched an advertising campaign. They produce a pamphlet describing and illustrating the dangers of smallpox. They declared that no fatalities had occurred in response

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to 40,000 vaccinations and that secondary infections were the result of a lack of cleanliness in the vaccinated. When the First World War broke out in 1914, the Public Health Authorities received additional powers. This was in large part driven by the poor health of new recruits to the armed forces. Thus, in 1914, the Ontario Government passed a Vaccination Act that made a general vaccination order mandatory in the face of an outbreak. The Medical Officer of Health was also empowered to require vaccination certificates from all pupils within his jurisdiction. Given the onset of war in Europe in which Canada was engaged, the Act was essentially unnoticed at the time. People had more important things to worry about. The war ended in November 1918. In November 1919, smallpox broke out in Toronto. It was first misdiagnosed as chickenpox. Many years before that, in 1906, the Ontario Anti-Vaccination League had persuaded the Toronto City Council to repeal the bylaw mandating vaccination of schoolchildren. As in the United States, anti-vaccination sentiment was strongly supported by homeopaths, labor leaders, and many parents. When smallpox broke out in 1919, the Medical Officer of Health, Charles Hastings, ordered mass vaccination of schoolchildren and in addition requested a citywide vaccination order on November 3. The Board of Health approved it, but the next day the Toronto city council declined to do so and split down the middle. They believed that the existing medical facilities and staff should be sufficient to handle the situation. Mayor Church refused to break the tie, but Hastings responded by ordering the vaccination of all school pupils and threatened to exclude any child that could not produce a vaccination certificate. The next day, the Health Department set up a vaccination clinic in the City Hall and up to 500 children were vaccinated daily. The Mayor was seriously angry and the debate in city council that day was animated. While the Provincial Medical Officer of health mandated that all civil servants receive their vaccine as well. Arguments arose as to who needed to be vaccinated. As a result of the debate, the Mayor called for a public meeting on the vaccination issue. It was held on November 19. It drew a mixed response from the Newspapers. The Telegram reported that only 400 people attended. The Toronto World reported 1200. The meeting unanimously endorsed a resolution condemning compulsory vaccination. Again, the Public Health bureaucrats fought back. They referred to an antivaccination league advertisement as “the last word in hysterical outbursts” (Arnup, 1992). Hastings considered it “too childish to reply to.” The secretary of the Provincial Board of Health, Dr McCullough, stated, “I do not bother my head with such rot as that. It’s not worth any intelligent man’s considering it for a moment.” The Provincial Board of Health tried to force the city to comply with a general vaccination order, but this was denied by the Ontario Court of Appeal. The anti-vaccinationists mobilized. Led by a homeopath, Henry Becker, they made a presentation to the city board of control. As in other places and

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other times, the anti-vaccinators exaggerated the hazards of the procedure. They claimed that vaccines spread syphilis. They argued that since parents paid school taxes then their unvaccinated child should stay in class. By November 13, there were 27 cases of smallpox in hospitals in the city. The Anti-Vaccination League of Canada held a mass demonstration. Toronto however never experienced violent anti-vaccination riots such as those in Montreal or Milwaukee. The crowd gathered outside City Hall with the usual banners such as “Stop the slaughter of the Innocents” displayed. Fortunately, the 1919 outbreak was mild, with only 11 deaths. In addition, many were already immune as a result of prior inoculation. Canada’s premiere vaccine production facility, Connaught Labs was located in Toronto and had been producing smallpox vaccine in state-of-the-art facilities. Despite the vociferous anti-vaccine rhetoric, 200,000 Torontonians sought out immunization during the smallpox outbreak, in a city of approximately 520,000. This effectively ended the outbreak. After 1920, the Anti-Vaccination League of Canada changed its name to the Anti-Vaccination and Medical Liberty League of Canada reflecting the role of non-traditional medical practitioners in the fight. As in the United States, they were strongly supported by homeopaths and other alternative medicine practitioners. Through the 1920s, the League continued to fight against the introduction of the new, modern medical sciences. However, they never succeeded in having the provincial Vaccination Act repealed (Arnup, 1992).

The arguments Freedom Those who opposed vaccination focused primarily on two issues, its safety (or lack of it) and the concepts of liberty and freedom. The latter arguments were used predominantly in response to compulsory vaccination. They demanded freedom to choose their health practices in an era where there were many different approaches to the subject. Freedom to raise their children as they saw fit. And freedom from the dictates of so-called experts whom they mistrusted or disbelieved. As time passed and medicine began to rest on a firmer evidentiary base, and vaccines became safer, the emphasis on freedom and liberty has become more prominent, especially in resistance to COVID-19 vaccination.

Safety The major safety argument used by the anti-vaccinationists was that it either spread smallpox through society on a large scale or alternatively, in the words of Herbert Spencer, “The wholesale syphilization of society” (Kaufman, 1967). Anti-vaccinators generated statistics to prove that vaccination was

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unsafe and often falsified their numbers to prove their point. Many of the hazards of vaccination were indeed real but could be considered accidental. It was often performed by laypeople or midwives with no medical training. The state of medical practice was such that in the absence of specific knowledge of infectious agents and hygiene, even experienced vaccinators ran the risk of causing secondary infections such as erysipelas. There were also many individuals, especially those engaged in nonallopathic medicine who felt constrained to publish their own opinions on the uselessness of vaccination. Some claims were ridiculous. Thus, a Dr JF Banton, an eclectic physician in Cleveland, Ohio, wrote in a brochure entitled Vaccination Refuted, published in 1882, that vaccination introduces into the bloodstream “a bioplasm, death laden-carrying with it all the vices, passions and diseases of the cow.” (Perhaps a reasonable hypothesis given that viruses would not be identified until 1895.) Dr Henry Lindlahr (1862e1924) was an enthusiastic naturopath and the editor of Nature Cure Magazine. He argued that “Vaccination dries up the mammary glands”. As a result, the widespread use of vaccination explains the “popularity of bust foods and developers.” Lindlahr was a 1904 graduate of the “National Medical University” of Chicago (Lindlahr Wikipedia). This “University” was run by a LD Rogers who promoted “auto-hemic” therapy. He claimed that not only was vaccination worthless but was one of the causes of cancer, tuberculosis, syphilis, and insanity (JAMA, 1922)! Louis Siegfried began publishing his journal The Quest in 1926. It focused on two themes: vaccination and vivisection. Siegfried focused primarily on the evils of compulsory vaccination. In the first issue of The Quest, he called those who supported vaccination “unfair, ungenerous, misleading and untruthful.” The Quest survived for longer than most anti-vaccination journals but folded when Siegfried died in 1932 (Lord, 2015).

Other issues Another issue that bothered the early anti-vaccinationists and is still heard today is that physicians made a lot of money from vaccines. Thus, the medical establishment has an economic interest in the procedure. This has been seen by anti-vaccinationists as an obvious conflict of interest and led some to question their objectivity in the matter. This resulted in a belief among anti-vaxxers that physicians systematically under reported adverse events and mortalities. As a result, many arguments have centered around the numbers and their reliability. There were in general, few religious arguments used by these antivaccination societies. Their prime arguments had one specific goal, repeal of the school mandates.

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References AMA Bureau of Investigation. The propaganda for reform. JAMA 1922;79(19):1626e8. Arnup K. “The victims of vaccination”: opposition to compulsory immunization in Ontario, 1900e90. Can Bull Med History 1992;9:159e76. Boller J. A brief history of Minneapolis’s anti-vaccination league. 2021. https://racketmn.com/abrief-history-of-mineapoliss-anti-vaccination-league. Banton JF. Vaccination refuted. 3661/2 Euclid Avenue, Cleveland, Ohio. 1882. Colgrove J, Samuel SJ. Freedom, rights, and vaccine refusal: the history of an idea. Am J Publ Health 2022;112(2):224e34. https://doi.org/10.2105/AJPH.2021.306504. Conis E. The history of the personal belief exemption. Pediatrics 2020;145(4):e20192551. Higgins C.M. Wikipedia. https://en.wikipedia.org/wiki/Charles-M.-Higgins#Anti-vaccination. Kaufman M. The American anti-vaccinationists and their arguments. Bull Hist Med 1967;41(5):463e78. Lindlahr H. Wikipedia. https://en.wikipedia/wiki/Henry-Lindlahr. Little LC. Know the facts about vaccination. Compiled by Lora C. Little. 1918. American Medical liberty League Chicago IL. Lord A. Anti-vaccination in America. 2015. https://americanhistory.si.edu/blog/anti-vaccinationamerica. Marsden JP. Variola minor in the United States. Clin Pediatr 1967;6(9). https://doi/10.1177/ 000992286700600902. Miley SL. Smallpox outbreak marked by anti-vaccine efforts. 2020. https://www.tribstar.com/ news/local-news/smallpox-outbreak-marked-by-antivaccine-efforts. Newton DE. Vaccination controversies: a reference handbook. ABC-CLIO; 2013. ISBN: 9781299548282. Pitcairn J. Wikipedia. Jr. https://en.wikipedia.org/wiki/john-pitcairn-jr. San Diego Union, Friday, Sept 11, 1908. Board finds 1401 children not vaccinated. Tolley K. School vaccination wars: the rise of anti-science in the American Anti-vaccination Societies, 1879e1929). Hist Edu Quart 2019;59(2):161e94. https://doi.org/10.1017/ heq.2019.3.

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Chapter 14

Medical liberty and vaccination The second half of the 19th century was a period of rapid medical advances. Galen’s humoral theories were progressively discredited. Microbiologists such as Louis Pasteur and Robert Koch and surgeons such as Joseph Lister developed and then confirmed the Germ Theory of disease. Over the last two decades of the 19th century, it was shown that many infectious diseases were a result of the invasion of the body by specific pathogenic bacteria. Recovery from such diseases depended upon the body’s defensive responsedits immune system. These new discoveries in microbiology and immunology were incremental and the American public learnt about, and espoused the new sciences gradually. Prior to the rise of the germ theory, many physicians had believed multiple other speculative theories and were thus obliged to convertdsome did, some didn’t. Previously, many believed that illness was caused by polluted air or miasmas that came from underground, from bad water, or from other filthy locations. They recognized that diseases such as cholera and smallpox were contagious, but they also believed that they were caused by the toxins present in these miasmas. As a result, many physicians maintained for a long time that sanitation rather than vaccination was the only effective way of preventing infectious diseases. In the absence of a consensus, other theories also thrived. Homeopathy, physiomedicalism, hydropathy, osteopathy, chiropractic, faithhealing, and numerous other practices filled the intellectual vacuum. As a result of the proliferation of these medical minorities, each pursuing a different theory of disease causation, not all “doctors” believed in viruses, immunity, or vaccination. The anti-vaccinationists especially were disbelieving of Pasteur’s discoveries and the germ theory, and as a result initiated the International Anti-Vaccination Congress in Brussels in 1880. Some physicians considered vaccination just another form of homeopathy! In practice, this resulted in intense competition between those with unique and original theories of disease causation and the growing power and reach of evidence-based medicine. Over time, data accumulated, evidence-based procedures worked, and mainstream medicine left these alternative theories behinddbut not without a struggle!

A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00022-X Copyright © 2023 Elsevier Inc. All rights reserved.

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Diverse medical theories It was common for those engaged in alternative forms of medicine to oppose vaccination since it did not fit with any of their theories. As pointed out previously, the early anti-vaccine groups had a diversity of medical viewpoints to choose from (Fig. 14.1). Thus, those who took a holistic view and had a concept of harmoniae naturae had great difficulty with Pasteur’s results and the germ theory of disease (Wallace, 1898). It is important to point out that the reader should not compare the rationale of the Victorian protests with today’s anti-vaxxers given the advancements in orthodox medicine, especially in microbiology and immunology. After all, the miasma theory seemed perfectly reasonable and logical at the time as did the humoral theory before it. Bad smells resulting from sewage and filth do have an association with poor air and water quality, food poisoning, and human disease. The West’s experience with the water-borne disease cholera, generally supported this connection. The great civic engineering projects of the 19th century that improved water quality and sewage disposal had a very positive effect on dramatically reducing the prevalence of diseases such as typhoid and cholera. The Victorian anti-vaccination movements were also rooted in the real fears of patients. In societies where life expectancy was around 30 years and infections the prime cause of death, the hazards of the strange, inexplicable process called vaccination were not just imagined but were very real, especially to the parents of young children (Anderson, 1990).

Homeopaths As described in Chapter 2, the 18th century largely remained the age of “heroic” medicine. Treatments such as bleeding, blistering, vomiting, sweating, purging, and administration of massive doses of laxatives such as calomel were commonplace. People expected to be tortured by physicians if they were to be cured. This was clearly unsatisfactory, and some alternative had to be found.

Physiomedicalism 1810 Eclectic medicine Homeopathy 1827 1790

Osteopathy Chiropractic 1874 National Christian 1895 League for Science Medical Freedom 1875 1910

1790 1800 1810 1820 1830 1840 1850 1860 1870 1880 1890 1900 1910 1920 AMA Flexner Koch Pasteur founded Report 1877 1880 1847 1910 GERM THEORY

FIGURE 14.1 A timeline showing the development of different forms of non-conventional or alternative medicine and their relationship to the development of evidence-based medicine and the “germ theory”.

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As discussed in Chapter 10, during the 19th century, the medical profession, increasingly aware of its shortcomings, splintered into multiple divergent sects. One of the first of these divergent theories of disease was homeopathy. Samuel Hahnemann (1755e1843) was a German physician who, like many others, was highly dissatisfied with the state of medical practice. He especially objected to bloodletting. He clearly recognized that the “heroic method” usually did more harm than good and thus sought an alternative approach to disease treatment. Beginning in the 1790s, he published a series of papers outlining his concept of homeopathy. He suggested that drugs in incredibly low doses (nosodes) were sufficient to cure disease. This was well received given that the alternative was ineffectual torture. Homeopathy arrived in the United States in 1830e40 and it prospered. The first American College of Homeopathy was founded in Ohio in 1850 (Nat Center Imm, 2014). Homeopathy was the converse of the heroic treatment. Extremely small doses of medicine were administered, and physicians relied on natural healing. As discussed earlier, this approach often produced much better results than the heroic treatment. Initially, therefore, homeopaths tended to be favored over allopaths (conventional physicians), but as medical practice changed and the results of evidence-based medicine began to improve, homeopathy began to fall behind. As a result, homeopaths became defensive. They opposed medical licensure, and many rejected such allopathic practices as vaccination (Valentinuzzi, 2020). Homeopaths thus played a major role in the anti-vaccination movement. They were prominent among the founders of the AVLA. They denounced mandatory vaccination laws and argued that sanitation was a much more effective preventative. It also should be pointed out that many of these alternative therapists were at serious risk of losing their livelihoods to allopathic physicians. As a result of the new discoveries regarding germs, infections, and immunity, homeopaths were among the most ardent of anti-vaccinationists in the 19th and early 20th centuries. This was a period when microbiology and immunology were in their infancy and the workings of the smallpox vaccine remained shrouded in mystery. Given that these early vaccines were relatively crude and often caused severe adverse effects, this was very much contrary to homeopathic teaching. Much of their resistance to vaccination at that time was also related to hostility to mainstream medical practice. Dr. JW Hodge of the New York Homeopathic Medical Society in 1902 argued that “vaccination ranks with human slavery and religious persecution as one of the most flagrant outrages upon the rights of the human race” (Kaufman, 1967). Nosodes are highly diluted biological preparations used in homeopathic medicine to treat disease (Rieder and Robinson, 2015). Homeopathic nosodes are now known to be so dilute and contain so little antigen that they do not trigger a significant immune response. There is no reliable evidence to suggest that they can in any way replace modern vaccines. Modern homeopaths

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recognize this and recommend that patients receive conventional immunization. Anecdotally, there is some evidence that some homeopaths believe that their nosodes can be protective. However, it must also be pointed out that homeopathic nosodes have not undergone the thorough analysis for safety and efficacy that modern vaccines must undergo. Homeopathic immunization against influenza and Leptospirosis have not been shown to be effective (Rieder and Robinson, 2015).

Eclectics Distaste for the painful and ineffective methods of regular physicians caused Wooster Beach in New Jersey to study herbal medicine as well as conventional medicine. In 1827, he opened a clinic in New York. As he practiced, he adopted procedures from multiple sourcesdwhatever worked. The term eclectics was used to categorize physicians who relied on natural remedies as well as conventional medicine. Their discipline and concepts evolved, they were flexible, and they adopted effective therapies from diverse medical sources. Many were however strongly anti-vaccination. Two prominent eclectics were Robert Gunn and Alexander Wilder who each played significant roles in establishment of the AAVL and AAVS in the early 20th century.

Hydropathy Hydrotherapy makes use of the properties of water such as temperature, dissolved salts, or pressure, to stimulate blood circulation and so treat certain medical conditions. It can be applied in many forms from cold showers to hot baths. It has a long history beginning in ancient Egypt, Rome, and Greece. Victor Preissnitz (1799e851), the founder of modern hydrotherapy, believed that smallpox should be encouraged since “it relieves the system of humors that ought to be carried out of it and is a healthy process.” (This reflected the humoral concept that smallpox developed within the body and the clinical disease resulted when the smallpox “toxins” tried to escape from the body through the skin.) Preissnitz was a very successful physician, and his ideas were widely adopted, especially in the United States. One American doctor who promoted hydrotherapy was Christian C. Schiefferdecker. He was a major opponent of vaccination in the 1850s and published a book entitled Dr. CGG Nittinger’s Evils of Vaccination in 1856. Schiefferdecker claimed that vaccination was “nonsense before reason” and “the greatest crime that has been committed in this last century” (Kaufman 1967).

Chiropractors Chiropractic is the third largest regulated health profession in the United States (after allopathic medicine and dentistry). Its early history reflects significant conflicts with the mainstream medical establishment. At the beginning of the

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20th century, many chiropractors were actively hostile to the germ theory of disease. They argued that disease resulted from ‘interruptions and misalignments in the body. They claimed that properly trained chiropractors could cure the flu (Hausman et al., 2014). However, chiropractors, like osteopaths, have largely adapted to modern medicine (Anderson, 1990). Chiropractic colleges have curricula based on evidence-based modern medicine and science, in addition to their instruction on chiropractic theory and practice. From its very beginning in the early 1900s, chiropractors were deeply divided among themselves with respect to vaccination. Even today, a vocal, conservative segment of the profession still maintain a strong anti-vaccination bias (Astor, 2021). This appears to be largely based upon the founding theories of chiropractic that dismissed the germ theory of disease and claimed that all diseases ultimately stemmed from misplaced vertebrae. The purists attributed every disease to spinal problems and hence resisted vaccination. It is the very height of absurdity to strive “to protect” any person from smallpox and other malady by inoculating them with a filthy animal poison .. DD Palmer, 1910

Daniel David (DD) Palmer, the source of the above quote and the founder of chiropractic, made a great effort to develop a single, all-encompassing theory of the cause of diseases (Palmer, Wikipedia). Chiropractic was also established at a time when the manifestly harmful concept of heroic medicine still maintained its hold on most physicians. Palmer postulated that diseases were caused by pressure on spinal nerve roots as a result of misaligned vertebrae. Thus, a patient had only to submit to minor spinal manipulation to be cured. Certainly, chiropractic spinal adjustment was a much safer procedure than submitting to bloodletting, purging, and vomiting performed by the practitioners of heroic medicine. Chiropractic was also effective in the treatment of strained backs and painful spines, common among workers engaged in heavy manual labor. Its present day success also reflects the unsatisfactory ability of conventional medicine to effectively treat chronic back disorders. While accepting the existence of germs, the Palmers, especially Bartlett Joshua (BJ) Palmer, disputed the notion that they caused disease. He claimed, for example, that every smallpox patient had a subluxation of the spine that permitted the microbes to breed at certain spots within the body (Campbell et al., 2000). Chiropractors at this early period felt that they had to clearly differentiate themselves from the vague, unproven germ theories (Gleberzon et al., 2013). Chiropractic opposition to the germ theory was especially strong in the first decades of the 20th century. The effectiveness of antibiotics introduced during the 1940s eventually reduced this opposition significantly. Today, however, the profession remains divided. Surveys have suggested that up to one-third of chiropractors believe that there is no scientific proof that immunization prevents disease. Like other anti-vaccinationists, they have

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identified contradictions and ambiguities in vaccine theory. Thus, they believe that the diseases commonly vaccinated against are actually relatively mild in most patients. They are aware that vaccines are never 100% effective, and they also point to the hazards of vaccination. Their opposition may be made to look reasonable by pointing out these features. They also believe, for example, that the risks of pertussis vaccination outweigh its benefits. However, the majority of modern chiropractors have embraced evidence-based medicine and vaccination (Campbell et al., 2000). In 1990, the International Chiropractors Association adopted a policy statement on vaccination recognizing that the use of vaccination is not without risk but that it “is aware of the beneficial consequences of some that are reasonably safe.” In 1993, they went a step further when the American Chiropractic Association stated that “vaccination has been shown to be a cost effective and clinically practical public health preventative measure for certain viral and microbial diseases.” They went on to affirm an individual’s right to freedom of choice in health care.

Osteopaths Osteopaths are an important component of modern medical care. In December 2020, the American Osteopathic Association (AOA) has issued a statement that says, in part “The AOA without reservation encourages the use of [these] vaccines and we remain ready to help administer and educate the public about them” (AOA, 2020).

Physiomedicalism Physiomedicalism is a system of natural medicine that originated during the early 19th century. It was based in part on the findings of Samuel Thomson (1769e1843). Thomson, like many others, recognized that the conventional treatments of the time such as bloodletting were totally ineffective. As a result, he established the use of herbal medicines and over time linked these to the evolving science of medicine. He focused on the importance of diet and digestion but also advocated for vapor baths and sweating, as well as certain botanical drugs. Thomson wrote two books outlining his beliefs (Reiling, 2011). Others took up the cause and physiomedicalism prospered for a time, and many physicomedical (or Thomsonian) colleges were established over the course of the 19th century, but most were closed after the publication of the Flexner Report. Physicomedicalists resisted the germ theory. They considered disease to reflect a manifestation of some “wrong of life” rather than due to a specific infectious agent. Herbal medicine survived the Flexner Report although training and practice remain highly variable. As a result, some herbalists are strongly opposed to immunization. They view vaccines as unnatural, unnecessary, and elitist. Others do not actively discourage the process (Halper and Berger, 1981).

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Patent medicines Prior to the development of the modern, highly regulated, drug industry, many individuals made a good living selling patent medicines. Commonly containing herbs, strong flavors, and lots of alcohol, these “medicines” were widely advertised with absolutely no evidence of their effectiveness and no legal restrictions on the claims made regarding their effectiveness. However, in the early years of the 20th century, both the states and the Federal Government began to pass laws ensuring the purity of foods and drugs. This was bad news for patent medicine manufacturers and as a result they joined forces with the anti-vaccinationists to oppose government intervention in public health including patent medicine registration. They also opposed medical licensure in an effort to appeal to irregular physicians who might buy or recommend their products. Anti-vaccination interests joined in the process. Given that many believed that vaccination was a mere money-making scheme by orthodox physicians, it is unsurprising that terms such as “medical trusts,” “medical rings,” and “medical statism” were commonly employed by anti-vaccinationists. Some considered Public Health regulations to be not only a threat to individual liberty but also to the old argument that it was contrary to the course of events mandated by God. Mandatory public health orders were considered tyranny. And many still considered vaccine useless! Even at the end of the First World War, there were those who understated the value of vaccines to soldiers in the field. In 1918, Dr. Leonard Keene from Johns Hopkins Medical School wrote in a syndicated column in the Seattle Times. “A few benighted sodden obstinate individuals with Hun minds still spread propaganda against inoculation to prevent sickness.”

Medical associations The American Medical Association The American Medical Association was founded in 1847. As laws were passed restricting the practice of medicine to those procedures acceptable to the AMA, irregular physicians characterized it as trying to deprive them of a living and fought its restrictions tenaciously. In March 1905, the American Medical Association established a propaganda department in an effort to expose quacks, fraud, and dubious patent medicines. They produced booklets that they gave away or sold (6 cents) to physicians and the public, exposing patent medicine fraud (“Palatable poison for the poor”). The next year, the Federal Pure Food and Drug Act served to identify and suppress the sale of unproven patent medicines, some promoted by anti-vaccinationists. In 1910, the Flexner Report on the medical profession further served to close medical practice to the untrained and many nonallopathic practitioners. Nevertheless, some medical dissidents were prominent among the antivaccinationists. One such example was James Martin Peebles (1822e1922),

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who wrote a book in 1900 entitled Vaccination: A Curse and a Menace to Personal Liberty. In it, he asserted that mainstream medicine was in league with the police and federal government (Colgrove and Samuel, 2022). Peebles claimed, “it is rather an oligarchy manned by certain ‘professional’ doctors, the repulsive rules and unconstitutional laws of which, are to be enforced by the militia.” An ardent spiritualist, like many other anti-vaccinationists, James Peebles was also a seller of a patent medicine that he claimed cured epilepsydhe flavored alcohol with bromides. He founded the Peebles Institute in Battle Creek Michigan and promoted the idea that good sanitation was the only way to prevent infectious diseases.

The National League for Medical Freedom In response to the rise of mainstream medicine and the subsequent margination of other medical theories, several Medical Liberty Leagues were formed in the early 20th century (Petrina, 2008). In general, they adopted the liberty arguments of the anti-vaccinators. They argued that Americans had a constitutional right to choose their own medical treatment and a right to freedom from medical interference, not just with respect to vaccination but also other forms of medical treatment. In May 1910, in New York City, these medical leagues joined together with Christian Scientists, chiropractors, and anti-vivisectionists to form the National League for Medical Freedom. Its prime purposes were to campaign against allopathic medicine, state intervention in medical care as exemplified by a Federal Department of Health, and the growing monopoly of the AMA! Many former members of the AVLA and AVSA were involved in these medical freedom leagues. This organization sought to oppose any legislation that increased the ability of the government to regulate the practice of medicine. Its president was B.O. Fowler, President of the R.C. Fowler Medicine company, a mail-order patent medicine distributor. The National League described its key political goal as to overturn a number of bills in congress that were designed to put government power firmly behind allopathic medicine. It aimed to secure an individual’s right to choose whatever practitioner he wanted. The organization was largely funded by the patent medicine industry and many of its officers were involved in the patent medicine business.

The American Medical Liberty League Almost every anti-vaccination argument eventually turned into an attack on allopathic physicians and their monopoly of medical licensure. They were accused of making enormous profits while at the same time spreading disease. In 1919, the American Medical Liberty League based in Chicago and the Citizens Medical Reference Bureau based in New York City were founded. Frank D. Blue, formerly the secretary of the AVSA, became the League’s

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President in 1920. These groups worked not only to overturn state compulsory vaccination laws, but they also wanted to prevent the adoption of a newly developed vaccine against diphtheria. They actively lobbied against any expansion of the Public Health system including the creation of Health Boards and the appointment of Health Officers. As with the National League, they were also closely associated with the patent medicine business. Two members of the Ensign family, a patent medicine business in Battle Creek, Michigan, were president and treasurer, respectively. They published the periodical The Truth Teller, an anti-vaccination paper devoted to alternative medicine. The league opposed vaccination, medical licensure, isolation for contagious diseases, pure food and drug laws, tuberculin testing of cattle (a test for bovine tuberculosis), and many other public health programs (Kaufman, 1967). Conspiracy theorists suggested that doctors withheld information regarding the dangers of vaccination because they didn’t want the public to know the truth (Hausman et al., 2014). These medical liberty organizations found common cause with other organizations campaigning against restrictions on “freedom.” (Tolley, 2019) Thus, many were campaigners against prohibition. Charles Higgins wrote “religious freedom, medical freedom, and alimentary freedom are equally inalienable rights of the American people and must be kept inviolate.” The directors of the anti-vaccination league of America and the Citizens Medical Reference Bureau were also backers of Sentinels of the Republic, an anticommunist organization founded in 1922 (Sentinel, Wikipedia).

The Flexner Report of 1910 In 1904, the American Medical Association created its council on medical education. Its function was to examine the state of medical education in the United States and Canada. When the committee first met, they established two minimum standards. One standard established the educational level required for admission to medical school. The second standard defined the minimum standards for medical education. This was 2 years training in human anatomy and physiology, followed by 2 years working on clinical cases in a teaching hospital. In 1908, the AMA sought to enforce these standards by contracting with the Carnegie Foundation to survey and report on the status of the American medical schools. The Carnegie Foundation, in turn, appointed Abraham Flexner to conduct the survey. Flexner was neither a physician nor a scientist. He was a former schoolteacher, and an expert on educational practices. He had attended Johns Hopkins University majoring in Greek and Latin. He eventually pursued MPhil at Harvard and visited schools in Britain, France, and Germany (Duffy, 2011). He wrote about his experiences and ideas in the book The American College. As a result, he came to the attention of the President of the Carnegie Foundation, Henry Pritchett. Pritchett invited Flexner to survey

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the medical schools across Canada and the United States and make suggestions for their improvement. The selection of a non-physician for the job was deliberate in order to ensure objectivity for what was sure to be a drastic revolution. Abraham Flexner did not disappoint. In the course of his survey, Flexner visited all 155 North American Medical Schools and examined their curricula, assessment methods, admission standards, and qualifying standards. He completed his report in 1910. Abraham Flexner, in his report, assigned schools to one of three categories. The first group, such as Johns Hopkins University in Baltimore, were of the highest quality. The second group were considered substandard, but their deficiencies could be corrected with appropriate financial support. However, Flexner placed most medical schools in a third, unsatisfactory category with low admission standards, poor laboratory facilities, and minimal clinical training. These unsatisfactory schools were producing a surplus of poorly trained physicians. Flexner was harsh in his assessment of certain medical schools while others he praised lavishly. His “Gold Standard” was Johns Hopkins University. There was no consistency between schools and their standards differed greatly. Thus, at the time of the survey, many “Medical Schools” were in effect trade schools owned by one or more doctors, unaffiliated with any college or university, and were proprietary, “for-profit” establishments. In many, a “degree” was awarded after only 2 years of study and both laboratory classes and dissection were optional. In many cases, their instructors were part-time local doctors. They were unregulated by state governments or professional medical organizations. Flexner made five recommendations (Flexner Report, Wikipedia). First, he suggested that the country should greatly reduce the number of medical schools by culling those of the poorest quality. Second, they should strengthen and enforce the entrance requirements. Third, they must train physicians in science and engage them in medical research in well-equipped and wellsupported laboratories. This provided an essential supply of trained clinical scientists (a notable feature of the leading German schools that Flexner had visited). Fourth, he recommended giving the medical schools control over the clinical instruction in hospitals, and fifth, they should strengthen state medical licensure requirements. Flexner’s Report was embraced by the Rockefeller and Carnegie Foundations who immediately directed their funds to the best medical schools. His report significantly altered the nature of medical education and by extension, the way in which medicine itself was practiced in the United States. As a result of Flexner’s Report, most of the poor-quality proprietary schools closed within a few decades. Thus, in 1904, there were 160 institutions granting MD degrees. By 1935, there were only 66. Of these, 57 were affiliated with a university. At the time of the Flexner Report, conventional, allopathic medicine still faced significant competition from alternative forms of “medicine.” Thus, for example, there was osteopathic medicine, chiropractic medicine, electrotherapy,

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physiomedicalism, eclectic medicine, and homeopathy. Medical schools that offered training in these subjects found themselves unable to provide the science-based/research curriculum of mainstream medicine. Flexner deemed any approach to medicine that did not advocate treatments such as antisera or preventative methods such as vaccines as mere quackery. These schools were obliged to drop these courses, change their curricula, or lose their accreditation. Some schools resisted for a while but eventually either closed or adapted. One obvious consequence of these reforms was a decline in opposition to vaccination by alternative therapists (Stahnisch and Verhoef, 2012). One unique discipline that brought its curriculum into compliance with the Flexner Report was osteopathy. As a result, there are now very few differences between the curricula of DO and MD-awarding schools. The osteopathic schools simply provide additional instruction in osteopathic procedures and medicine.

References American Osteopathic Association. AOA statement regarding vaccine misinformation and hoaxes. AOA Media; 2020. AOA Statement: Chicago, December 23 2020, https://osteopathic.org/ 2020/12/23/aoa-statement-regarding-vaccine-misinformation. Anderson R. Chiropractors for and against vaccines. Med Anthropol 1990;12(2):169e86. https:// doi.org/10.1080/01459740.1990.9966020. Astor M. Vocal anti-vaccine chiropractors split the profession. Astor: N Y Times; 2021. https:// www.nytimes.com/2021/07/14/health/anti-covid-vaxers.html. July 14 2021. Campbell JB, Busse JW, Injeyan S. Chiropractors and vaccination: a historical perspective. Pediatrics 2000;105(4). https://www.pediatrics.org/cgi/content/full/105/4/e43. Colgrove J, Samuel SJ. Freedom, rights, and vaccine refusal: the history of an idea. Am J Publ Health 2022;112(2):224e34. https://doi.org/10.2105/AJPH.2021.306504. Duffy TP. The flexner report -100 years later. Yale J Biol Med 2011;84:269e76. Gleberzon B, Lameris M, Schmidt C, Ogrady J. On vaccination and chiropractic: when ideology, history, perception, politics and jurisprudence collide. J Can Chiropr Assoc 2013;57(3):205e13. Halper J, Berger R. Naturopaths and childhood immunizations: heterodoxy among the unorthodox. Pediatrics 1981;68(3):407e10. Hausman BL, Ghebremichael M, Hayek P, Mack E. ‘Poisonous, filthy, loathsome, damnable stuff’ the rhetorical ecology of vaccination concern. Yale J Biol Med 2014;87:403e16. Kaufman M. The American anti-vaccinationists and their arguments. Bull Hist Med 1967;41(5):463e78. National Center for Immunization. Homoeopathy and vaccination NCIRS Fact sheet 2014. Petrina S. Medical liberty: drugless healers confront allopathic doctors, 1910-1931. J Med Humanit 2008;29:205e30. https://doi.org/10.1007/s10912-008-9063-3. Rieder MJ, Robinson JL. ‘Nosodes’ are no substitute for vaccines. Pediatric child Health 2015;20(4):219e20. Reiling J. Physiomedicalism. JAMA 2011;306(7):773. https://doi.org/10.1001/jama.2011.1084.

208 A History of Vaccines and their Opponents Stahnisch FW, Verhoef M. The Flexner report of 1910 and its impact on complementary and alternative medicine and psychiatry in North America in the 20th century, evidence-based complementary and alternative medicine. 2012. https://doi.org/10.1155/2012/647896. Tolley K. School vaccination wars: the rise of anti-science in the American anti-vaccination societies , 1879-1929. Hist Educ Q 2019;59(2). https://doi.org/10.1017/heq.2019.3. Valentinuzzi ME. Vaccines and homeopathy. IEEE Pulse 2020;11(4):44e8. https://www.embs.org/ pu;se/articles/vaccines-and-homeopath. Wallace AR. The wonderful century: its successes and failures. London: Swan Sonnenschein; 1898. Wikipedia Flexner report. https://en.wikipedia.org/wiki/Flexner-report. Wikipedia. Sentinels of the Republic. https://en.wikipedia.org/wiki/sentinels-of-the-republic.

Chapter 15

Developments and dead ends in immunology At the beginning of the 19th century, medical practice had scarcely budged since medieval times. British and American physicians were poorly educated. A textbook from 1848 claimed that common causes of illness included diseased parents, night air, sedentary habits, wet feet, and abrupt temperature changes. Cholera could be caused by rancid food, cold fruits, and passionate fear or rage (hence choleric). The death of young children as a result of infectious diseases was commonplace. These diseases killed thousands annually. By 1850, average life expectancy in the West was still around 40 years. Most medical professionals believed that miasmas (bad smells) caused many diseases including smallpox. Thus, there was no factual basis to understand how vaccination workeddit just did! Jenner published his first report on vaccination using cowpox in 1798. It was not until almost 100 years later that the next human vaccine was produced. It was directed against rabies. As noted previously, it is difficult to imagine just how Jenner considered that his vaccine worked. Without the slightest concept as to how either variolation or vaccination worked, there was considerable confusion among physicians regarding its usage and effectiveness. Society had absolutely no concept of infectious agents, specific infectious diseases, nor of acquired immunity. Were diseases due to miasmas or imbalanced morbid humors, or both? In the absence of any coherent explanation, individuals were free to introduce variations into the procedure. It was, for example, totally unclear in that era that multiple different infectious diseases occurred among their patients, both human and animal. Smallpox was confused with measles, canine distemper with rinderpest, syphilis with gonorrhea, and cowpox with horsepox.

Horsepox and vaccination The concept of species-specific infectious disease was unrecognized in the early 19th century. As a result, many unsuccessful attempts were made to use the principles of vaccination to protect humans and domestic animals against diverse diseases. As early as 1787, Edward Jenner took his young nephew George into a stable with him to look at a horse with diseased heels. A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00020-6 Copyright © 2023 Elsevier Inc. All rights reserved.

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“There,” said he, pointing to the horse’s heels, “is the source of small-pox. I have much to say on that subject, which I hope in due time to give to the world” (Jones, 1884). Subsequently, Jenner conducted a series of studies on cowpox and in 1798 reported that he could infect humans with cowpox and transfer it between humans. Then unfortunately cowpox largely disappeared from the dairies in his neighborhood (Boylston, 2018). In frustration, Jenner turned to horses and in 1797 made many attempts to cause cowpox by using scab-like material from the heels of horses. Even in this Jenner was frustrated, and indeed confused. He reported to a friend in late 1797, “I even procured a young horse, kept him constantly in the stable, and fed him with beans to make his heels swell, but to no purpose.” When Jenner published his landmark report, “An Inquiry into the causes and effects of the Variolae Vaccinae” in 1798, he believed that he had sufficient evidence to prove a direct link between “grease,” a skin disease of horses, and cowpox. He believed that the matter excreted from the grease lesions on the heels of the horse required to be modified by passing it through the system of a cow in order to generate the peculiar protecting power which occurred when the lesions of smallpox developed. For example, James Bryce in 1802 stated the following: “Some have asserted, that the cowpox is not generated in the constitution of the cow but produced on her by inoculation with certain diseased fluids of the horse; while others are of opinion that this ailment is truly vaccine, being generated solely in the constitution of the cow: Of the former opinion is Dr. Jenner.” Bryce went on to say, “The horse, it is well known, is subject to an inflammation and swelling of the heels, which is called the grease, from which, at a certain period of the affection, there issues a very acrid, thin matter: and this applied to the udder or teats of the cows, Dr. Jenner supposes, gives rise to a pustular affection on those parts, which is the cowpox” (Bryce, 1802). Not everyone supported Jenner’s ideas about this matter. Bryce went on to say, “Against this opinion of Dr. Jenner concerning the origin of cowpox, it is argued, that experiments have been made by Dr. Woodville and by Mr. Coleman with much care and attention, in order to produce cowpox, by directly inoculating the udders and teats of cows with the recent matter of grease from the horse, but that, in no instance, have they been successful.” Bryce clearly differentiated between the two diseases. “. we are let to conclude, 1. That there are two kinds of grease, as affecting horses, differing much from each other in the power of giving disease to the human or brute animal. 2. That one of these is a general as well as a topical disease, being evidently attended with fever, and, at a certain period, with an eruption upon the skin; while the other is merely a local affection. . . .4. That the disease thus communicated, whether by direct inoculation with the matter of the grease as issuing from the horse, or after it has been regenerated in the constitution of the cow, secures the person who has been infected from all future attacks of smallpox: in short, that is the Cowpox” (Bryce was correct!).

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A later writer clarified this issue in the language of the late 19th century (Jones, 1884). Jones pointed out that Jenner was confused by the differentiation of grease and horsepox (Variolae equinae), especially when such diseases coexisted. It is also clear that over time Jenner himself eventually recognized his mistake in considering that equine grease was the source of smallpox. He finally realized the fact that horses were susceptible to “an eruptive disease of a various character” and that this disease could provide humans some protection against smallpox. The confusion regarding grease stems from the fact that several different agents can cause inflammation of the heals of horses. In Jenner’s time, many such cases would have been caused by horsepox. Today, equine grease is considered to be a form of bacterial dermatitis (Tizard, 1999). As a result, it is now believed that many of the horse skin exudates used for vaccination did indeed come from cases of horsepox, a virus that cross-reacted with smallpox, and so were likely protective. Horsepox material, it was claimed, was successfully inoculated into humans where it produced vesicles similar to those induced by cowpox and conferred immunity to smallpox in the process called “equination.” Dr. John Loy succeeded in transferring lymph from cases of “equine variola” to the teats of cows and inducing typical cowpox lesions (Loy, 1801). He inoculated horsepox directly into a child and got a severe local reaction and mild febrile response. Subsequently, he vaccinated the child with cowpox and got no reaction, suggesting that the child had developed some immunity. Taking wound fluid from this child, Loy proceeded to inoculate five other children and got a response in each case. Ten days later, he inoculated them with cowpox and got no reaction. The confusion regarding the identity of equine grease and the resulting unpredictable vaccine failures provided support and encouragement for the opponents of vaccination. Nevertheless, despite these failures and much confusion, such attempts continued for almost 100 years. Given the belief that cowpox was simply smallpox in cows (and horses) such attempts were rational by the standards of the time. For example, similar studies were conducted by Dr. Martin in Boston in 1881. Martin got his material from a coachman with vesicular sores on his hand and nose, who had been treating horses with sore heels (Welch and Schamberg, 1905). He collected the exudates from these lesions and inoculated several children and heifers. In all these cases, he obtained a typical vaccination response. There have been in fact multiple reports of humans acquiring horsepox from animals (Cameron, 1908). Following Jenner’s discovery and the confirmation of its effectiveness, the British government decided to vaccinate all its soldiers. The contract to produce this vaccine was given in 1801 to Dr John Loy who used material from horses exclusively. In 1803, the Italian physician Dr Luigi Sacco read a book by Dr Loy and as a result also used equine “grease” with great success in children. By October 1801, he was reported to have “equinated” over 8000

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people (Baxby, 1979). (Sacco sent his strain to a colleague, Jean de Carro in Vienna who subsequently distributed it to Turkey, Baghdad, Bombay, Ceylon and Berlin!). Thus, while cowpox was the preferred material for vaccination through the 19th century, horsepox was used on occasion. It is likely that at least some of the vaccinia stocks used in humans were of equine rather than bovine origin. While horsepox has become almost extinct in the West, it has been possible to sequence the genome of a Mongolian strain of horsepox. This has been shown to be related to, but distinct from conventional vaccinia strains. Horsepox genes are present in different vaccinia strains and most current laboratory strains of vaccinia appear to be more closely related to horsepox than to cowpox (Esparza et al., 2017, 2018) (Fig. 15.1). While physicians were totally unaware of how vaccinia worked, it did not stop them from seeking to use this methodology to prevent other diseases. Many believed vaccinia to be an effective treatment for unrelated diseases in humans including the plague and cholera. This is not surprising in view of a total lack of understanding of its mode of action. One such example is quoted by Creighton (Creighton, 1889). De Carro found evidence at Constantinople that cowpox was an antidote to the plague; six thousand had been cowpoxed in that city and not one of them had taken the plague; there were villages near the capital where true cowpox of the teats occurred, and it was the unanimous testimony of the residents that neither plague or smallpox ever entered them.

It was similarly believed that vaccination moderated the severity of scarlet fever, if it did not actually prevent an attack. These early claims were soon shown to be spurious, but some others lasted for much longer. Attempts to protect humans against smallpox using material from sheep pox lesions (ovination) were also for the most part unsuccessful. However, Luigi Sacco in Milan claimed that the ovination lesions were indistinguishable

American Vaccinia strains Horsepox Eurasian Vaccinia strains Variola (Smallpox) Cowpox strains Monkey pox FIGURE 15.1 The relationship between vaccinia, cowpox, smallpox, and horsepox. It is clear that vaccinia strains are highly diverse which is unsurprising given the careless ways in which they were derived and handled over the course of the 19th century.

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from those caused by vaccinia. He reported that the effects were identical to those seen in children who had received vaccinia. He claimed to have inoculated 300 children with sheep pox lesion fluid and determined that “ovination” was protective against smallpox. Other investigators in France and England were unable to repeat his results. Sacco was a great enthusiast of vaccination for everything, and he not only found that vaccination saved sheep from sheep pox but also dogs from distemper and horses from glanders (Seaton, 1868). Subsequent experience eventually also showed that cowpox could not protect against sheep pox. To quote Creighton. “As a matter of fact, the vaccine inoculation does not ward off the smallpox of sheep, although it ‘takes’ in them just as in man, It has turned out to be a commercial failure.” On the other hand, Crookshank took the opposite view “The failures in subsequent attempts do not invalidate the successful experiment, just as the numerous failures to raise a “vaccine vesicle” by variolation of cows, in no way disprove the results of more fortunate experimenters” (Crookshank, 1889).

Syphilization The rise of the germ theory and rational approaches to vaccination eventually superseded the empirical experiments of the early investigators in vaccinology. Nevertheless, physicians were drawn into dangerous experiments based on the principles they believed accounted for vaccination. For example, the “depletion theory” suggested that vaccination served to deplete the body of some essential nutrients needed by the infectious agent. This theory was held by Louis Pasteur and another French physician Joseph-Alexandre AuziasTurenne (1812e1870). Auzias-Turenne therefore applied this theory in his efforts to vaccinate patients against the bacterial disease, syphilisd syphilization. He believed that administration of material from the lesions of a syphilitic patient to a “healthy” patient could result in the development of immunity due to “syphilitic saturation” (Sherwood, 1999). While he claimed he could prevent syphilis, Auzias-Turenne mainly employed his procedures in attempts to cure the disease. In 1844, Auzias-Turenne conducted some experiments on monkeys and claimed that they developed immunity following his syphilization procedure, although other French physicians were unable to repeat his results. The technique is best described in an editorial in the Medical Times and Gazette of September 5, 1857. “The processes, however, by which these happy events (protection!) are brought to completion are not . simple. A microscopic puncture, an infinitesimal dose of vaccine matter (pus from an active syphilis lesion), a satisfactory pustule, a few days constitutional uneasiness, and a laudable escharethese are the moderate elements of a respectable vaccination. But considerably more complicated is the operation by which the system is worked up to a chancre-proof pitch. No single operation of the venereal virus suffices to this end. Chancre after chancre must be established,

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day after day, week after week, ay! Even month after month, must the operator persevere, until at last, the signs appear which declare that the system has got its quantum sufficiency, and these longed-for signs are: That the body no longer responds to the inoculator’s intention; he may insert his virus, but he cannot any more produce a chancre. The system is implemented. The man is syphilizated!” (Editorial, Syphilization, 1857; Dracobly, 2003). In 1859, Auzias-Turenne and his colleague Camille Gilbert administered multiple painful injections to hundreds of patients, most of whom already had syphilis. They claimed initially that though the first injections produced a localized chancre (a typical smallpox lesion), after patients had received multiple injections, perhaps as many as 20 per session, they developed immunity. If patients developed syphilis, this was explained on the basis that they had not been totally syphilized. It took 20 years, until 1866 for the medical profession to agree that syphilization was not an effective treatment or vaccine. Despite this conclusion, a similar series of experiments were conducted in London at the Lock Hospital in 1867. (The Lock Hospital specialized in treating venereal diseases.) Each patient (24 women and 3 men) received between 102 and 468 inoculations to determine if they could be cured or immunized over a period of 3 or 4 months (Hanley 2017). The doctors concluded that the treatment was ineffective. Even then, there were some who persisted in believing in its efficacy including Auzias-Turenne himself who went to his grave believing that he could have cured syphilis if only he were given more time (Sherwood, 1999). There is still no effective vaccine against syphilis.

Syringes and needles While we today expect to receive our vaccines by injection, this was not possible until the needle and syringe were invented. Thus, in 1844, an Irish Doctor, Francis Rynd, constructed the first hollow steel needle by folding and annealing a flat strip of steel to make a tube (Craig, 2018). This was then drawn through increasingly smaller dies to make a fine, but still hollow needle. It was then sharpened at one end and a hub attached it to other fittings. By itself it was of limited usefulness, but in 1853, the needle hub was first linked to a syringe. The credit for this discovery is attributed to a Scottish Surgeon, Alexander Wood, who combined the hollow steel needle with a glass syringe to inject morphine into a human. That same year, a French physician, Charles Pravaz, adapted Rynd’s needle to administer a blood coagulant to a sheep using a series of measuring screws in a syringe (Snelling, 2014). Wood’s design was more practical. His syringe had the ability to deliver small, measured amounts of fluid into a tissue, so he is generally given credit for the discovery. The design of the hypodermic syringe with a needle has essentially been unchanged since its invention. The invention of the needle and syringe opened up new avenues for immunization although it also resulted in another problem for vaccinesdneedle phobia (Clark et al., 2016).

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Vaccination Up until almost the end of the 19th century, the only vaccined“the vaccine”, was directed against smallpox. That began to change after 1870 (Fig. 15.2).

Louis Pasteur During the later half of the 19th century, the new science of microbiology led inexorably to the recognition that some infectious diseases were caused by microorganisms, especially bacteria. Thus, Robert Koch reported in 1877 that he could infect mice using blood from cows with anthrax. He could see the anthrax bacilli in bovine blood. He could grow the bacterium and show that pure cultures of the anthrax bacillus could cause typical anthrax in animals. The French chemist and microbiologist Louis Pasteur was one of the pioneers of microbiology and the microbial theory of infectious diseases. He followed up Koch’s discoveries by collecting, growing, and investigating any bacteria that appeared to be able to cause disease. In 1879, he received a bacterial sample from Henri Toussaint (1847e90), a professor at the Toulouse Veterinary College. This bacterium, now called Pasteurella multocida, is the cause of fowl cholera. Inoculation of this bacterium into chickens causes lethal disease. While investigating fowl cholera, Pasteur’s assistant E´mile Roux Pasteur Anthrax vaccine 1881 Pasteur Fowl cholera vaccine 1879 Koch Anthrax bacillus 1877 1870

Pasteur rabies vaccine 1885

Typhoid Vaccine Behring 1896 Diphtheria Biologics antitoxin Control 1891 Act 1902

1880 1890 Koch tuberculosis bacillus Roux 1882 Yersin Diphtheria Toxin 1888

NYC 1900 produced diphtheria antitoxin 1896

1910

FIGURE 15.2 The years between 1870 and 1900 saw the full development of our understanding of germs. They were no longer a theory. Robert Koch isolated several major pathogens while Louis Pasteur demonstrated the basic principles of vaccination. These effectively rendered all preceding theories and speculations irrelevant.

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allowed a culture of P. multocida to age in the laboratory cupboard for several weeks. When this aged culture was eventually injected into chickens, it failed to sicken or kill them. Being economical, Pasteur retained the chickens and sometime later injected them with a fresh culture of the bacterium. To his surprise, they remained healthy. Pasteur had clearly been thinking about the process of smallpox vaccination and speculating on the application of this process to other infectious diseases. As a result, he immediately recognized that what had happened was, in many respects similar to vaccination! The organisms had lost their virulence. In honor of Jenner, Pasteur confusingly called the procedure vaccination as well. In 1880, Pasteur presented his first vaccination results to the members of the Academy of Medicine and Sciences in Paris in a treatised“Of Infectious Diseases, Especially the Disease of Chicken Cholera.”

Anthrax and rabies Fowl cholera was not the most significant disease problem affecting French agriculture at that time. Anthrax, in contrast, was a major killer of sheep and cattle (and some farmers), so Pasteur began to develop a vaccine against the anthrax bacterium (Bacillus anthracis). He was scooped by Henri Toussaint! In July 1880, Toussaint presented a report to the Academy of Medicine describing the results of his vaccine trials. He had simply killed the anthrax bacilli by heating them at 558C for 10 min. This killed vaccine effectively protected dogs and sheep (Toussaint, 1880). Toussaint’s result surprised and bothered Pasteur since his working hypothesis regarding the mechanism of immunity was that a vaccine somehow depleted the vaccinated animal of essential nutrients. (The same theory believed by Auzias-Turenne when he used multiple doses of “vaccine” to treat or prevent syphilis.) As a result, the pathogenic bacterium could not survive in a vaccinated host. It followed from the depletion theory that protection could only be conferred by the use of vaccines containing live organisms. Pasteur was skeptical of Toussaint’s results and set out to disprove them. He would not admit that he was wrong! Pasteur thus concentrated his efforts on attenuating B. anthracis so that it could no longer cause disease. One method he developed was to grow the organism at an unusually high temperature (42e438C) for multiple generations. This worked, but his early results were erratic and inconclusive. In March 1881, Pasteur reported to the Academy that his anthrax vaccine was working (Pasteur et al., 1881). However, he was promptly interrupted by another Academy member, Jules Gue´rin. Gue´rin, a surgeon, was 80 years of age then and a staunch opponent of the germ theory. He repeatedly asked Pasteur to explain how his vaccine worked and then claimed not to understand his explanations. The meeting ended in chaos. The Academy met again a week later where Pasteur publicly declared that he would no longer “respond to the indiscreet, intemperate and unhealthy curiosity of M. Gue´rin.”

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Gue´rin tried to attack Pasteur and had to be restrained. The next day he declared that Pasteur was a liar and challenged him to a duel. However, Gue´rin backed down when it became clear that Pasteur had the support of the members of the Academy. These events did however provoke a challenge to a public trail of his anthrax vaccine by a group of local veterinariansda challenge that Pasteur accepted. In May 1881, Pasteur put on a public demonstration of his anthrax vaccine at Pouilly-le-Fort outside Paris. He used two groups of animals. The vaccinated group, consisting of 24 sheep, 1 goat and 6 cattle, received two doses of the vaccine 15 days apart. The unvaccinated group of similar composition received nothing. On May 31, 30 days after the first dose, all the animals were challenged with a live anthrax culture. On June 2, more than 200 interested observers turned up to see the results. It was spectacular!!! All the unvaccinated animals were dead or dying while all the vaccinated animals survived. It was a major media event and a triumph of immunology. The media coverage of this experiment made Pasteur famous and introduced the public to the great potential of vaccines in combatting infectious disease. While Pasteur claimed publicly that he had used a live attenuated vaccine, only he and his colleagues knew that he had actually killed the anthrax bacteria in the vaccine with potassium bichromate (Geison, 1995). Henri Toussaint, who received no credit, published only two more scientific papers before having a mental breakdown and dying at the age of 43. Pasteur and Roux next went on to develop a vaccine against the viral disease, rabies. They infected rabbits with rabid brain tissue (They didn’t know it was caused by a virus!). Once the disease developed, they removed the rabbit’s spinal cord and dried it for 5e10 daysdthus attenuating the virus, and then prepared an emulsified injectable. By drying the spinal cords for different times, Pasteur and Roux were able to produce rabies viruses with different degrees of attenuation. They could then inoculate dogs with a series of emulsified cords. The first injections contained highly attenuated virus. These were followed by cords containing viruses of increasing virulence. The dogs usually developed strong immunity to rabies. In preliminary studies, they showed that they could protect a dog after it had been bitten by a rabid animal. Pasteur had been working on this project for some time when in July 1885, a child, 9-year-old Joseph Meister, was brought to them. Meister had been badly savaged by a rabid dog 2 days previously. Under considerable pressure since the boy was sure to die, the anxious Pasteur vaccinated him. He gave Meister 14 injections over 10 days using spinal cord emulsions beginning 3 days after he had been bitten. He began with the driest and eventually proceeding to fresh, infected cord. Meister survived to become the gate-porter of Pasteur’s grave and committed suicide rather than permit German troops open the crypt in 1940. In July 1886, a 7-year-old boy named Harold Newton Newell became the first person to receive Pasteur’s rabies vaccine in the

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United States. He only received the first four inoculations, and his fate is unknown (Hoenig et al., 2018)! It should be pointed out that these were the first examples of post-exposure prophylaxis. The vast majority of vaccines are administered well in advance of an infection in order give the body an opportunity to develop a high level of immunity prior to disease exposure. In the case of rabies vaccination, the vaccine is given after infection. This is only possible because rabies has a very long incubation period, and a protective immune response has time to develop before clinical disease results.

Dead vaccines Although Pasteur was highly successful in developing practical vaccines for animals, he had no concept as to how they worked. He believed the depletion hypothesis that implied that vaccines only worked if they contained living organisms. However once news of his vaccine discoveries was published, other microbiologists rapidly took up the cause. In 1886, Daniel Salmon and Theobald Smith working in the United States, were able to protect pigeons by inoculating them with a heat-killed culture of “hog cholera virus”dnow known as the bacterium Salmonella choleraesuis. Thus, killed vaccines also worked. This eventually led to the rapid development of a great diversity of killed bacterial vaccines for use in humans, especially typhoid, pertussis, and cholera (Lombard et al., 2007) (Box 15.1). Other advances soon followed (Fig. 15.2). In 1888, E´mile Roux and Alexandre Yersin at the Pasteur Institute showed that a bacterium-free filtrate of a diphtheria culture contained a lethal toxin. In 1890, Emil von Behring working with Shibasaburo Kitasato immunized guinea pigs and rabbits with killed tetanus or diphtheria broth cultures. They demonstrated that as a result, the serum of these immunized animals contained an “antitoxin” that could neutralize these bacterial toxins. This antitoxic activity could be passively transferred to nonimmune animals. They called these antitoxic substances, antibodies. In 1894, Emil Roux successfully treated 300 children with diphtheria using anti-diphtheria serum. In 1896, this was regarded as “the most important advance of the century in the medical treatment of acute infective disease” (Roux, 1934). Almroth Wright in Britain and Richard Pfeiffer and Wilhelm Kolle in Germany in 1896 almost simultaneously developed killed vaccines against Salmonella typhi, the cause of typhoid fever. The original vaccine was relatively crude and somewhat toxic, but it was effective and progressively improved subsequently (Chapter 8).

Antiviral vaccines Pasteur and his successors succeeded in laying the foundations of modern immunology and in developing numerous new antibacterial vaccines.

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BOX 15.1 Living and killed vaccines The earliest vaccines developed at the beginning of the 20th century were designed to present to the immune system microbes that had either been killed or else significantly weakened so that they were unable to cause a serious infection. These weakened organisms are classified as modified live organisms. Modified live viruses infect host cells and undergo replication. The infected cells then process endogenous antigen. In this way, live virus vaccines trigger a response dominated by cytotoxic T cells, a cell-mediated response. Killed organisms, in contrast, act as exogenous antigens. They stimulate immune responses dominated by antibodies. This may not be the most appropriate response to some organisms, but it may be safer. Salmon and Smith demonstrated that killed Salmonella bacteria could serve as an effective vaccine in animals. This simple empirical approach was rapidly adopted and many diverse killed bacterial vaccines were rapidly developed. For example, killed typhoid vaccines were first developed in 1897 and administered to British soldiers in time for the South African War. They worked but were somewhat toxic and caused significant morbidity (Sore arms and a feverdChapter 8). Today whole cell killed Bordetella pertussis vaccine is still given to children in many countries to protect against whooping cough since it is cheaper than the less toxic acellular vaccine. This approach to developing vaccines can be summarized as “isolate, inactivate and inject.” The great advantages of this type of vaccine are its safety and simplicitydand thus reduced cost. This type of vaccine may contain either a very complex antigenic mixture such as that found in killed whole organisms, or the vaccine components may be purified to various degrees. Unnecessary or toxic components may be removed while the vaccine can be enriched with those antigens that are directly responsible for triggering a protective immune response. The degree of purification demanded will depend upon the costs of the purification process and any adverse effects mediated by the unwanted/unnecessary components. Increased knowledge of microbial genetics has revolutionized the way in which vaccine antigens can be generated. Modern vaccines may now contain components of organisms that have been killed by chemical or physical means; inactivated toxins (toxoids); or highly purified subunits, the antigenic components of microorganisms that have been purified from cultures by chemical or physical processes or have been produced by recombinant DNA and RNA technologies.

However, it was not until 1898 that Loeffler and Frosch showed that the agent of foot-and-mouth disease could pass through a bacteria-proof filter. It was not a bacterium but a very much smaller virus. There was a great reluctance by bacteriologists to abandon the methodology that had yielded such great results. For example, for many years, scientists clung to the notion that influenza was due to a bacterium. Indeed, many severe cases of influenza are characterized by secondary bacterial invasion. As a result, it is by no means difficult to

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isolate multiple bacteria from the tissues and body fluids of patients suffering from the flu. Bacteriologists had no shortage of alternative candidate agents to investigate. During the great influenza pandemic of 1918, many people were immunized with vaccines directed against these bacteria. They had no effect on the course of influenza. By the beginning of the Second World War, vaccine technology was firmly established. Many important infectious diseases had been controlled by effective vaccines. The subsequent development of vaccines centered on previously uncontrolled diseases such as polio, and on increasing vaccine safety. The development of Salk’s inactivated polio vaccine after it had been grown in cultured monkey kidney cells was the first step in the development of the modern cell-culture-based vaccine industry (Fig. 15.3). Because of the risks associated with modified live organisms, investigators also began to create vaccines based on individual viral components or subunits. Polysaccharide and virus-like particle vaccines began to be produced in the 1980s. DNA and RNA-based vaccines have been produced much more recently (Box 15.2). As a result of these impressive advances, most major infectious diseases remain relatively well controlleddthanks to vaccines. There is however room for improvement and a continuous push for greater safety. 1893.

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Diphtheria antitoxin

1914 Typhoid vaccine 1914 Rabies vaccine 1915. Inactivated Pertussis

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19

10

1923.

19

0 92

1

Diphtheria toxoid. 1923.

Tetanus toxoid

1935 Yellow Fever.

30

19

1946 DPT

40

19

50

19

60

19

1955 Inactivared polio (Salk) 1961. Oral polio (Sabin) 1963. measles 1967 mumps 1969 Rubella 1971 MMR 1974 meningococcus 0 1977 Pneumococcus 7 1981. Pertussis acellular. 1981. Hepatitis B 19

80

19

1995.

Hepatitis A recombinant

90

19

2006. Human papilloma virus

0

0 20

10

2020. COVID 19

20

20

20 FIGURE 15.3

A time line of new vaccine development over the course of the 20th century.

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BOX 15.2 Types of vaccines Vaccines induce adaptive immunity and prolonged immunological memory to infectious agents. The very first vaccines such as Jenner’s smallpox vaccine simply induced a mild infection. Cowpox/vaccinia could cause a self-limiting infection in humans that resulted in a prolonged and effective cell-mediated immune response. Modern live attenuated vaccines that work in a similar matter include measles, mumps, and rubella vaccines as well as Sabin’s oral polio vaccine Pasteur’s fowl cholera and rabies vaccines also consisted of attenuated strains. This type of vaccine runs a risk of mutating, reverting to virulence, and causing a serious infection in some individuals. This has happened during the final stages of polio eradication in Nigeria, Pakistan, and Afghanistan. A safer method of making a vaccine is to use either whole killed organisms or subunits of these organisms. While safer, these killed vaccines tend to be less immunogenic and may need the addition of an adjuvant or simply administration of more doses. Jonas Salk’s injectable polio vaccine is of this type. Other such vaccines include tetanus and diphtheria toxoids, hepatitis B, and influenza vaccines. A third method of triggering protective immunity is to use noninfectious microbial DNA or RNA in vaccines. These can stimulate long-lasting antibody- and cell-mediated immunity without the use of adjuvants. For example, the highly effective COVID-19 vaccines consist of purified viral RNA that encodes the critical spike protein of the virus.

References Baxby D. Edward Jenner, William Woodville and the origins of vaccinia virus. J Hist Med Allied Sci 1979;34(2):134-162. Boylston AW. The myth of the milkmaid. N Engl J Med 2018;378:414e5. Bryce J. Practical observations on the inoculation of cowpox. Edinburgh: Creech W; 1802. Cameron AF. Horse-pox directly transmitted to man. Br Med J 1908:1293e4. Clark SJ, Cowan AE, Filipp SL, Fisher AJ, Stokley S. Understanding non-completion of the human papillomavirus vaccine series: parent-reported reasons for why adolescents might not receive additional doses, United States, 2012. Publ Health Rep 2016;131:391e5. Craig R. A history of syringes and needles. https://medicine.uq.edu.au/blog/2018/12/historysyringes-and-needles; 2018. Creighton C. Jenner and Vaccination. 1889. London Sonnenschein. Crookshank EM. History and pathology of vaccination. A critical enquiry. London: Lewis; 1889. Dracobly A. Ethics and experimentation on human subjects in mid-nineteenth-century France. The story of the 1859 syphilis experiments. Bull Hist Med 2003;77(2):332e66. Editorial. Syphilization. In: Medical times and gazette; September 5 1857. Esparza J, Schrick L, Damaso CR, Nitsche A. Equination (inoculation of horsepox): an early alternative to vaccination (inoculation of cowpox) and the potential role of horsepox virus in the origin of the smallpox vaccine. Vaccine 2017;35:7222e30. Esparza J, Nitsche A, Damaso CR. Beyond the myths: novel findings for old paradigms in the history of the smallpox vaccine. PLoS Pathog 2018;14(7):e1007082. https://doi.org/10.1371/journal.ppat.1007082.

222 A History of Vaccines and their Opponents Geison GL. The private science of Louis Pasteur. Princeton, New Jersey: Princeton University Press; 1995. Hanley A. Syphilization and its discontents: experimental inoculation against syphilis at the london Lock Hospital. Bull Hist Med 2017;91(1):1e32. https://doi.org/10.1353/bhm.2017.0001. Hoenig LJ, Jackson AC, Dickinson GM. The early use of Pasteur’s rabies vaccine in the United States. Vaccine 2018;36:4578e81. Jones J. Contagious and Infectious diseases, Measures for their prevention and arrest. Small pox (variola); modified small pox (Varioloid); chicken pox (varicella); cow pox (Variolae vaccinae); vaccination, spurious. vaccination. circular no.2. Extract from the Board of Health to the General Assembly of Louisiana. 1884. Lombard M, Pastoret PP, Moulin AM. A brief history of vaccines and vaccination. Rev Sci Tech 2007;26:29e48. Loy JG. A pamphlet entitled experiments on the origin of the cowpox. 1801. England. Pasteur L, Chamberland C, Roux E. Le vaccin du charbon. C R Hebd Seances Acad Sci 1881;32:666e8. Roux PPE. 1853-1933. Obit Notices Fellows R Soc. 1; 1934. p. 197. https://doi.org/10.1098/ rsbm.1934.0005. Seaton EC. A Handbook of vaccination. Philadelphia: Lippincott; 1868. Sherwood J. Syphilization: human experimentation in the search for a syphilis vaccine in the 19th century. J. Hist Med 1999;54:364e86. Snelling N. The history of the hypodermic needle. https://www.medibank.com.au/livebetter/bemagazine/wellbeing/the-history-of-the-hypodermic-needle; 2014. Tizard I. Grease, anthraxgate, and kennel cough: a revisionist history of early veterinary vaccines. Adv Vet Med 1999;41:7e24. Toussaint H. Procede pour la vaccination du moutonet du jeune chien. C R Hebd Seances Acad Sci 1880;91:303e4. Welch WM, Schamberg JF. Acute contagious diseases. Philadelphia: Lea Brothers; 1905.

Further reading Plotkin S. History of vaccination. Proc Natl Acad Sci USA 2014;111:12283e7. Smith KA. Louis Pasteur, the father of immunology? Front Immunol 2012;3:68.

Chapter 16

Antibacterial vaccines and their opponents Once Louis Pasteur had demonstrated that smallpox vaccination was not unique but that similar processes could be used to protect against other infectious agents, other microbiologists quickly stepped in and developed an assortment of different vaccines, especially against the major bacterial diseases. At that time, in the 1880s, viruses were unknown, but the science of bacteriology had developed rapidly. It had proved possible to culture the bacteria that caused such diseases as tuberculosis, typhoid fever, tetanus, diphtheria, and whooping cough. Early studies also showed that simply injecting killed bacteria into an animal could trigger a protective immune response. The organism did not have to be alive for its antigens to activate the immune system and trigger protective immunity. In a relatively short time, crude prototype vaccines had been developed against the wound disease tetanus caused by Clostridium tetani, the lethal throat infection, diphtheria caused by Corynebacterium diphtheriae, and the enteric disease typhoid fever caused by Salmonella typhi. In these early years, the first priorities were not childhood diseases but infectious diseases that caused major losses among the military. These were most notably cholera, plague, and typhoid. These vaccines were never mandated to civilians in the United States. However, during the SpanishAmerican War in 1898 fought mainly in Cuba, while 243 soldiers were killed in action or died of wounds, 1580 died of typhoid fever. As a result, the US army commissioned the development of a typhoid fever vaccine. It was simply a suspension of killed bacteria. In June 1911, the War Department mandated the typhoid vaccine be administered to “all troops entering federal service” as well as to all service personnel under 45 years of age (Smith et al., 2011). These early vaccines were crude since minimal effort had been made to purify them or remove toxic bacterial components. When administered to soldiers by injection, they were painful, caused severe local swelling, and sickened these young men for a few daysdbut they worked (Chapter 8). Typhoid ceased to be an issue in the US army (Fig. 9.2). It should also be pointed out at this stage that the anti-vaccinationists of the 19th century were in a sense very rational since there were absolutely no proven mechanisms by which smallpox vaccination worked. In the end, its use A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00024-3 Copyright © 2023 Elsevier Inc. All rights reserved.

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was eminently justified by the results, the elimination of smallpox. As the 20th century progressed, however, the lack of information on mechanisms and a lack of objective results became much less of an issue. Nobody today seriously suggests that vaccines don’t work although many are keen to point out their failures. As a result, opposition to vaccination focuses on specific vaccines such as measles, mumps, rubella (MMR), or the presence of mercurycontaining preservatives such as thiomerosal. A few anti-vaccinators remain committed to alternative medical therapies. Most however declare, not that they are against all vaccines but against specific vaccines, against failure to reveal adverse events, and about maintaining the principle of informed consent. They claim to be concerned not about vaccination itself but about the sheer number of vaccines administered to children at a very young age. As expressed elsewhere, vaccines are unique in that they are given to healthy, not sick individuals, so adverse events are entirely unacceptable.

Diphtheria Diphtheria is an acute disease caused by infection with the bacterium Corynebacterium diphtheriae. The organism colonizes the nose and pharynx. The bacteria grow on these surfaces and produce a potent toxin that kills cells, and destroys tissues, leading eventually to the formation of a characteristic, thick membrane-like structure, the pseudomembrane, in the victim’s throat. This pseudomembrane may cause death by suffocation. The diphtheria toxin is also absorbed into the bloodstream where it circulates and damages the heart (myocarditis), nerves, and kidneys (nephritis). Death is often a result of the heart damage (Acosta et al., 2021). Before the advent of effective vaccines, there were 100,000 to 200,000 cases of diphtheria reported annually in the United States. Vaccines containing diphtheria toxoid became available in the 1940s and the number of cases declined to 19,000 by 1945 (Acosta et al., 2021). Between 1996 and 2018, 14 cases and one death from diphtheria were reported in the United States. The diphtheria bacterium was first observed in diphtheritic membranes by Edward Klebs in 1883 and cultivated by Friedrich Lo¨ffler in 1884. In 1888 Emile Roux and Andre Yersin identified the diphtheria toxin (Fig. 15.1). Subsequently, Emil Behring and his colleagues in Berlin and Roux and his colleagues in Paris showed that the serum from immune animals could neutralize its toxic effects. In late 1891, two seriously ill diphtheritic children were saved by the administration of serum from an immune sheep produced by Emil Behring. Sheep are small and do not produce a lot of serum. Roux in Paris therefore used horses that produced a lot more serum than the sheep and at a higher titer (antibody level). By 1894, both groups of investigators had treated hundreds of children and shown that antitoxin treatment had more than halved diphtheria mortality rates (Mortimer, 2011). This was the first specific cure for an infectious disease, ever (Fig. 16.1)!

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BOX 16.1 Active and passive immunization There are two procedures by which a person may be made immune to an infectious disease: passive and active immunization. Passive immunization produces temporary immunity by transferring antibodies from a resistant to a susceptible individual. These passively transferred antibodies (or antisera) give immediate protection, but since they are gradually metabolized, this protection wanes, and the recipient eventually becomes susceptible again. Active immunization, in contrast, involves administering antigen to an animal so that it responds by mounting an adaptive immune response. Vaccines can be considered to be military training stimulants for the body’s immune system. Instead of forcing the immune system to learn how to solve a defensive problem during an ongoing microbial invasion, a vaccine simulates an attack on the body by a specific invader. The body learns how to effectively combat the invasion and remembers the lesson in time for the “real thing.” Reimmunization or exposure to infection in the same animal will result in a secondary response and greatly enhanced immunity. The disadvantage of active immunization is, as with all adaptive immune responses, that protection is not conferred immediately. However, once established, immunity is long-lasting and capable of restimulation. Passive immunization requires that antibodies be produced in donor animals by active immunization and that these antibodies be given to susceptible humans to confer immediate protection. Serum containing these antibodies (antisera or immune globulins) may be produced against toxigenic organisms such as Clostridium tetani or Corynebacterium diphtheriae, using antisera raised in horses. Antisera made in this way are called immune globulins and are commonly produced in young horses by a series of immunizing injections. The clostridial toxins are proteins that can be denatured and made nontoxic by treatment with formaldehyde. Formaldehyde-treated toxins are called toxoids. Donor horses are initially injected with toxoids, but once antibodies are produced, subsequent injections may contain purified toxin. The responses of the horses are monitored, and once their antibody levels are sufficiently high, they are bled. Bleeding is undertaken at intervals until the antibody level drops, when the animals are again boosted with antigen. Plasma is separated from the horse blood, and the fraction that contains the antibodies is concentrated, measured, and dispensed. Tetanus immune globulin is given to wounded individuals to confer immediate protection against tetanus. Active immunization has major advantages over passive immunization. These include the prolonged protection and the recall and boosting of this protective response by repeated injections of antigen or by exposure to infection. An ideal vaccine for active immunization should therefore give prolonged strong immunity. In obtaining this strong immunity, the vaccine should be free of adverse side effects. (In effect, it should stimulate adaptive immunity without triggering the inflammation associated with innate immunity.)

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DIPHTHERIA TOXIN

Immune horse serum (DIPHTHERIA ANTITOXIN)

Immunized horse

Unprotected child

Protected child

FIGURE 16.1 Principle of passive immunization against diphtheria. Antibodies are made in large amounts in immunized horses. These animals are bled, their antibodies purified, and the diphtheria antitoxin stored until required. If administered to a patient the antibodies are protective since they neutralize the diphtheria toxin.

Diphtheria antitoxin was commercialized in Europe in the early 1890s. American bacteriologists brought production details back to the United States from Europe, and consequently, Public Health Departments were the first to establish their own production facilities. As a result, American physicians also gradually gained experience in its use. The demand for antitoxin exceeded that which Public Health Departments could produce, and eventually commercial producers stepped in to meet the growing demand. These companies also actively marketed their products. In April 1893, the Director of the New York City Health Department Dr. Herman Biggs established a program to control diphtheria by appropriating funds for a bacteriologic laboratory (Park, 1916). Dr. William H. Park (1863e1939) was appointed to be the bacteriologic diagnostician and given two assistants. At first, they simply isolated the organism from suspected diphtheria cases in children. Park was soon able to determine the prevalence of healthy carriers and the importance of these carriers in spreading the disease. In October 1894, Biggs traveled in Europe and heard talks by both Behring and Roux regarding the use of antitoxin to treat diphtheria. He was so impressed that he cabled Park from Europe instructing him to begin antitoxin production immediately. Over the next few years, the New York City Health Department got involved in large scale antitoxin production. Not having funds to purchase horses, Park and his colleagues first appealed to the New York Herald who raised $8000 to purchase the horses for the Health Department (Schaeffer, 1985). (It has

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been suggested that Biggs and his staff also paid for some horses out of their own pockets but that proved unnecessary (Markel, 2007; Park, 1931). The Health Department eventually found the required funding.) They established stables and filled them with 60 horses repeatedly immunized with the diphtheria toxin so that the horses responded by making large amounts of antibodies (antitoxin, nowadays called diphtheria immune globulin). The horses were bled at regular intervals, and their serum separated from their clotted blood and harvested. The first doses of this serum became available in January 1895 (Park, 1931). That fall, an outbreak of diphtheria occurred in the Mt Vernon branch of the New York Infant Asylum. Park was given permission to administer the antitoxin to every child in the institution. “The epidemic stopped immediately” (Park, 1931). Park also reported on an experiment he had conducted at Willard Parker Hospital, one of the three infectious diseases hospitals run by the Board of Health, over the winter of 1896. One of the leading pediatricians at the hospital Dr. Joseph E. Winters was a prominent and vocal opponent of antitoxin use. Winters believed that the antitoxin would cause both hemolysis and “antitoxin septicemia” and was thus extremely dangerous (Podolsky and Smith, 2011). Park arranged for alternative patients to receive the antitoxin while the other would not. The test lasted 6 weeks, the patents who received the antitoxin did well while those who did not, fared badly. The difference was so great that the trial was discontinued. Park maintained that the results were both conclusive and persuasive. Unfortunately, the results of this trial were never formally published. The New York City stables became the major source of diphtheria antitoxin for much of the United States during the 1890s. During their first year, 1894, they produced over 25,000 protective doses. In 1894, there were 2870 deaths from diphtheria in New York City. By 1900, this had dropped to 1400, and it continued to decline for many years thereafter. The NYC health Department continued to mass-produce diphtheria antitoxin until well after the Second World War, but commercial companies progressively took over the market. The threat of diphtheria has been largely removed by routine childhood immunization, and diphtheria is readily treated with antibiotics. That was not always the case. One of the most significant outbreaks of diphtheria in the United States occurred over the winter of 1924e25 in Nome, Alaska.

The Ididarod Nome is a small town in the far northwest coast of Alaska. Even today, there is no road to Nome from central Alaska. As a result, all supplies are usually delivered by boat in the summer, or nowadays by air. Since the Behring Sea freezes over in winter, Nome was effectively cut off from the rest of the world during the winter months prior to the development of air transport. The only possible land connection was a rough sled trail, the Iditarod trail, which ran

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from the railroad in Nenana in central Alaska to Nome across 674 miles of tundra, forest, and mountains. In the summer of 1924, the only doctor in Nome Dr. Curtis Welch noted that his stores of diphtheria antitoxin had expired. He ordered more, but they had not arrived before ice closed the port for the winter. In December 1924, several children began to sicken with sore throats. This grew so severe that some died and by January Welch recognized that he was dealing with an outbreak of diphtheria. He administered some of the expired antitoxin to a 7-year-old girl, but it was ineffective. Deeply concerned about a potential epidemic, Welch informed the town council and sent radio telegrams to the other cities in Alaska telling them about the outbreak. He also informed the US Public Health Service. .

An epidemic of diphtheria is almost inevitable here STOP I am in urgent need of one million units of diphtheria antitoxin STOP Mail is only form of transportation STOP I have made application to Commissioner of Health of the Territories for antitoxin already STOP

By the end of January 1925, there were over 20 confirmed cases of diphtheria in the Nome area and the mortality was close to 100%. The city had two choices. One was to fly the serum in by aircraft. Unfortunately, the planes at that time could not reliably operate under Alaskan winter conditions. Likewise, there were no experienced pilots available in Alaska at that time. For that reason, the Nome City Council was obliged to arrange a dogsled relay (Onion). A search for diphtheria antitoxin found about 300,000 units in an Anchorage hospital; enough for 30 patients. This antitoxin had been produced in New York City. It would have to suffice for now! It was first taken by rail to Nenana. The route from Nenana to Nome initially followed the Yukon River and then crossed overland to Norton Sound and then along the southern shore of the Seward Peninsula to Nome (Fig. 16.2). The weather could not have been worse. Temperatures in the interior were at 50 F Winds were sweeping across the state and causing huge snowdrifts. Along the shore of Norton Sound there was essentially no shelter from gales and blizzards. The best dog mushers in Alaska who worked for the Northern Commercial Company as mail deliverers were positioned along the route. Most of them were native Athabaskans. The first dog musher was handed the 20 lb package at the train station in Nenana on January 27 at 9 p.m. It was -50 F. He traveled over 50 miles, lost three of his dogs as a result of frozen lungs, and suffered severe frostbite himself. And so it went, 17 different stages of about 20e30 miles each until the serum was handed over to a musher from Nome at Shaktookik on January 31. That musher, Leonard Seppala undertook a 91-mile leg, crossing the sea ice in a blizzard at night with a wind chill estimated at 85 F and 70 mph winds. Gunnar Kassen finally delivered the serum to Nome at 5:30 a.m on February 1. Despite sled crashes during the 674-mile journey,

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Seward Peninsula Fairbanks

NOME Norton Sound

NENANA

Yukon River ANCHORAGE

SEWARD

FIGURE 16.2 The Ididarod route. How diphtheria antitoxin was transported from Nenana to Nome, Alaska, in the face of an epidemic.

not a single ampoule was broken, but it was only sufficient to treat 30 patients. The antitoxin was thawed and administered by noon. Nome needed more antitoxin. Attempts to deliver it by plane failed. As a result, a second batch was delivered by dog sled under similar atrocious weather conditions and arrived on February 15. Kassen’s dog team was led by a Siberian Husky named “Balto.” This team eventually toured the continental United States where they were regarded as heroes. They eventually ended up as exhibits at the Brookside Zoo in Cleveland, Ohio. When Balto died in 1933, his remains were stuffed and mounted and are now in the Cleveland Museum. Balto’s teammate, Togo, was also stuffed and mounted and currently lives in a gift shop in Wasilla, Alaska!

The Balto debate In 1925, a group of dog lovers proposed putting up a monument to Balto in Central Park, New York. In response, the Citizens Medical Reference Bureau filed an objection with the Board of Park Commissioners. The New York Times,

230 A History of Vaccines and their Opponents

on March 29, 1925, reported under the headline “SERUM FOES OPPOSE A STATUE TO BALTO,” that the objectors claimed that diphtheria antitoxin and other biological remedies were of dubious value. Mr HB Anderson, secretary of the Bureau claimed that Dr. WH Park, at that time Director of Laboratories of the City of New York, had “frankly admitted” the growing conviction that diphtheria could never be conquered by antitoxin (NYT, 1925). William Park responded, “That is an organization that has been putting forward the most horrible statements and lies.” “This particular statement is an absolute misrepresentation. The death rate has been cut tremendously by diphtheria antitoxin, which is a most efficient remedy. There were 1200 deaths from diphtheria in 1919, for instance, and this year only about 500.” Park went on to say; “I believe, and I have said that in time, the death rate from antitoxin (sic) will be reduced by 90%, but I doubt if the final 10 per cent of the cases can be prevented because of the seeming impossibility of carrying public health education to the point where one of our greatest remedies is thoroughly used. Both the anti-toxin and immunization methods are extremely effective agents in warring on this disease.” Park commented, “As for the proposal to put up a monument to Balto in Central Park, it has come from a few dog lovers and, while I know nothing about the progress of the plan, I doubt if it has been taken seriously.” The plan was indeed taken seriously and today there is a bronze statue of Balto to be found in New York’s Central Park near the Children’s Zoo.

The St Louis incident of 1901 In October 1901, a physician in St Louis, Dr. RC Harris, was called to treat a 5-year-old girl suffering from diphtheria. He gave her a dose of diphtheria antitoxin. To be on the safe side, he also gave antitoxin to her two younger siblings (DeHovitz 2014). 4 days later, he was called back to the home where he found his patient suffering from severe tetanus. She died later that day. Her two siblings also died within a week! This disaster, that eventually killed 13 children, resulted from the use of equine antitoxin contaminated by the tetanus bacillus (JAMA, 1901). In 1894, the St Louis Health Department had established its own antitoxin production stables and began distributing antitoxin doses a year later. (Commercial antitoxin was becoming available but the St Louis Health Commissioner wanted to be able to provide it to the poor.) By 1901, the production of antitoxin in St Louis was a routine procedure and the product was very successful and effective. On September 30, 1901, one of their antitoxin-producing horses, “Jim” was bled routinely, and two flasks of blood obtained. On October 2 Jim became ill with tetanus and had to be euthanized. The antitoxin obtained from Jim was ordered to be destroyed. The first cases of tetanus in children that had received the contaminated antitoxin were reported on October 26. The health

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department recalled all existing bottles of antitoxin. The 13th child died on November 7. As a result, there was a surge in distrust of diphtheria antitoxin nationwide. Its use dropped. In Chicago, as a result, the diphtheria case fatality rate rose by a third. A Court of Inquiry in St Louis found that a “janitor” Mr. Taylor had been responsible for destroying the flasks containing the contaminated antiserum, but he was unaware of its poisonous nature. His supervisor Dr. Ravold and Mr Taylor were both dismissed. Ravold strongly objected to Taylor’s dismissal saying that he was not supposed to be competent to look after professional affairs. St Louis ceased antitoxin production. The AMA report in their journal took an apparently callous stand on this. “There is to be considered not only the sad fate of the children who possibly escaped diphtheria only to die of tetanus, but also the general effect which such lamentable mishaps are sure to exercise upon the public. The medical profession knows only too well to what evil purposes happenings of this kind are used by the anti-vaccinationists, anti-vivisectionists, ‘christian scientists’ and crochety persons in general. Prejudice and fear thus engendered among the communities may cause a degree of harm that in the end becomes immeasurably greater than the immediate damage” (JAMA November 9, 1901, P. 1255). The owner of The St Louis Post-Dispatch was Joseph Pulitzer. The diphtheria scandal was clearly an opportunity to sell more papers. He began writing lurid headlines that attracted national attention. When the Camden tragedy struck a few months later, Pulitzer continued to promote the scandal (Hamrick, 2021). In response to the St Louis incident and a similar one in involving smallpox vaccination in Camden, New Jersey, in the Fall of 1901 that resulted in the death of nine children, public confidence in vaccines dropped significantly. The investigations into the causes of these outbreaks directly caused Congress to pass the Biologics Control Act in the spring of 1902. This Act established federal regulation of the vaccine industry for the first time, as well as new quality standards and it authorized investigations into adverse events. It was the precursor to the passing of the Pure Food and Drug Act of 1907. It is worth noting that it was the growth and success of the science of Microbiology that made this Act effective. For the first time, bacterial contaminants in foods, vaccines, and drugs could be cultured and identified (Lilienfeld, 2008).

Active immunization Despite the discovery and widespread use of diphtheria antitoxin, by 1900, diphtheria still caused one in seven deaths in British children (Mortimer, 2011). While administration of the antitoxin at an appropriate time could prevent death, it took some time to optimize the production of antiserum in horses. Likewise, diphtheria was not always easy to diagnose. In addition, in

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some patients, the horse serum produced a hypersensitivity disease known as serum sickness. It became increasingly clear that antiserum alone could never completely control diphtheria. It was obvious that active immunization through a vaccine was needed. Recognizing this problem, William Park working for the New York City Health Department began a series of studies on the use of diphtheria toxin neutralized by precise quantities of antitoxin as a possible vaccine. Thus, the toxin could produce immunity while the antitoxin prevented serious adverse effects. The toxin-antitoxin complexes formed floccules that could be used as the vaccine. Park used this vaccine in conjunction with the Schick test. This test devised by Bela Schick involved injecting a very tiny amount of diphtheria toxin into the skin of children. Susceptible children mounted a local inflammatory response, immune children neutralized the toxin, and showed no response. Children were tested before and after vaccination and showed that the test went from positive to negative. In a study conducted in the early 1920s, Park and his colleagues tested thousands of children and found that positive reactions (susceptible to diphtheria) were four times more common in unvaccinated than vaccinated children. As a result, hundreds of thousands of American children received Park’s toxin-antitoxin vaccines up until 1927. Unfortunately, Park’s vaccine was difficult to make and hard to standardize. The ratio of toxin to antitoxin was variable as was the dose to be administered to each child. Vaccine contamination was also an issue. If children were already sensitized to horse serum, the vaccine could cause fever, joint pains, and allergic reactions. As a result, other investigators looked to alternative means to detoxify diphtheria toxoid. In 1924, Gaston Ramon, a French veterinarian working at the Pasteur Institute demonstrated that adding dilute formaldehyde to the filtrates from cultures of the diphtheria bacillus abolished their toxicity while they still retained the ability to trigger a protective immune response. Organisms killed for use in vaccines must remain as structurally similar to the living organisms as possible. Therefore, crude methods of killing that cause major changes in antigen structure are usually unsatisfactory. Chemical inactivation must not alter the structure of the antigens responsible for stimulating protective immunity. One such chemical is formaldehyde; it confers structural rigidity on these proteins and so neutralizes their toxicity. Ramon called his formolized culture an “anatoxine.” English-speaking scientists preferred to call it a “toxoid.” It was soon shown that this toxoid was both effective and much easier to make and as a result replaced Park’s vaccine. It should be noted that the use of formaldehyde in vaccines has been used as ammunition by anti-vaccinationists given that it is both toxic and a possible carcinogen. However, it can be chemically neutralized and has never been shown to cause any problems as a result of vaccination. Formaldehyde is also ubiquitous and is found in many natural products including meats, mushrooms, and fruits such as oranges.

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During his studies on toxoids, Ramon also observed that the antibody levels in horses immunized with tetanus or diphtheria toxoids were higher in animals that developed injection site abscesses. Ramon then induced sterile abscesses in animals by injecting starch, breadcrumbs or tapioca together with the toxoids, and was able to enhance antibody production still further. Thus, substances that induced inflammation (innate immunity) at the injection site promoted antibody formation (adaptive immunity). In 1926, Alexander Glenny working in London, did essentially the same thing by injecting a foreign antigen together with alum (aluminum potassium sulfate)da much safer procedure. As a result, the addition of aluminum salts to enhance vaccine efficacy became a standard procedure. To maximize the effectiveness of vaccines, especially those containing killed organisms or highly purified antigens, it is now common practice to add substances, called adjuvants, to some vaccines (adjuvare is the Latin verb for “to help”). These adjuvants trigger innate responses that in turn promote the adaptive responses and so provide long-term protection. Adjuvants can increase the speed or the magnitude of the adaptive response to vaccines. They may permit a reduction in the dose of antigen injected or in the numbers of doses needed to induce satisfactory immunity. For example, the addition of an alum adjuvant to the diphtheria toxoid reduced the required doses from three to two. Diphtheria toxoid gradually replaced the toxin-antitoxin mixture as the accepted vaccine and remains in use today. The amount of aluminum delivered in a vaccine is considerably less than that found in infant formula or even in breastmilk. Eventually, in 1948, diphtheria toxoid was combined with tetanus toxoid and killed B. pertussis in the triple combination vaccine called DTP. Diphtheria vaccine usage has been consistently high. Thus, of children born in 2016e17 in the United States, 93.3% had received at least 3 doses of DTaP vaccine by 24 months of age while 80.6% had received 4 doses of the vaccine (CDC, 2022) (Fig. 16.3).

400

I

300

I

200

I

Cases per 100,000 Diphtheria vaccine 1932

100

0

I

DPT 1953

I I 1920 1930

I 1940

I 1950

I 1960

I 1970

I 1980

I 1990

I 2000

FIGURE 16.3 The decline in diphtheria cases in the United States following the introduction of an effective vaccine in 1932.

234 A History of Vaccines and their Opponents

Tetanus Tetanus is a lethal neurologic disease caused by the toxin of a bacterium called Clostridium tetani. Cl. tetani is found in the soil and in the digestive tracts of animals and humans. It thrives if it gets into deep wounds. This bacterium secretes a potent toxin that acts on the nervous system to interfere with muscle function, including breathing, and so resulting in death. The disease occurs worldwide as a result of wound contamination. Before the availability of a vaccine, tetanus was responsible for 500e600 deaths in the United States annually (Tiwari et al., 2021). In 1889, a Japanese scientist, Kitasato Shibasaburo, was able to isolate the organism and demonstrate how its toxin could produce disease in animals. He also showed that tetanus toxin would induce protective antibodies that would neutralize the toxin’s effects. In 1897, Edmond Nocard demonstrated that animals could be protected by injection of these protective antibodies in the form of an “antitoxin.” Tetanus was constant problem for soldiers wounded in battle. It assumed great importance during the First World War where the widespread use of barbed wire ensured that soldiers were constantly receiving wounds that were often heavily contaminated. Widespread administration of tetanus antitoxin derived from horses was critical and saved innumerable lives. The clostridial toxins are proteins that can also be made nontoxic by treatment with formaldehyde. The resulting vaccines containing tetanus toxoid were first made available in 1924. Tetanus toxoid can be used either alone or combined with diphtheria toxoid as diphtheria and tetanus toxoid (DT) vaccine. Or it can be combined with diphtheria toxoid and acellular pertussis vaccine as DTaP. It is recommended that this vaccine be administered to children under 7 years of age. Tetanus toxoid with an aluminum hydroxide adjuvant is given by intramuscular injection for routine prophylaxis, after being injured. The antibodies directed against the toxin have a higher affinity for the toxin than do the toxin receptors on nerve cells. Thus, in infected wounds, the antibodies bind the toxin as it is produced. The toxin molecules cannot therefore bind their receptors on neurons and are effectively neutralized.

Pertussis Whooping cough is an acute respiratory disease caused by the bacterium Bordetella pertussis. This bacterium was first isolated by Jules Bordet and Octave Gengou in 1906. In the early 20th century, whooping cough was one of the commonest childhood diseases and a major cause of childhood mortality in the United States. Before a vaccine became available in the 1940s, there were more than 200,000 cases reported annually. Since routine vaccination was introduced, its prevalence has dropped by at least 75% but whooping cough remains a major health problem among children worldwide. Of the vaccine preventable diseases, whooping cough rivals measles in its importance.

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Complications are common. Pneumonia develops in 15% of patients while neurologic complications occur in up to 4% of affected children (Gangarosa et al., 1998). As a result, it causes millions of cases and hundreds of thousands of deaths annually. It is estimated that in 2014, there were 24 million new pertussis cases worldwide resulting in almost 161,000 deaths. The disease can also persist for many months, so prevention is of critical importance. Vaccines containing killed whole B. pertussis bacteria have been available in the United States since 1914. It was many years later, in 1948, that they were combined with diphtheria and tetanus toxoids in a single dose vaccine (DTP). Controlled trials were conducted in the 1940s that determined that four doses of whole-cell DTP vaccine were 70%e90% effective in preventing serious whooping cough (Fig. 16.4). One problem with the use of whole killed bacteria in vaccines is that they contain many subcomponents and molecules that are either nonantigenic or induce nonprotective responses, or most importantly, may be toxic or allergenic. These unwanted components can cause toxic side effects. The early, whole-cell Pertussis vaccines were obvious examples of this. About half of vaccinated children suffered redness, swelling, and “soreness” at the injection site. Fever and mild systemic effects were also common. These local responses were of such severity and significance that parents and anti-vaccinationists demanded a safer product. This in turn led to the development of acellular pertussis vaccines. Acellular pertussis vaccines only contain the purified immunogenic components of the bacterium and thus vaccinated persons only respond to those subunits. These components may be further purified so that only the most important antigenic fragments or subunits are used in the vaccine. By definition, these acellular pertussis vaccines are noninfectious and nonreplicating. Thus, their great advantages include increased safety and greatly reduced toxicity. As a result, whole-cell DTP vaccines are no longer licensed in the United States (Havers et al., 2021).

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236 A History of Vaccines and their Opponents

Combination vaccines Mixing three vaccines in one vial has the great advantage that a child will require fewer injections. Vaccines containing purified antigens and nonliving organisms run no risk of causing infections in an immunodeficient child and can be given as early as 2 months of age. Combined vaccines mean fewer clinic visits saving both time and money and are less traumatic for the child. Acellular pertussis (aP) vaccine is currently combined with tetanus toxoid and diphtheria toxoid as DTaP or Tdap. DTaP and Tdap contain the same acellular pertussis components, but Tdap contains a reduced dose of diphtheria toxoid. They are given by intramuscular injection and contain aluminum as an adjuvant but no preservative. Vaccination with DTP and its variants has been highly effective and as a result there has developed an impression in some societies that these diseases are getting milder and less common. Consequently, attention has shifted from the hazards of the disease to the hazards of vaccination. Hostility to DTP vaccination has become an important force in many countries. In a comparative study in different Western countries the impact of aggressive opposition to DTP has been investigated and its consequences determined (Gangarosa et al., 1998). Thus, high vaccine coverage has been successfully maintained in countries such as the former East Germany, Poland, and the USA. Countries where DTP vaccination was disrupted because of anti-vaccine movements include Sweden, Japan, UK, Russia, Ireland, Italy, the former West Germany, and Australia. As a result, the incidence of pertussis has been 10- to 100-fold lower in countries where high vaccine coverage was maintained. Comparisons of neighboring countries with different responses have confirmed these differences. DTP vaccines are not obsolete. They still have an important role to play in combating these important bacterial diseases.

USA Pertussis remains under control in North America although its prevalence has climbed slightly since the 1990s. As discussed below, concerns regarding the safety of DTP-based vaccines peaked in the early 1980s. This resulted in lawsuits against vaccine manufacturers, increased vaccine prices, and some vaccine companies went out of business. Despite this, DTP vaccines are highly efficacious. School entry requirements have kept vaccination levels at 90% e95%. Compensation for post-vaccination injuries has also helped. It is of interest to note that the prevalence of pertussis in the USA between 1974 and 1996 hovered around 1-2 per 100,000. In neighboring Canada, it ranged from around 10 per 100,000 in the early 1970s to over 30 per 100,000 in 1994. It is likely that some of this difference may have been due to the use of a less potent vaccine in Canada (Gangarosa et al., 1998). In the school year 2020e21 in the United States, it is of interest to note that 93.6% of kindergarten children had received the state-required five doses of DTaP vaccine. That year, 2.2% of kindergartners had an exemption for at least one vaccine (Seither et al., 2022).

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United Kingdom The history of vaccination in Britain as demonstrated by the prolonged fight against compulsory smallpox and typhoid vaccinations was sufficient to dissuade the British Public Health authorities from instituting anything similar for diphtheria (Mortimer, 2011). Other Western countries adopted immunization against diphtheria in the 1920s, but the British stuck to isolation and disinfection (Hardy, 2000). As a result, the disease continued to kill, with perhaps 2500e3000 children dying annually up to 1940. This was completely at variance with countries such as the United States, Canada, Ireland, or France. The complexity of the process was also used as an excuse since unlike the single dose of vaccine required for smallpox, children needed multiple doses of the toxoid. The expense of the procedure was also an issue since the vaccination would have to be paid for by impoverished local authorities in the midst of the great depression. However, things progressively changed. British fever hospitals began to immunize their staff as early as 1923. Private individuals who could afford it could have their children vaccinated but the public at large were ignored (Mortimer, 2011). British vaccine hesitancy persisted fed by an overall prejudice against compulsory vaccination and negative anecdotal reports of adverse events occurring in other countries. When the Second World War began in August 1939, however, the situation changed. The British government effectively assumed responsibility for the health of children. Thus, in January 1940, the medical journal The Lancet asked in an editorial, why diphtheria persisted and why were children not being immunized with antitoxin? Almost immediately, that month, the Ministry of Health launched a mass childhood diphtheria immunization campaign and provided local authorities with the finances needed to support the program. Implementation was incredibly rapid, and opposition was negligible. After all, there was a war on, and it became one’s patriotic duty to have your children vaccinated. It would be inappropriate to have unvaccinated children mixing with others while sheltering from a bombing raid. By the end of 1942, between a half and a third of British children under 15 had been vaccinated (Mortimer, 2011). Between 1932 and 1944, diphtheria mortality rates fell by 75% and by 1949 had dropped by 90% (Mortimer, 2011). However, governmental vaccine hesitancy in this case had cost many children’s lives. British caution also extended to the use of pertussis vaccines. The UK only introduced routine vaccination against pertussis in the 1950s following extensive trials in 1945e46 (Hardy, 2000). Local authorities had administered the pertussis vaccine in association with diphtheria until its official introduction in 1957. By the 1970s, the use of the trivalent DTP whole-cell pertussis vaccine had become routine. Whooping cough had been for many years the most lethal childhood disease in the country. Thus, in 1956, there were an average of 122,000 cases each year resulting in 374 deaths. By 1975, these numbers had dropped to 20,400 cases and 24 deaths.

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Canada In Canada, a single, very enthusiastic individual spearheaded the antidiphtheria campaign. John FitzGerald had founded Connaught Laboratories in Toronto in 1914. Their initial business was the production of diphtheria antitoxin in horses. However, in 1925, following a visit to Ramon in Paris, they began to produce diphtheria toxoid. It was the prime not-for-profit source of diphtheria toxoid for all of Canada (Mortimer, 2011). In 1925, the University of Toronto also appointed Fitzgerald as head of its School of Hygiene. In that position he was able to communicate effectively with public health officials and encouraged them to promote diphtheria vaccination. As a result, the prevalence of diphtheria in Toronto fell by 90% within 5 years. The rest of Canada soon followed. Mortimer suggests that it was this positive Canadian experience that finally persuaded the British to mount their belated diphtheria campaign in 1940 (Mortimer, 2011).

Opposition While the DTP vaccines have been in use since the 1940s, they have not been immune to controversy. In the mid-1970s, reports of significant adverse reactions began to circulate in the United Kingdom, the United States, and Australia. The problem first began when physicians at Great Ormond street Children’s hospital in London published a paper in January 1974 suggesting that 36 children had suffered from severe neurologic complications following DTP vaccination (Kulenkampff et al., 1974). The paper speculated that there might be a link between the two events. (It should be pointed out that causation and coincidence are not the same. Just because two incidents occur close together in time does not mean that they are causally related. Thus, it was impossible to determine if these neurologic complications were actually caused by the vaccine.) However, the damage had been done. Segments of the medical profession backed the concerned parents and focused on the hazards of the Pertussis component of the vaccine. The vaccination rate dropped precipitously. The growth of sentiment against pertussis vaccination was fueled when in 1977, Dr. Gordon Stewart, Professor of Public Health at the University of Glasgow, published a series of 160 case reports linking neurological disorders to the use of DTP (Stewart, Wikipedia). Stewart became well known for his opposition to pertussis vaccination. He claimed that he saw many cases of pertussis in vaccinated children. He claimed that deaths from pertussis had declined significantly before the advent of vaccination. (They had; almost certainly as a result of, improved medical care.) He also claimed it was safer to get pertussis than get the vaccine (Stewart, 1977). He argued against a pertussis vaccination campaign. In part because of Stewart’s statements,

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vaccination coverage dropped significantly in the UK. His work was reported on favorably by the WRC-TV program in 1982 “Vaccine Roulette.” However, the program falsely claimed that Stewart was a member of the Committee on Safety of Medicines. In 1977, he denied that a drop in vaccination coverage would eventually result in a pertussis epidemic. Over the next 2 years, however, DTP vaccination coverage in Britain dropped from around 80% to about 40% (Blume, 2006). As a result, over 100,000 children were hospitalized with pertussis and 600 of them died. In the mid-1980s, Stewart was the lead witness in a case alleging that pertussis vaccination had resulted in stunted mental development in a boy. However, the case collapsed, and Stewart faded from public view. As vaccination rates declined in the UK, the British Government was advised by its own experts to mount a pro-vaccination campaign if a pertussis epidemic was to be avoided. It declined to do this until it had received a report from a Joint Commission on Vaccination and Immunization (JCVI), an independent advisory committee established to examine the data and determine the safety of immunization. The committee confirmed the safety of DTP vaccination. The JCVI also launched the National Childhood Encephalopathy Study. This study identified every child in the UK between the ages of 3 and 36 months who had been hospitalized for neurologic illness and determined whether DTP vaccination was associated with increased risk. The results indicated that such risks were very low and as a result promoted a proimmunization campaign (Nuwarda et al., 2022). While waiting for the report of the Joint Commission, the Government tried to restore confidence by establishing a Royal Commission on civil liability and compensation for personal injury. The Commission stated that “Vaccination is recommended by the State for the benefit of the community, and where it causes injury, the State ought to provide compensation as part of the cost of providing protection for the community as a whole.” As a result, the government acted to provide financial compensation to those who could show that their children had been damageddThe Vaccine Damage Payment Act of 1979. This was insufficient to prevent a pertussis epidemic in the winter of 1978e79 (Millward, 2016). £10,000 was awarded to the parents of 349 children in 1979 and 255 children in 1980. The claim rate dropped significantly thereafter. Despite the evidence, the news media dramatized the devastating stories of the affected children. There was a threefold increase in newspaper articles on vaccines from 342 in 1991 to 1450 in 2000. However, articles dealing with vaccine safety climbed during that same period from 17% in 1990% to 39% in early 2001 (Cookson, 2002). Parents who appeared in the media drew additional support from other likeminded parents. A group, “The Association of Parents of Vaccine Damaged Children (APVDC)” was founded in 1973 by two mothers who believed that their children had been damaged by vaccination. They sought compensation

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on the grounds that they were not fully informed of the potential risks of administering DTP to their children and since the government had recommended vaccination, then it was liable for damages. The parents in the APVDC case argued in court for recognition, but compensation was rejected by the courts due to a lack of evidence showing that DTP immunization was harmful. Despite the decline in the prevalence of pertussis since the 1950s, this loss of confidence in the vaccine resulted in reduced vaccination rates and a series of pertussis epidemics. Vaccination coverage declined from 70% to 80% in 1974% to 31% in 1980 (Cabrera- Lalinde, 2022). This resulted in a pertussis outbreak that placed considerable strain on the National Health System. Nevertheless, in the late 1970s, many physicians in the UK remained reluctant to recommend such vaccination for all their young patients. Confidence has been gradually restored over time as more efficacy and safety data have become available. Vaccination rates climbed to 91% by 1992. As a result, the prevalence of pertussis in Britain has declined again (Fig. 16.5) (Gangarosa et al., 1998). A similar response occurred in Ireland where vaccine coverage fell from more than 60% in the early 1970s to 30% after 1976. Pertussis epidemics occurred in 1985 and 1989. Anti-vaccination activism directed against whole cell pertussis vaccines resulting in decreased vaccination coverage has clearly cost lives (Cabrera-Lalinde, 2022).

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FIGURE 16.5 Cases of pertussis in the United Kingdom since vaccination was introduced in 1940. Note that as a result of opposition to pertussis vaccination, vaccination rates plummeted in the 1970s resulting in a pertussis epidemic in that country. From Gangarosa EJ, Galazka AM, Wolfe CR, Phillips CM, et al. Impact of anti-vaccine movements on pertussis control: The untold story. The Lancet 1998;351:356e361. With Permission.

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Among their findings was that there was no causal relation between DTP vaccine and autism. There was insufficient evidence to indicate any causal relation between DTP use and aseptic meningitis, chronic neurologic damage, erythema multiforme or other rashes, Gullain Barre´ Syndrome, hemolytic anemia, juvenile diabetes, learning disabilities and attention deficit disorder, peripheral mononeuropathy, and thrombocytopenia. They found that the evidence did not indicate a causal relation between DTP vaccine use and infantile spasms, hypsarrhythmia, Reye Syndrome, or Sudden Infant Death Syndrome (SIDS). On the other hand, they did find that the evidence is consistent with a causal relation between DTP vaccination and anaphylaxis and between the pertussis component of DTP and protracted inconsolable crying, acute encephalopathy and shock, and “unusual; shock-like state.” In 1982, an NBC affiliate in the Washington DC area aired a television documentary entitled “DPT: Vaccine Roulette.” This hour-long investigative report described seizures and brain damage occurring as a result of the pertussis component of the vaccine. As in so many cases, it also minimized its benefits. It also emphasized that vaccination was driven by paternalistic medical practitioners (Conis, 2015). It featured emotional profiles of children believed by their parents to have been harmed by the DTP combination vaccine. Dissident doctors testified that the vaccine was no longer necessary and that government scientists had suppressed data showing that the vaccine was harmful. At the end of the program, a vaccine scientist appeared on screen and said that convulsions were not a contraindication for DTP vaccination. This was then followed by a reporter who read the American Academy of Pediatrics’ warning against administering the vaccine to children who had previously suffered convulsions. Vaccine Roulette inspired a group of parents to form an organization called Dissatisfied Parents Together, in 1982. They advocated for safer vaccines, greater government oversight, and federal compensation for the families of children harmed by vaccines. Sometime later, in 1991, a book entitled A Shot in the Dark by Barbara Loe Fisher emphasized the risks of vaccination with whole cell pertussis vaccine. Ms Fisher reported that her eldest son had been left with multiple learning disabilities following his fourth DTP dose. As pointed out above, these are no longer used in this country. Angry parents formed victim advocacy groups while professional medical organizations such as the Academy of Pediatrics and the CDC mounted a counter response. Several lawsuits were again mounted against vaccine manufacturers. The Dissatisfied Parents Together group working in association with the American Academy of Pediatrics were instrumental in securing the Passage of the National Childhood Vaccine injury Act of 1986. Dissatisfied Parents Together eventually changed their name in the early 1990s becoming the National Vaccination Information Center (NVIC). The organization asserts that prime function is to advocate for vaccine safety and informed Consent Protections. It bears no relation to the National Vaccine Advisory Committee which is a body within the USDHHS (National Vaccination Information Center, Wikipedia).

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Analysis Parental vaccine hesitancy remains a barrier to routine childhood immunization and hence an increased risk of disease transmission (Nguyen et al., 2022). A survey of US parents suggests at the time of publication (2022), about a quarter are vaccine hesitant. The highest proportion of hesitancy is among parents who are non-Hispanic Black (37%), or Hispanic (30.1%), mothers with a high school education or less (31.9%), and households living below the poverty level (35.6%). In contrast, 16.4% of non-Hispanic white populations had hesitancy. This contributes to an estimated 25% under-vaccination in these children. Mothers were more likely to be hesitant than fathers. Approximately, 11% of parents said that they knew someone who had had serious long-term side effects and this hesitancy is based on their perceptions. A parent’s decision on vaccination is objectively based on an estimate of its relative risks and benefits. Thus, under-vaccination with DTP is often an example of “omission bias.” People would rather avoid doing something in preference to taking potentially harmful action. Hence not vaccinating in spite of the risks is preferable to doing something such as vaccination that actually has defined risks (Asche et al., 1994) (Box 16.1).

References Asch DA, Baron J, Hershey JC, Kunreuther H, et al. Omission bias and pertussis vaccination. Med Decis Making 1994;14. 118-13. Acosta AM, Moro PL, Harari S, Tiwari TSP. Epidemiology and prevention of vaccine-preventable diseases. 14 ed. Centers for disease Control and prevention; 2021. Chapter 7 Diphtheria. Blume S. Anti-vaccination movements and their interpretations. Soc Sci Med 2006;62:628e42. Cabrera-Lalinde I. The online information environment. How misinformation affected the perception of vaccines in the 20th century based on the examples of the polio, pertussis and MMR vaccines. The Royal Society; 2022. ISBN:978-1-78252-567-7. CDC. ChildVaxView: Childhood DTaP Vaccination Coverage. https://www.cdc.gov/vaccines/imzmanagers/coverage/childvaxview/data-reports/dtap/imdex.html. Conis E. Vaccination resistance in historical perspective. Organization of American historians. www.oah.org/issues/2015/august/vaccination-resistance. Cookson C. Benefit and risk of vaccination as seen by the general public and media. Vaccine 2002;20:S85e8. DeHovitz RE. The 1910 St Louis incident: the first modern medical disaster. Pediatrics 2014;133(6):964e5. https://doi.org/10.1542/peds.2013-2817. Gangarosa EJ, Galazka AM, Wolfe CR, Phillips CM, et al. Impact of anti-vaccine movements on pertussis control: the untold story. Lancet 1998;351:356e61. Hamrick P. Eight of history’s most misguided anti-vaxxers. 2021. https://www.mentalfloss.com/ article/651410/anti-vaxxers-in-history. Hardy A. “straight back to barbarism”: antityphoid inoculation and the Great War. 1914. Bull Hist Med 2000;74(2):265e90. Havers FP, Moro PL, Hariri S, Skoff T. Epidemiology and prevention of vaccine-preventable diseases. 14 ed. Centers for disease Control and prevention; 2021. Chapter 16, Pertussis.

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Howson CP, Howe CJ, Fineberg HV, editors. Committee to review the adverse consequences of pertussis and Rubella vaccines. Institute of Medicine; 1991. ISBN: 0-309-55597–3. Tetanus from anti-diphtheria serum. J Am Med Assoc Nov 9, 1901:1255e6. The tetanus cases in Camden NJ. J Am Med Assoc Dec 7, 1901:1539e40. Kulenkampff M, Schwartzman JS, Wilson J. Neurological complications of pertussis inoculation. Arch Dis Child 1974;49:46e9. Lilienfeld DE. The first pharmacoepidemiologic investigations. Perspect Biol Med 2008;51(2):188e98. Markel H. Long Ago against diphtheria, the heroes were horses. New York Times; 2007. https:// www.nytimes/2007/07/10/health/10hors.html. Millward G. A disability Act? The vaccine damage payments Act 1979 and the British government’s response to the pertussis vaccine scare. Soc Hist Med 2016;30(2):429e47. Mortimer PP. The diphtheria vaccine debacle of 1940 that ushered in comprehensive childhood immunization in the United Kingdom. Epidemiol Infect 2011;139:487e93. https://doi.org/ 10.1017/s095026881000302X. National Vaccine Information Center. Wikipedia. https://en.wikipedia.org/wiki/National-vaccineinformation-center. New York Times. Serum foes oppose a statue of Balto. NY Times; March 29, 1925. Nguyen KH, Srivastav A, Lindley MC, Fisher A, et al. Parental vaccine hesitancy and association with childhood diphtheria, tetanus toxoid and acellular pertussis; measles, mumps and rubella; rotavirus; and combined 7-series vaccination. Am J Prev Med 2022;62(3):367e76. Nuwarda RF, Ramzan I, Kayser V. Vaccine hesitancy: contemporary issues and historical background. Vaccines 2022;10:1595e615. Onion R. The dramatic push to immunize children against diphtheria got a boost from a sled dog named Balto. https://slate.com/technology/2021/02/balto-diphtheria-immunization. Park WH. A Brief Biography. 1916 American Association of Immunologists. www.aai.org/about/ history/Past-Presidents-and-officers/William-H-Park. Park WH. History of diphtheria in New York city. Am J Dis Child 1931;42(6):1439e45. Podolsky SH, Smith GD. Park’s story and Winter’s tale.: alternate allocation clinical trials in turn of the century America. J R Soc Med 2011;104:262e8. https://doi.org/10.1258/ jrsm.2011.11k019. Schaeffer M. William H. Park (1863-1939): his laboratory and his legacy. Am J Publ Health 1985;75(11):1296e302. Seither R, Laury J, Mugerwa-Kasujja A, Knighton CL, Black CL. Vaccination coverage with selected vaccines and exemption rates among children in kindergarteneUnited States, 202021 school year. MMWR (Morb Mortal Wkly Rep) 2022;71(16):561e8. Smith PJ, Wood D, Darden PM. Highlights of historical events leading to national surveillance of vaccination coverage in the United States. Publ Health Rep 2011;126(Suppl 2):3e12. https:// doi.org/10.1177/00333549111260S202. Stewart, G. Wikipedia. (epidemiologist) https://www.wikipedia.org/wiki/Gordon-Stewart-(epidemiologist). Stewart GT. Vaccination against whooping cough. Efficacy versus risks. Lancet 1977;(8005):234e7. Tiwari TSP, Moro PL, Acosta AM. Centers for disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 14 ed. 2021. Chapter 21 tetanus.

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Chapter 17

Polio vaccines and their opponents The progressive decline in the importance of infectious diseases in the United States during the 20th century was interrupted in 1940e50 by a series of epidemics of the viral disease, poliomyelitis. This disease was very frightening because it caused paralysis and death in young children. It was objectively scary as well, in view of the need for hospitals to equip themselves with large numbers of iron lungs that served as aids to respiration for those unfortunates whose respiratory muscles had become paralyzed. The growing numbers of polio patients placed, as epidemics do, an intolerable strain on health care systems. In 1952, the polio pandemic reached its peak with nearly 60,000 cases across America of which 3000 were fatal and 21,000 victims were left paralyzed. Fortunately, the uninfected were rescued by the development of very effective vaccines (Nathanson and Kew, 2010). The term poliomyelitis refers to inflammation of the gray matter (polio-) of the spinal cord (myelitis). The gray matter contains the nerve cells, the neurons. (The other component of the spinal cord, the white matter, consists of myelinated nerve axons.) While poliomyelitis is a disease known since ancient times, it does not appear to have caused major epidemics until the 20th century. Prior to that time, under unhygienic conditions in rural communities with primitive sanitation and poor water quality, the virus circulated freely. As a result, most children were infected with the poliovirus when very young and so developed lifelong immunity. Indeed, many babies would have become infected while they were still protected from the disease by antibodies transferred from their mother. Poliomyelitis is caused by human enterovirus C (poliovirus), a positive stranded RNA virus that belongs to the genus Enterovirus of the family Picornaviridae. Its genome consist of a single strand of RNA. Three types of poliovirus, types 1, 2, and 3, each with a different capsid protein have been identified. (These different types can be distinguished by their reaction with specific antiserums and are thus called serotypes.) All three poliovirus types were strictly human pathogens. Poliovirus type 1 was historically the most common but is currently confined to remote rural parts of Pakistan and Afghanistan. The last isolation of wild poliovirus type 2 occurred in India in 1999. It has not

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been detected since and was declared eradicated in 2015. Poliovirus type 3 was last detected in 2012 in Nigeria and Pakistan and declared eradicated in 2019.

The disease Poliovirus invades the intestinal tract. An individual usually ingests the virus with fecally contaminated food or water (the fecal-oral route) and the virus then invades and grows in the tissues of the intestine. As a result, infected humans shed large amounts of virus in their feces. In societies without sewage treatment facilities and thus contaminated drinking water, poliovirus spreads rapidly. Public swimming pools were long recognized as a significant source of infection in the United States and Canada. In about 95% of infections, the virus causes only a transient viremia (when the virus can be found in the bloodstream), and these individuals show no evidence of disease. In the remaining 5%, however, there is an initial incubation period of 3e30 days while the virus invades other tissues such as muscles and lymphoid tissues. The virus may then cause a fever, sore throat, stiff muscles, and headache. This too generally resolves rapidly with no residual problems. In fewer than 1% of infected individuals, however, the poliovirus travels through the bloodstream to the brain and spinal cord. There it selectively destroys a specific subset of motor neurons (called anterior horn cells) located in the patient’s spinal cord. As a result of this nerve cell destruction, the patient can no longer control their arm and leg muscles, and they become paralyzed. This paralysis normally only lasts for several days or weeks but may be permanent. Bulbar poliomyelitis is a severe variant of the disease that results from destruction of the neurons located in the brain stem. These neurons innervate the muscles in the pharynx and soft palate and their destruction prevents both breathing and swallowing. The most severe disease affects the respiratory centers in the brain medulla. Destruction of neurons in that part of the brain results in paralysis of the respiratory muscles and consequently suffocation and death. Polio rarely caused disease in the very young, so it was not considered a major issue in babies despite being called infantile paralysis. However, in “clean” societies where water supplies were normally virus-free, children tended to become infected at a later age and it was they who developed paralysis and died. Death usually resulted from paralysis of the respiratory muscles. These patients therefore required assistance in breathing and had to be placed in an “iron lung” if they were to survive. Most, but not all paralyzed patients recovered some functionality. Nevertheless, the disease affected many victims for the rest of their lives, many needed wheelchairs, crutches, or leg braces. Some survived only to spend the rest of their days in an iron lung (Trevelyan et al., 2005).

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The National Foundation for Infantile Paralysis (The March of Dimes) was established in 1938 to support polio research and, over time, increasingly focused its attention on what seemed the only possible solutionda vaccine (Box 17.1). Basil O’Connor, as the Director of the Foundation, considered two possible vaccines. A killed vaccine being developed by Jonas Salk, and a live, attenuated vaccine being developed by Albert Sabin. O’Connor decided that Salk’s vaccine was likely to be available first, so the Foundation allowed itself to go into debt in order to support Salk’s research (Oshinsky, 2005).

BOX 17.1 Viral vaccines There are many different ways of making antiviral vaccines. Vaccines may simply contain inactivated viruses. The classical example of this is Jonas Salk’s poliomyelitis vaccine that consisted of formalized monkey cell tissue culture derived virus. Like killed bacterial vaccines, these inactivated viral vaccines are cheap to produce and relatively safe. For example, influenza vaccines are made by first growing large quantities of the influenza virus in embryonated chicken eggs. The virus is isolated and then broken up with detergents. The important influenza virus antigen, the hemagglutinin, is then purified and is the major vaccine immunogen. However, immunity to killed viruses such as influenza may be short-lived. One additional problem with viral vaccines is that many of the important viruses such as influenza and the SARS coronavirus consist of multiple highly variable strains. Consequently, they may not be effective when strains change, and new vaccines must be produced at regular intervals. Attenuation Virulent living organisms cannot normally be used in vaccines; otherwise, they will cause disease. (Variolation was an exception.) Under normal circumstances, viral virulence must be reduced so that, although still living, the organisms in vaccines may grow to a limited extent but can no longer cause disease. This process is called attenuation. The level of attenuation is critical to vaccine success. Attenuation must be a key property of the organism and not dependent on fully functional host defenses. However, the attenuated organisms need to be sufficiently invasive and persistent to stimulate a protective immune response. Once organisms are attenuated sufficiently to be used safely, these vaccines are classified as “Modified Live Vaccines” (MLV). The traditional method of virus attenuation has been prolonged tissue culture. This was the method used by Albert Sabin when he developed his human oral polio vaccine. In this case, virus attenuation was accomplished by culturing the organism in cells to which they were not adapted. Sabin grew human poliovirus in monkey cells. Mutants developing during this cell-culture passage lost the ability to cause paralysis in humans. These were then selected for lack of virulence in monkeys. However, now the virus has mutated once again, and a novel type 2 poliovirus has appeared in Africa.

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Jonas Salk Jonas Salk was born in New York in 1914. He obtained his medical degree from the New York University School of Medicine in 1939. After completing his internship at Mt. Sinai Hospital in 1941, Salk joined Dr. Thomas Francis at the University of Michigan at Ann Arbor, where he became deeply involved in the development of a killed influenza virus vaccine. (Until this time the major vaccines, smallpox, rabies, and yellow fever, all contained live attenuated viruses.) Memories of the influenza pandemic at the end of the First World War in 1918 made this a matter of high priority. This killed flu vaccine was developed in 1943. It contained formalin-inactivated influenza virus. This experience led Salk to try a similar strategy when developing the polio vaccine. In 1947, he moved to the University of Pittsburgh and established a Virus Research Laboratory that was funded by the National Foundation for Infantile Paralysis. The keys to making a new polio vaccine were threefold. Jonas Salk’s first task was to collect poliovirus from multiple sources and determine if they were identical. His group confirmed that there were three serotypes and as a result, any effective vaccine would have to contain viruses of all three types. The second need was the ability to produce a constant supply of virus. In 1949, Thomas Weller, Frederick Robbins, and John Enders working at the Boston Children’s Hospital became the first to grow poliovirus in non-nerve cell cultures. They used several different cell types including skin and muscle cells as well as monkey kidney cells. In 1954, they received the Nobel Prize for this discovery. A reliable supply of vaccine virus was thus assured. The third step was to develop a reliable and consistent way of inactivating the virus. This had to be done with a carefully calibrated dose of formaldehyde that inactivated every single viral particle in the solution. Salk’s experience with influenza viruses played a key role in successfully optimizing the inactivation process. Encouraged by the results of the Enders’ group, in 1948, Salk developed methods of growing large amounts of the polio virus in monkey kidney cells. He then showed that he could inactivate this virus by the use of very dilute formaldehyde. The vaccine containing the inactivated virus was then administered by injection. Salk first demonstrated that his vaccine was safe and could protect experimentally-infected monkeys. In the spring of 1952, Salk quietly began small scale trials of his vaccine in immune children (children that had already recovered from polio) at a local children’s home and showed that the vaccine boosted their antibody levelsd thus, it clearly stimulated their immune responses. He followed this by vaccinating a group of nonimmune children. Salk injected the children himself. The vaccine appeared to be both safe and effective. Two years later, with the support of the Infantile Paralysis Foundation, Salk began large scale trials. Basil O’Connor recruited Thomas Francis to manage them.

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The 1954 polio vaccine trials were the largest medical experiments in history to that time. Beginning in April 1954, more than 1,349,135 children aged between 6 and 9 participated as “Polio Pioneers.” (They received a Polio Pioneer card and a badge.) The trials occurred in 211 counties in 44 states. The counties were selected by each state’s health officers based on population, disease prevalence, and available resources. 210,000 children received the placebo and 440,000 received the vaccine. An additional 1,180,000 children served as unvaccinated controls. Children received two doses, 2e4 weeks apart, followed by a third, 7 months later. The results of the trials were announced to the press by Thomas Francis on April 12, 1955, at the University of Michigandthe 10th anniversary of Franklin Roosevelt’s death. Hundreds of reporters showed up. Francis declared that the trials had shown that the vaccine was about 70% effective against type 1 poliovirus and 90% effective against types 2 and 3. It was 94% effective against bulbar poliomyelitis, the most severe form of the disease. The vaccine was licensed by the Food and Drug Administration (FDA) within hours. The news traveled across the country. Overnight, Salk became famous and an instant heroda scientific superstar. His name was posted across the front pages of newspapers in banner headlines. Church bells pealed across the country. People huddled round their radios. The news was announced in offices, stores, and factories. In the face of a huge demand, there was a rush to vaccinate. While the vaccine had been rapidly licensed, the government had made no arrangements whatsoever to handle the enormous demand. At a time when there was great opposition to any suggestion of “socialized medicine,” the Secretary of Health Education and Welfare in the Eisenhower administration, Oveta Culp Hobby, believed that the Federal Government should play no role in distributing the vaccine. The high price and short supply made the government look foolish. Congress however did pass a bill that allocated federal funds to states to enable them to provide free immunization to persons under 20 years of age, and pregnant women. Large scale vaccination only began in the United States in 1957 and as a result, the prevalence of polio dropped precipitously from nearly 58,000 cases in 1952 to 3200 cases in 1960. In contrast, the Canadian Government, anticipating these results, had set up a compulsory vaccination program and moved very much faster.

Albert Sabin Meanwhile, a second polio vaccine was also being developed. Albert Sabin received his medical degree from NYU in 1931. Sabin spent most of his career at the University of Cincinnati as Professor of Research Pediatrics. After the war, Sabin returned to Cincinnati and continued the studies on polio that he had initiated in 1936. He demonstrated that poliovirus multiplied in the intestinal tract before spreading to the central nervous system. Unlike Jonas Salk, Albert Sabin believed that non-pathogenic viruses that grew in the

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intestine would be much more likely to trigger prolonged strong immunity than injected, killed viruses. As a result, beginning in 1951, he worked to develop an oral polio vaccine (OPV) using a virus that had lost its ability to cause disease. This loss of virulence is called attenuation. Sabin grew his polio viruses in monkey cell tissue cultures until they had lost the ability to cause disease in humans. He first tested his vaccine on himself and his family members; members of his research team and 30 volunteers from a nearby penitentiary. They all developed antibodies, and nobody got sick. The enthusiasm for the newly available Salk vaccine made it very difficult for Sabin to get his vaccine tested in the United States. Sabin therefore had to look elsewhere for a large population of children that had not received the Salk vaccine. By the 1950s, polio was a growing problem in the Soviet Union and consequently, the Russians were looking for a vaccine. They considered Salk’s vaccine, but it was expensive and difficult for them to produce and administer. Sabin, on the other hand was keen to help and have his vaccine tested. He convinced the Health Ministry of the Soviet Union to conduct these studies. By 1957, clinical trials began involving two million Russian children. The OPV doses were either mixed with candy or simply dropped directly into the children’s mouths. At the end of the year the results were so good that the Russians decided to vaccinate 77 million individuals under the age of 20. Other trials took place around the same time in Eastern Europe, Singapore, the Netherlands, and Mexico. In 1959, Dr. Dorothy Horstmann was sent by the World Health Organization to assess the results of the Russian trialsdshe reported that Sabin’s OPV was safe and effective. (Dr. Horstmann was the scientist who first showed that poliovirus underwent a transient viremic stage before entering the nervous system. This meant that it would be vulnerable at that time to destruction by antibodies in the blood. She was the first woman Professor of Medicine at Yale University). In 1956, the Infantile Paralysis Foundation adopted a new slogan, “Polio isn’t licked yet.” Salk’s vaccine required three initial injections and an annual booster. While this vaccine had reduced the prevalence of paralytic polio in the United States by 90%, there was some evidence that it was less effective against type 3 poliovirus. Millions of children had yet to be vaccinated. Sabin’s OPV was cheaper, generated rapid intestinal immunity (it was shed in the stools and as a result had the potential to immunize contact children), and could be administered without a needle. It was commonly administered in drops or dropped onto a sugar cube that was then eaten. Because it induced rapid immunity, it could be used effectively at the beginning of an outbreak to stop viral spread. In 1960, permission was granted for Sabin to run a vaccine trial on 180,000 children in his own city of Cincinnati. The community joined in enthusiastically and as a result, polio was eradicated from the city! Sabin’s vaccine was licensed in the United States in 1961. Another mass vaccination effort took place. OPV effectively replaced the Salk vaccine in the United States. By 1975, only 10 polio cases were recorded in the USA (Fig. 17.1). Because it was so easily delivered orally, health

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60,000

Total cases reported

Salk’s Vaccine 1957

50000

40000

30000

20000

10000

The 1916 New York Epidemic

Sabin’s vaccine 1961 1965 65 cases 1970 30 cases 1975 10 cases

0 1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975

FIGURE 17.1 The rise and fall in the number of poliomyelitis cases in the United States between 1900 and 1975. Courtesy of the CDC.

authorities organized “Sabin Sundays” when millions of children and adults turned up at churches and schools to receive their free doses. A Federal public health campaign featured a cartoon bee, Wellbee who urged children to “drink the free polio vaccine.” People were really frightened for their children during the polio epidemic. They saw picture of children confined to large, ugly iron lungs. Iron lungs were incredibly intimidating. These children needed careful attention and nursing care, but there was a shortage of trained personnel. Likewise, in the 1950s following their achievements during the Second World War, people really looked up to scientists. They had developed a deep respect for what scientists do. This may have been the high point for scientific respect during the 20th century. People believed that science and medicine would make their lives better. People believed in the polio vaccine and couldn’t get it fast enough (Brink, 2021). Its arrival was greeted with wild enthusiasm. Coercive measures were never required Very few voices spoke out against polio vaccination, but they made little headway in a population that was desperate to prevent the disease.

Opposition While overwhelmingly popular among the American public, especially parents, polio vaccines were not without their critics. One lonely voice that stood

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out in opposition was Duon C. Miller, the owner of a cosmetics company located in Coral Gables, Florida (Keppler, 2021). Miller established an organization called Polio Prevention Inc. He then distributed literature that claimed that “Thousands of little white coffins will be used to bury victims of Salk’s heinous and fraudulent vaccine.” Miller believed that polio was not an infectious disease rather, it was a state of malnutrition caused by American diets, especially soft drinks. He asserted that “disease and malfunction do not strike us; we build them within ourselves.” By 1953, he was distributing flyers in Key West schools asserting that gamma globulin (antibody) treatments for polio could cause Negro, Japanese, and other racial characteristics, to appear in the descendants of those treated if the treatment had been derived from people of those races.

Polio prevention Inc mailed this statement to Minnesota parents, Just how low can these money-hungry medicos stoop? In their greed for money the plan before a child is born to undermine his health to insure their income permanently. With these damnable cola drinks the “quacks” have laid a perfect foundation for another child victim of polio (more dollars for the medicos).

In his leaflets Miller wrote, Children permitted to indulge heavily in soft drinks, (especially colas), oversweetened and refined starchy foods are the greatest sufferers from polio. No child or adult on a completely competent and balanced diet ever contracts polio.

Miller considered himself to be a medical expert and made several health claims regarding his cosmetic products that got him in trouble with the FDA. In March 1954, he was charged by the federal government for sending “Libelous, scurrilous and defamatory” statements through the mails. For example, his pamphlets not only assailed the vaccine but also contained personal attacks on Jonas Salk and Basil O’Connor the head of the National Foundation for Infantile Paralysis. He accused the Foundation of being unChristian-like and “rotten” for refusing to accept the Polio Prevention Group’s evidence for the cause and cure of polio. Miller was fined and forbidden to send any mail related to medical matters for 2 years. He reluctantly eventually complied, and died in 1969 (Duon H. Miller, Wikipedia).

Chiropractors A second source of opposition to polio vaccination came from some chiropractors. Some practitioners clung to the founding hypothesis of chiropractic that all diseases originated in the spine. They dismissed the germ theory and the concept of contagious pathogens. As a result, some believed that vaccines in general have no effect nor is there proof that vaccines can prevent any disease. It is no coincidence therefore that the profession was divided and that

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even today, some chiropractors remain very much opposed to COVID-19 vaccination (Astor, 2021). Sabin’s live vaccine was given orally and was thus more acceptable to young children and their parents than Salk’s injection. The attenuated viruses invaded the recipient’s intestinal tract and triggered a local immune response in the intestine that prevented further invasion by poliovirus. In contrast Salk’s injectable vaccine stimulated an antibody response in the bloodstream and provided shorter lasting immunity. As a result, Sabin’s vaccine was the vaccine generally employed in the United States although Salk’s vaccine was favored in Canada. Two problems were associated with Sabin’s vaccine. One was the fact that the vaccine virus grows in the intestine and is shed in the patient’s feces. As a result, it may be transmitted to other individuals and can also be detected in the environment. A second, more significant, problem with Sabin’s vaccine was that it can, on occasion, actually cause polio. This was not common, occurring in 1 in 2.6e8 million recipients. Although infrequent, polio vaccine is given to millions of recipients resulting in 6e8 cases annually and paralytic polio is a devastating disease. In order to encourage vaccine use, Congress established a fund to compensate anyone injured by the vaccine. Nevertheless by 1999, wild poliovirus was eradicated from the United States, but vaccine-associated disease persisted. As a result, in 1999, the US Advisory committee for Immunization Practices changed its vaccine recommendations so that children should receive two doses of the inactivated Salk vaccine before receiving 2 doses of oral Sabin vaccine. This was reconfirmed in 2009 (Katz, 2004). Jonas Salk received many international awards and was globally recognized as a hero by the public; though not so with many in the scientific community. In Salk’s own words, he was “looked upon as a hero by the public, but to be looked upon by certain of your scientific colleagues as if you perpetrated the crime of having become a hero, as if it was something you sought.” Sabin and Salk were generally hostile and never cooperated. Indeed, in 1948, Sabin had even suggested that Salk’s formaldehyde inactivation procedure could not kill poliovirus. The feeling between the two men was so bitter that some believe that this was why neither received the Nobel Prize. Jonas Salk died in 1995 in La Jolla, California; Albert Sabin died in 1993 in Washington, DC. Neither Salk nor Sabin ever sought to patent their vaccines. When asked about the patent, Salk replied, “There is no patent. Could you patent the sun?” The feud between the two men persisted even after their deaths with a dispute as to which vaccine was better (Loughlin, 2018). The Western Hemisphere was declared free of polio in 1994.

The British situation The British counterpart of the March of Dimes, the National Fund for Poliomyelitis Research, was founded in 1952. Like its American counterpart,

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its prime goal was to develop an effective vaccine. After the Salk vaccine was introduced into the UK in 1956, routine vaccination effectively reduced the disease prevalence with the last disease outbreak occurring in the 1970s and the last natural polio infection was recorded in 1984. These vaccination campaigns met little resistance from anti-vaccinationists but were at times disorganized and severely underfunded. One notable incident that affected public perceptions of the polio vaccine was the Cutter incident. This obliged Britain and other countries to reassess their vaccination strategies. As a result, the British Medical Research Council recommended that they use a vaccine containing a less virulent strains of the virus than the one used by Salk. The Government also encouraged British production of the Salk vaccine. In 1957, there was an outbreak of polio in the city of Coventry. Unfortunately, the supply of vaccine was quite unable to keep up with the demand. The Government was concerned that it would be blamed so that they permitted American imports to alleviate the shortage. It took several years for British polio vaccine production to catch up. The lack of vaccines resulted in consistently negative press coverage and much confusion regarding who was eligible to be vaccinated. Some local health authorities stopped vaccinating altogether for a time, not as a result of antivaccine sentiment but simply because of bureaucratic confusion and loss of public confidence.

The Cutter incident Because of the huge demand for Salk’s polio vaccine and the need for largescale production, several different vaccine companies were recruited to manufacture it. Some were large and experienced while others were small and inexperienced. Cutter Laboratories in Berkeley, California, was one of the latter. In April 1955, Cutter produced a batch of 120,000 doses of the inactivated Salk vaccine. Unfortunately, the company had deviated from the Salk protocol and the virus had not been completely inactivated by the formaldehyde. The manufacturing and inspection processes had failed. In April 1955, children, primarily in Western States, received the vaccine produced by Cutter. The first case of paralytic polio developed within days. The number of affected children began to mount alarmingly. Investigations revealed that Cutter Laboratories were the source of the vaccine. The mass vaccination campaign was temporarily halted. Of the children who had received the faulty batch, 40,000 developed the self-limiting infection and remained healthy; about 56 individuals developed paralytic polio and five died. Secondary spread to families and unvaccinated children resulted in a further 113 cases of paralysis and five more deaths. A congressional enquiry concluded that in the rush to produce vaccine, the FDA had failed to test all the vaccine batches. It is now considered likely that Cutter allowed some virus batches to clump so that when the formalin was added it could not reach and kill every viral particle. Production soon resumed, but it also raised the public perception that the Salk vaccine was

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unsafe and paved the way for Sabin’s vaccine. (In an effort to restore public confidence, Elvis Presley was vaccinated on the set of “The Ed Sullivan Show” on national television in October 1956!) The Cutter incident also had a positive effect since it led to greater federal regulation of vaccine production and safety as well as increased enforcement activity so that today, human vaccines are quite remarkably safe (Cabrera-Lalinde, 2022). The Cutter incident also opened the whole vaccine area to litigation. Cutter was liable to pay damages to those affected by this vaccine. The wave of litigation almost put vaccine manufacturers out of business. The National Vaccine Injury Compensation Program was introduced in 1986 to protect vaccine manufacturers from litigation. Unfortunately, vaccines are not very profitable and are complex to make. As a result, risk aversion and litigation have discouraged many companies and only a small number now manufacture vaccines in the United States. Even following the Cutter incident, parents still wanted their children to be vaccinated. They still trusted the Doctors and as a result the disease has almost been eradicated from the planet. Sadly, in June 2022, a case of polio was diagnosed in an unvaccinated immunocompetent adult from Rockland County, New York. The patient had been hospitalized with flaccid lower limb weakness. Vaccine-derived poliovirus type 2 was isolated from this patient. It was also identified in wastewater samples in two neighboring New York counties (Link-Gelles et al., 2022). Presumably the virus had been imported from one of the three countries where oral polio vaccination is ongoing. It is relevant to note that according to the New York State Immunization system, 3-dose polio vaccination coverage of young children in Rockland County in July 2020 was only 67%.

Global eradication In May 1988, the World Health Assembly passed a resolution seeking to eradicate poliomyelitis from the globe by 2000. Their strategy was based on routine vaccination of entire populations followed by surveillance programs and “mop-up” campaigns as necessary. The Sabin oral vaccine was the basis of this program because of its ease of application and its long-lasting protection. It was also much cheaper to produce than Salk’s. There was no need to use expensive needles and syringes. Initially, the eradication program made rapid progress. In 1988, 125 countries had had endemic polio, and it is estimated that 350,000 children had been paralyzed every year (Cabrera-Lalinde, 2022). By 1994, the Americas were polio-free. By 2000 the Western Pacific and by 2002 Europe were declared free of the disease. India that had had 200,000 cases annually through the 1990s was declared polio-free in 2014. Globally, the number of polio cases has dropped by 99%, and the disease now persists in only three countries: Pakistan, Afghanistan, and Nigeria.

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Nigeria The “Kick Polio out of Africa” campaign was launched by Nelson Mandela in 1988 as part of the World Health Organization’s (WHO) program to eradicate polio in the whole of Africa by 2000 (Cabrera-Lalinde, 2022). By 2003, this had not been achieved. As a result, the Global Polio Eradication Initiative began to focus on Nigeria which accounted for 45% of the polio cases worldwide at that time. It had scarcely started when pressure from religious leaders triggered a 16month boycott and suspension of the campaign. Members of the Supreme Council for Sharia in Nigeria argued that the West had somehow corrupted the vaccine (Sabin’s OPV), especially after the events of 9/11. Since 9/11, there had been a deepening mistrust between the Muslim world and the West that had a direct influence on their perceptions of polio vaccination. Muslim clerics insisted that parents should not vaccinate their children. As a result, polio vaccination stalled, and poliovirus was uncontained and free to spread. Much of the opposition to polio vaccination in Nigeria occurred at the community level. The erosion of trust in Muslim communities was a result of political tensions and social neglect. In 2003e04, local religious leaders in five Muslim-majority states, Kano, Kaduna, Niger, Bauchi and Zamfara, claimed that the vaccine was contaminated with human immunodeficiency virus (HIV), with carcinogens, or with sterilizing agents such as estradiol. This was publicly promulgated by a Nigerian physician, Ibrahim Datti Ahmed (Andrade and Hussein, 2018). These leaders argued that the campaign was designed to control, not polio, but the spread of Islamic beliefs. They claimed that the polio vaccines had been “corrupted and tainted by evildoers from America and their Western allies.” Ahmed claimed that “We believe that modern-day Hitlers have deliberately adulterated the oral polio vaccines with anti-fertility drugs and viruses which are known to cause HIV and AIDS.” They are part of a dastardly Western plot to eliminate Muslims (This conspiracy theory eventually received even greater traction in Pakistan, especially in tribal areas controlled by the Taliban) (Andrade and Hussein, 2018). While initially believed to reflect religious opposition, the mistrust went much deeper, especially in the Muslim north of the country. There were ongoing regional struggles related to regional power groups, to already inadequate health structures, and to an overall mistrust of the central Nigerian government. As discussed in Chapter 21, vaccination is fully compatible with Islamic laws, but local extremist groups chose to reinterpret these laws in order to manipulate local communities. This is despite the fact that the Organization of the Islamic Conference supported the polio-eradication initiative. Social inequality also exacerbated vaccine resistance, and many questioned the availability of vaccines while other healthcare was almost nonexistent. Population control policies adopted during the 1980s attempted to set a limit of four children per woman. This led the public to conclude that there was a possible connection between vaccination and sterilization (Cabrera Lalinde, 2022).

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In many remote rural communities in Nigeria, traditional healers are their first-line healthcare workers and possibly their only ones. In many Muslim communities, polio is considered a disease of the spiritual world. Traditional healers, as a result of their knowledge of local conditions and cultures, are often community leaders. In northern Nigeria, these leaders have both traditional and religious powers. They are the communities’ main source of reliable information and enforcers of local authority. They are the custodians of traditional and cultural customs, and as such wield significant authority. They play a key role in the decision-making process within local communities. For some of these leaders, the theory that vaccination can prevent disease is difficult to believe. Polio is a manifestation of the female spirit that when anger consumes the limbs of humans. She can certainly not be appeased or contained simply by giving a few drops of a simple liquid to a child. The only ones who can do this are the traditional healers who are believed to have the ability to connect to the supernatural world. The vaccine boycott and resulting public health disaster came to an end when Kano’s religious leaders, persuaded by their government, the WHO, and UNICEF decided to participate in a meeting that demonstrated vaccine safety. However, during the boycott, the disease had leaked over Nigeria’s borders to cause cases of polio in 14 other West African countries. By 2015, there were no new cases in Nigeria. However, polio returned in 2016 as a result of local civil war and fighting, especially in Borno State in the remote Northeast of the country. Much of the delay in completing the eradication task was a result of having to vaccinate in the presence of marauding Islamist terrorist militia groups such as Boko Haram (Webster, 2017). Boko Haram does not accept western medical science and actively discourages such western practices as vaccination. It used violence against vaccination workers and destroyed healthcare facilities. In 2013, at least nine vaccination team members in the state of Kano were murdered by Boko Haram. This group effectively cut off entire provinces in Nigeria and neighboring Cameroon and blocked access to vulnerable children (Bigna, 2016). When the Nigerian army reoccupied these areas, they found that wild poliovirus was still circulating. In response, the government mounted a huge emergency vaccination campaign and vaccinated 830,000 children in the first 2 weeks. Unfortunately, during the boycott and subsequently, the number of confirmed polio cases doubled.

Vaccine-induced polio In August 2020, Africa was declared free of “wild” polio (Scherbel-Ball, 2020). Unfortunately, recent isolates of polio virus in water supplies in Lagos, the capital of Nigeria, have proved to be virulent mutants of Sabin’s oral vaccine strain of type 2 poliovirus. For many years, OPV contained three types of poliovirus: 1, 2, and 3. Because the type 2 virus had not been detected since 1999, it was believed to have been eradicated and so vaccines were adjusted to

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contain only types 1 and 3. Within a few years, the number of type 2 outbreaks rose significantly and began to spread among West African countries with low immunity as well as east to the Sudan (Roberts, 2020). Thus, in 2018, the type 2 vaccine virus caused 33 deaths and paralyzed 105 children. In 2019, it caused 196 cases of paralysis. Work has been underway to develop a new improved oral type 2 vaccine that cannot revert to virulence so easily. This novel oral polio vaccine (nOPV2) has completed clinical trials and the results have been very encouraging. As a result, the World Health Organization authorized its use in November 2020 (Martin et al., 2022). About 111 million doses of the nOPV2 vaccine were administered worldwide between March and October 2021. Stool samples taken from vaccinated individuals show no evidence of reversion to virulence. It should be noted that in 1996 (Pertwee et al., 2022), Pfizer conducted a drug trial in Nigeria to test an anti-meningitis drug. Unfortunately, during the trial 11 children died and many others developed significant disabilities. Pfizer asserted that it had obtained approval for the trial from the appropriate authorities as well as the verbal consent of the patients before the study. The deaths were due to the meningitis, not to the drug. There was, however, a widespread perception that the company had behaved unethically and resulted in the Nigerian public being more willing to accept the anti-vaccination disinformation. In a survey, over half of Nigerians believed that it was “definitely” or “probably” true that harmful side effects of vaccines were being deliberately concealed (Pertwee et al., 2022).

Pakistan In mid-2022, wild poliovirus type 1 (WPV1) only persisted in Pakistan and neighboring Afghanistan. Its transmission has never been interrupted. The major barriers to its total elimination include religious based refusals, and parental refusal to vaccinate based on widespread conspiracy theories. Pakistan is a densely populated south Asian country in which at least 25% of the population live below the poverty line. Healthcare is very limited in the more remote regions of the country and almost 60% of children at risk of infectious disease are not immunized (Rahim et al., 2021). It is also a deeply conservative Muslim country, and religious beliefs play an important role in most people’s daily lives. Parts of the country are politically unstable. As a result of armed insurgency and militancy in the country’s northern regions, regions that are very religiously conservative have significantly impeded the country’s ability to control polio. Polio vaccination campaigns have suffered very high levels of hesitancy and refusals. As a result of the murder of vaccination workers and the police guarding them, vaccination campaigns have had to be suspended and large numbers of children in these areas remain unvaccinated.

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Pakistan’s polio eradication program began in 1994 (Rahim et al., 2021). National surveillance began and door-to-door vaccination teams began operating. Millions of children were vaccinated and as a result cases declined from 20,000 in 1994 to 199 in 2001, and 28 cases in 2005. The Stop Transmission of Polio (STOP) campaign started in 1994 and initially progress was good. It was long apparent that the majority of polio cases in Pakistan were occurring in the northern province of Khyber Pakhtunkhwa (KP) and adjacent tribal areas, as well as in the city of Karachi. KP remains the most infected region of the country with poor sanitary conditions, contaminated reinking water, and widespread polio transmission. After the events of 9/11 and American intervention in Afghanistan, the situation changed dramatically. Violent conflicts developed between armed militants and the Pakistani armed forces. As a result, polio cases began to rise from 32 in 2007 to 198 in 2011. The violence mainly affected the KP area as did polio with over 70% of known cases. The number of these cases climbed to 306 in 2014. The militants were actively hostile to the vaccination program. The propaganda against the polio vaccination program viewed it as a conspiracy against Islam mounted by the United States and Israel in order to sterilize young Muslim women and control their birth rate (This was similar to the conspiracy theory that circulated in Nigeria at that time) (Ullah et al., 2016). Vaccination workers were attacked and killed. The police assigned to guard the vaccinators were also targeted. The extremists effectively banned polio vaccination and as a result almost 400,000 children in the tribal north could not be vaccinated during 2010e11. The rumor was also spread that the vaccine was not “Halal.” It was said to contain pig fat (or gelatin) and alcohol (both prohibited to Muslims) (Warraich, 2009). It was a plot by evil infidels to corrupt righteous Muslims. It was also claimed that at least some of the vaccines being used had expired. In addition, there is deep resentment at the heavy-handed visits of vaccination teams backed by the police. Local teams of vaccinators have been recruited in an effort to overcome local resistance, but these local vaccinators are susceptible to pressures from within their own community. As a result, there have been occasions where the vaccinators have shown patents how to avoid vaccination by marking their children’s fingers with ink. The numbers of parents who refused to have their children vaccinated with the oral vaccine grew enormously. This refusal has mainly been restricted to the KP region and the tribal areas of Pakistan. These are the most conservative regions in a highly conservative country. The mixture of poverty, illiteracy, violent conflict, mistrust of authority, and conspiracy theories simply block the process. The killing of Osama bin Laden by US forces in Abbottabad in 2011 was followed by the suspension of the UN vaccination campaign in 2012 after two vaccination workers were murdered. It was reported that the CIA had used a Pakistani doctor, Shakil Afridi, to set up a fake hepatitis B vaccination

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campaign in Abbottabad as a cover for the search for the Al Qaeda chief. Spies posing as hepatitis B vaccinators got into Bin Laden’s home, obtained DNA samples from his family members, and so determined his whereabouts. This operation had a very negative effect on Pakistan’s polio vaccination initiatives by confirming the suspicions of many Pakistanis that the polio campaign also had nefarious motifs. It also jeopardized the lives of many humanitarian aid workers in Pakistan (Shah, 2012). In 2011, the Pakistani Government struck back against the militants. As they gained the upper hand, vaccinations resumed, and polio cases began to drop once more. Muslim clerics were tasked with convincing parents that the vaccines were not anti-Islamic and protected their children from a disabling disease. Edicts were issued by religious scholars in favor of vaccination and were carried by vaccination teams to be produced on request. In 2015, the Government had the vaccine tested and certified by the Drug Regulatory authority of Pakistan as “Halal.” As a result, the number of polio cases that had peaked at 306 in 2014, dropped to a single case in 2016 (Rahim et al., 2021). Things changed again in early 2019. In a final effort to eliminate polio the government announced that all children up to age 10 were required to get polio drops. On April 22, 260,000 polio workers were mobilized with the goal of administering the vaccine to 39,000 children. A rumor started on the very first day of the campaign claimed that children were falling ill after having received the polio drops. That same day a number of children develop nausea and vomiting as well as diarrheadit was very warm weather. As a result, frightened parents rushed 40,000 children to hospitals. In Peshawar (the capital of KP), the panic descended into violence. Health clinics in many towns and cities were sacked and burnt by angry mobs. Some mosques announced through their loudspeakers that all vaccinated children would die within 24 h. Word spread through illegal radio stations. Polio workers and their police guards were attacked and killed. Parents by the thousands refused vaccination. Health officials claimed it was all a preplanned conspiracy. The anti-polio drive was suspended indefinitely. As a result, case numbers began rising again. From 12 in 2018 to 147 wild polio virus cases and 22 oral vaccine strain mutant cases in 2019, to 84 in 2020, to a single case in 2021 but then, 14 months later, a jump to 14 cases by July 2022. These last cases are all due to WPV1 infections in unvaccinated children and are clustered in southern KP. Vaccination has resumed but refusals remain very high. The open border with Afghanistan also means that many children remain inaccessible to vaccination teams (Mbaeyi et al., 2022).

Afghanistan Since 2017, wild poliovirus type 1 has been detected only in Afghanistan and Pakistan. The number of polio cases in Afghanistan increased from 29 in 2019 to 56 in 2020. From January to November 2021, only four wild polio cased

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have been reported (Sadigh et al., 2022). During the Afghan civil war, the Taliban opposed polio vaccination as a Western plot. The local Taliban issued fatwas denouncing vaccination as an American ploy to sterilize Muslim populations. The Taliban assassinated vaccination officials including Abdul Ghani Marwat who was the head of the government’s vaccination campaign in Bajaur Agency in the Pakistani tribal areas on his way back from meeting with a religious cleric in 2007 (Warraich, 2009). However, once they regained power in 2021, the Taliban changed course. That November, they launched a nationwide polio vaccination campaign after years of opposition (Shepherd, 2021). In fact, only four cases of wild poliovirus type 1 (WPV1) were reported in the country in 2021. Their new campaign seeks to build upon the advances made by the former government and is targeting 9.9 million children up to 5 years of age. The Taliban government has taken the lead in promoting oral vaccination after years of vaccine hesitancy. In the meantime, the hardline Islamic State’s Khorasan chapter (IS-K) continues to oppose vaccination. At least four members of a polio vaccination team in the eastern provinces of Afghanistan were killed and three others wounded by IS-K in 2021. In addition, some Taliban splinter groups in the border regions between Afghanistan and Pakistan continue to issue death threats to vaccination workers despite the government in Kabul. Skepticism toward polio vaccination still remains high in many rural communities (Saif, 2022). It should be noted that the Saudi Arabian Government requires all pilgrims visiting Mecca (the Hajj and Umran) to be first vaccinated against polio and has mandated that all pilgrims entering the country must also receive an oral dose of polio vaccine on arrival (Chapter 21).

The endgame What was hoped to have been the final stretch in then poliovirus eradication campaign has suffered setbacks as a result of the COVID-19 pandemic. Numbers have begun rising again in Pakistan. Polio has also spilled across the porous western border of Pakistan into Iran. Resurgence of disease due to the novel oral vaccine strain (nOPV2) has also been reported in China and Myanmar. Finally, the spread of COVID-19 forced suspension of mass polio vaccination from February to August 2020 in several countries dealing a further setback to a program already in trouble and possibly permitting poliovirus to spread to other countries. However, in 2022, as of August 9 there have been 19 cases of wild type strain 1 infections globally and 223 cases due to circulating vaccine derived oral type 2 poliovirus. This year 2022, vaccine derived polio has been reported in 15 countries. There have been four wildtype 1 cases reported in Mozambique related to a strain from Pakistan. Vaccine-derived poliovirus type 2 has spread to cities in other countries including New York and London (Box 17.1).

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References Andrade GE, Hussain A. Polio in Pakistan: political, sociological and epidemiological factors. Cureus 2018;10(10):e3502. https://doi.org/10.7789/cureus.3502. Astor M. Vocal anti-vaccine chiropractors split the profession. 2021. https://www.nytimes.com/ 2021/07/14/health/anti-covid-vaxxers.html. Bigna JJR. Polio eradication efforts in regions of geopolitical strife: the Boko Haram threat to efforts in sub-Saharan Africa. Afr Health Sci 2016;16(2):584e7. Brink S. Can’t help falling in love with a vaccine: how polio campaign beat vaccine hesitancy. 2021. https://www.npr.org/sections/health-shots/2021/05/03/9888756973. Cabrera-Lalinde I. The online information environment. How misinformation affected the perception of vaccines in the 20th century based on the examples of the polio, pertussis and MMR vaccines. 2022. Keppler N. The loneliest anti-vaxxer. Slate Nov 26, 2021. https://flipboard.com/article/theloneliest-anti-vaxxer/f-23ec51e12e%2Fslate.com. Katz SL. From culture to vaccineeSalk and Sabin. N Engl J Med 2004;351:1485e7. Link-Gelles R, Lutterloh E, Ruppert PS, Backenson PB, et al. Public health response to a case of paralytic poliomyelitis in an unvaccinated person and detection of poliovirus in wastewaterNew York, June-August 2022. MMWR (Morb Mortal Wkly Rep) 2022;71(33):1065e8. Loughlin K. Salk and Sabin: the disease, the rivalry and the vaccine. Hektoen Int 2018. https:// hekint.org/2018/01/30/salk-sabin-disease-rivalry-vaccine/. Martin J, Burns CC, Jorba J, Shulman LM, et al. Genetic characterization of novel oral polio vaccine type 2 viruses during initial use phase under emergency use listingeworldwide, March-October 2021. MMWR (Morb Mortal Wkly Rep) 2022;71(24):786e90. Mbaeyi C, Baig S, Safdar MR, Kahn Z, et al. Toward poliomyelitis eradication-Pakistan JanuaryJuly 2022. MMWR (Morb Mortal Wkly Rep) 2022;71(42):1313e8. Nathanson N, Kew OM. From emergence to eradication: the epidemiology of Poliomyelitis deconstructed. Am J Epidemiol 2010;172:1213e29. Oshinsky DM. Polio: an American story. Oxford University Press; 2005. Pertwee E, Simas C, Larson HJ. An epidemic of uncertainty: rumors, conspiracy theories and vaccine hesitancy. Nat Med 2022;28:456e9. Rahim S, Ahmad Z, Abdul-Ghafar J. The polio vaccination story of Pakistan. Vaccine 2021. https://doi.org/10.1016/j.vaccine.2021.11.095. Roberts L. Global polio eradication falters in the final stretch. Science 2020;367(6473):14e5. Sadigh KS, Akbar IE, Wadood MZ, Shukla H, et al. Progress towards polio eradicatione Afghanistan. January 2020-November 2021. MMWR (Morb Mortal Wkly Rep) 2022;71(3):85e9. Saif SK. Taliban initiate polio vaccination campaign, Tedros meets Afghan health minister in Geneva. Health Policy Watch News 2022. https://healthpolicy-watch.news/93812-2/. Scherbel-Ball N. Africa declared free of wild polio in ‘milestone’. 2020. https://www.bbc.com/ news/world-africa-53887947. Shah S. CIA tactics to trap Bin Laden linked with polio crisis, say aid groups. 2012. https://www. theguardian.com/world/2012/mar/o2/aid-groups-cia-osama. Shepherd A. Taliban lifts ban on polio vaccinations in Afghanistan. Br Med J 2021;375:n2656. https://www.bmj.com/content/375/bmj.n2656. Trevelyan B, Smallman-Raynor M, Cliff AD. The special dynamics of Poliomyelitis in the United States: from epidemic emergence to vaccine-induced retreat. Ann Assoc Am Geogr 2005;95:269e93.

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Ullah SF, Deen FA, Hussain Y. Genesis of polio vaccination hindrance syndrome in Pakistani society, Religio-medical aspects. Open J Soc Sci 2016;4(3). https://doi.org/10.4236/ jss.2016.43015. Warraich HJ. Religious opposition to polio vaccination. Emerg Infect Dis 2009;15(6):978. Webster P. Nigeria’s polio endgame impeded by Boko Haram. Can Med Assn J 2017;189(25):e877e8. Wikipedia. Duon H. Miller. https://en.wikipedia.org/wiki/Duon-H.-Miller.

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Chapter 18

Measles, mumps, and rubella: three contentious virus diseases In 2019, the World Health Organization listed vaccine hesitancy as one of the top 10 threats to global health. As a result of this hesitancy, outbreaks of some vaccine-preventable infectious diseases are starting to recur. This generally happens in areas, and among communities where vaccination rates are low. Thus, while almost gone, in 2019, there were 1282 confirmed cases of measles in the United States. Vaccine hesitancy is therefore a serious public health threat, and its consequences are potentially disastrous. In some respects, such hesitancy is surprising given the recognized manifold benefits of vaccination, but the reasons for hesitancy are complex and associated with key factors encountered throughout this book, most notably safety, efficacy, and liberty. Governments have rarely invested in examining or seeking to solve vaccine hesitancy problems. In addition, the medical profession has often been slow to refute spurious claims regarding both safety and efficacy. As vaccines against measles were developed in the 1960s and 1970s, medical authorities tended to assume that they would be greeted with the same enthusiasm that had greeted polio vaccine. But measles was nowhere near as scary as polio. Many families just shrugged it off. Parents would get their children vaccinated if their doctors recommended it but not everyone did. In the United States, this resulted in middle-class parents with good medical insurance getting their children vaccinated, but the poor and lower-class children did not. Health authorities tried many promotional tactics but eventually felt obliged to resort to compulsion. Measles vaccination was made a prerequisite for enrolling in school. Public awareness of the adverse effects of vaccination is a result of many factors. The most obvious is the efficacy of vaccines themselves. Thus, an effective vaccination program will reduce the prevalence of a specific disease. With this reduced disease prevalence then the fear of serious illness declines. Eventually, the benefits of vaccination appear to a layperson to be more theoretical than real. As a result, acceptance of the immunization program declines and interest shifts to the persistent, real, (or perceived) adverse effects

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of vaccines. These gradually assume much greater significance, especially since they may occur in otherwise apparently healthy children.

Adverse effect principles In determining whether a vaccine causes an adverse effect, the Center for Disease Control and Prevention has recommended following three basic principles. First, is the effect consistent? The adverse responses should be the same if the vaccine is given to different group of recipients, by different investigators, and irrespective of the method of investigation. Second, is the effect specific? The association should be distinctive, and the adverse event linked specifically to the vaccine concerned. It is important to remember that an adverse event may be caused by vaccine adjuvants and components other than the major antigens. Finally, there must be a temporal relationship. Administration of the vaccine should precede the earliest manifestations of the event or result in a clear exacerbation of an ongoing condition. The US Center for Disease Control and Prevention (CDC) has classified adverse events thus: 1. Vaccine-induced events: These are events that would not occur in the absence of vaccination and are therefore attributed to the vaccine. An example would be an allergic response to a vaccine component such as egg protein. 2. Vaccine potentiated reactions: These are events that might have occurred anyway but may have been precipitated or potentiated by the vaccine. 3. Programmatic error: These are events that occur in response to technical errors in vaccine storage, preparation, handling, or administration. 4. Coincidental events: These are simply events that happen by chance or result from some unrelated illness. Many of the alleged adverse effects of vaccines are coincidental. Perhaps the best example of this is the association between receiving the measles-mumps-rubella vaccine and the development of autism spectrum disorder in children.

Measles Measles is caused by a paramyxovirus of the genus Morbillivirus. Its genome consists of single stranded, negative sense RNA. The virus was first isolated in 1954. Measles virus causes a systemic viral infection that is spread by the respiratory route. Infection is followed by an incubation period of 11e12 days. The patient gradually develops a fever (103e105 C), then they develop a cough, coryza, and conjunctivitis (Gastanaduy et al., 2021). Koplik spots, unique to measles, develop within the patient’s mouth. The virus replicates rapidly and causes a viremia 2e3 days after infection when it spreads through the bloodstream to regional lymph nodes. As the virus continues to replicate, a

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secondary viremia also occurs 5e7 days after the onset of infection. Infected lymphocytes and dendritic cells from these lymph nodes circulate through the skin where the virus then infects skin cells. As a result, a characteristic skin rash develops around 14 days. The rash persists for 5e6 days beginning on the face and upper neck and spreading downwards to the hands and feet. Severely affected areas may peel off in scales. The rash eventually fades. The vast majority of measles cases in the United States recover uneventfully. However, complications may include diarrhea, otitis media, pneumonia, encephalitis, subacute sclerosing panencephalitis, and death. In poor countries where children suffer chronic malnutrition, measles can kill as many as 10% of those infected. About 1 in 3000 cases can develop inflammation of the brain and spinal corddpost-measles encephalomyelitis. This complication can result in the death of up to 15% of those affected. In another 25% of encephalomyelitis cases, the patient may suffer permanent brain damage and lasting disability. A much rarer condition, subacute sclerosing panencephalitis occurs in about 1 in 100,000 cases and is invariably lethal (Misin et al., 2020). Measles induced damage to the auditory nerves may result in deafness. Measles is also an immunosuppressive virus that can permit the development of secondary bacterial infections leading to pneumonia or gastroenteritis. These complications are most common in children under five and in adults. However, in pregnant women, measles increases the risks of miscarriage and premature birth.

Current status Prior to the 1960s in the United States, almost everyone contracted measles, usually in childhood. By the late 1950s and up to 1962, the year before the introduction of measles vaccination, there were approximately 500,000 cases reported annually in the USA, with 48,000 people hospitalized as a result. Of these, 4000 developed encephalitis, a life-threatening inflammation of the brain. Measles-related complications such as pneumonia and encephalitis resulted in about 500 deaths annually. This number of measles-related deaths was relatively low compared to earlier in the century as a result of improved medical care, antibiotic therapy of secondary bacterial infections, and better overall nutrition. Prior to the introduction of vaccines, measles occurred almost universally among American children and as a result more than 90% were immune by the time they reached age 15. They were also inadvertently boosted as a result of subsequent exposures. Measles is still a common disease in developing countries.

Measles vaccines As described in Chapter 17, Dr. John Enders won the Nobel Prize for Medicine in 1954, for discovering how to grow the polio virus in monkey kidney cells. In

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that same year, at Boston Children’s Hospital, Enders and Thomas Peebles switched to studying measles. By collecting blood and throat-washing samples from children with measles and growing the samples on cultured cells, Peebles was able to isolate the virus. One such sample was taken from a 13-year-old student, David Edmonston. This cultured measles virus was named the Edmonston strain and was subsequently used for the development of the measles vaccine. During the late 1950s and early 1960s, continuing research in the United States and a large trial that vaccinated over 700,000 children in the West African country of Upper Volta (present day Burkina Faso) culminated in the development and licensure in 1963 of two measles vaccines: a killed vaccine and a live attenuated vaccine. The killed virus vaccine was produced and administered between 1963 and 1967. Use of the killed vaccine was however discontinued because it produced a relatively short-lasting immunity. The attenuated virus strain was produced by repeatedly growing and transferring the Edmonston virus through different cell cultures in the laboratory. This prolonged serial passage in cell culture eventually resulted in changes in the genetic make-up of the virus. It was able to infect cells, but could no longer cause disease in humansdit was effectively attenuated. Additional efforts further attenuated this vaccine virus and improved its safety profile. This improved version of the vaccine was released in 1968. One dose is 93% effective in preventing measles infection while two doses are 97% effective (Fig. 18.1). Measles vaccine 1963

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Once measles vaccines became available, a nationwide immunization program was initiated. In 1966, the government began a program to eliminate measles from the United States. This program was mainly based upon use of the attenuated virus vaccine for routine vaccination of infants; vaccination of children upon entry to public school; and disease surveillance and control of outbreaks. By 1968, only 22,200 cases of measles were reported, a drop of nearly 95% compared to pre-vaccination levels. Beginning in 1971, measles vaccine was also combined with two other childhood vaccines, directed against mumps and rubella viruses. Before the measles, mumps, rubella (MMR) vaccine became widely available, in the 1960s, measles affected about 3000 persons per million. As a result of widespread vaccination, this figure dropped in the 1980s to 13 cases per million and to 1 case per million by 2000. In the United States, they fell from about 500,000 cases annually to several thousand in the 1980s and to just a few hundred annually since the mid-1990s. In 2005, a combined measles, mumps, rubella, and varicella vaccine was also licensed. However, vaccination coverage was not universal and was well below the calculated 90%e95% level required to protect and ultimately eradicate measles from the US populationdthe herd immunity effect. Thus, measles continues to occur in the population, cycling between years of low measles incidence followed by years with large outbreaks. As a result of the continued national immunization program, despite sporadic outbreaks, measles was declared eradicated in the United States in 2000. The claim was justified at the time since transmission of the virus within the country had been interrupted for 1 year, and all reported cases had been imported from foreign countries. This feat was accomplished by employing a strategy that maximized population immunity by the timely immunization of preschool children and re-vaccination of school aged children. However, the risk of viral reintroduction and spread remains a constant threat. Reintroduction can be caused by immigration from, or travel to, areas with continued high measles activity (which is most of the rest of the world). This threat is exacerbated as sections of the US population actively resist vaccination because of social, religious, psychological, philosophical, and safety issues. The continued sporadic measles outbreaks that have occurred since the declared elimination of measles in the US demonstrate the ongoing risks and consequences resulting from international travel and the presence of an unvaccinated population. Some religious communities, due to issues pertaining to research, the presence of forbidden animal proteins or fats, purity of the body, inappropriate interference in God’s work or plan, predestined fate, etc., have high rates of under-immunized children. This sets up an environment for disease resurgence. Several recent incidents in the past decades are illustrative. Between 1985 and 1994, there were 13 documented outbreaks of measles in the United States mainly among religious groups that were opposed to vaccination. These outbreaks eventually involved more than 1200 cases and

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led to nine deaths. An analysis by Salmon et al. demonstrated that during the 10-year period, between 1982 and 1992 persons with religious or personal exemptions from vaccination were 35 times more likely to contract measles than were vaccinated individuals (Salmon et al., 1999). In addition, it was found that persons living in communities with high levels of such exemptions were themselves at greater risk of contracting measles. Significant outbreaks of measles occurred in New York City, North Carolina, and Texas in 2013. During a 4-month period in the spring of 2014, 383 cases of measles were reported in Ohio. The source of the outbreak was traced to four people from the Amish community who had returned from a visit to the Philippinesda country that was in the midst of a measles outbreak at that time. The spread of measles was limited almost exclusively (99% of the cases), to the Amish community, a population that is vaccination hesitant. More than half the victims had not been vaccinated. In February 2015, a measles outbreak originated in the California amusement park, Disneyland. It also appears to have originated in the Philippines. Given the attraction of the park it is unsurprising that measles spread rapidly to other states as well as to Canada and Mexico. By June that year, 178 people from 24 other states had developed the disease. Most were considered secondary or tertiary to the Disneyland outbreak. In response to the Disneyland outbreak, the California Legislature strengthened their school vaccination laws while the opponents of vaccination protested against them. However, the bill passed and was signed into law. California became the third state in the US to abolish religious exemptions to vaccination (Tolley, 2019). In another example, in the latter part of 2018, a non-vaccinated person with a history of recent travel to Israel was identified as the source of an outbreak in New York and New Jersey. During a 6-month period, 275 cases of measles were identified, with the majority of the cases being members of the Orthodox Jewish community, a community that also has low vaccination compliance. By early 2020, the United States was in the midst of the worst measles outbreak since the “elimination” of the disease in 2000. During 2019, there were 1282 cases of measles in 31 states, with the highest concentration of cases occurring in New York and Washington. Of these cases, 128 patients were hospitalized, and measles-related complications such as pneumonia and encephalitis occurred in 61 cases. Many factors contributed to the disease spread but low vaccination rates of school-aged children were paramount. About 90% of the cases occurred in people not vaccinated or with an unknown vaccination history. The COVID-19 pandemic of 2020e22 has caused significant disruptions in the childhood vaccination programs in many underdeveloped countries. As a result of a shortage of funds, manpower, and vaccine, measles cases and deaths have surged, especially in Africa.

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Mumps Mumps is an acute viral disease caused by a parainfluenza virus. Its genome consists of single-stranded RNA. During the First World War, mumps was one of the most common causes of hospitalization among US soldiers. In 1934, it was shown that mumps was caused by a virus present in saliva. The virus is spread by the respiratory route and grows in the nasopharynx and regional lymph nodes, but this is followed by a viremia as a result of which, the virus spreads to multiple tissues. The virus then causes inflammation in these tissues. Nonspecific signs include muscle pains, malaise, headache, and lowgrade fever. It characteristically causes inflammation and swelling of the salivary glands (parotitis) and the testes (orchitis). Mumps may also present with respiratory symptoms (Marlow et al., 2021). Complications of mumps include orchitis, oophoritis, pancreatitis, hearing loss, meningitis, and encephalitis. These are more common in adults than in children. Mumps was one of the most common causes of aseptic meningitis and sensorineural hearing loss in children in the United States prior to the introduction of the vaccine.

Mumps vaccines The mumps vaccine was first released in 1967 (Fig. 18.2). However, many physicians considered mumps to be a “mild” disease and as a result there seemed to be no great imperative to have children vaccinated. The medical community reflected a spectrum of attitudes from those keen to vaccinate, those who deemed it unnecessary, and those who only recommended it for

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post-pubertal men who were at risk of developing severe orchitis. Once the vaccine became available, increased investigations into mumps outbreaks revealed hitherto underappreciated complications. Eventually, a federal advisory committee recommended in 1977 that all children be vaccinated prior to school admission. As in previous examples, the predicted pushback occurred. Concerned individuals demanded to know more. They wanted to see the package inserts and the lists of known adverse events. There was skepticism about mumps vaccines and the motives of the medical profession. Opponents noted that vaccines could contain aluminum (in the form of alum, an adjuvant), thiomerosal as a preservative, and formaldehyde as a virus-inactivating agent. All are known toxic agents under other circumstances. Why were there no warning labels? In 1982, the NBC broadcast a program entitled DPT: Vaccine Roulette emphasized the paternalistic attitude of the medical profession and a growing loss of confidence in its authority (Conis, 2015). Mothers of children claiming to have been harmed by vaccine complained that doctors had not listened to them. Some spokespeople suggested that the government had actively suppressed reports of vaccine adverse effects. Other physicians suggested that vaccines were no longer necessary. Vaccine Roulette resulted in concerned parents forming Dissatisfied Parents together (DPT) and lobbying for the National Childhood Vaccination Injury Act of 1986.

Rubella Rubella was once considered to be a variant of measles (rubeola). That is not the case. It is caused by Rubella virus, the only member of the genus Rubivirus in the family Matonaviridae. It is an enveloped, single-stranded RNA virus. Rubella virus was first isolated in 1962. Rubella is spread by the respiratory route, and it grows in the nasopharynx and lymph nodes in young children. It causes a rash, low grade fever, malaise, enlarged lymph nodes, and upper respiratory tract symptoms (Lanzieri et al., 2021). It can cause arthralgia in adult women. Most importantly, rubella virus can cross the placenta in pregnant women and infect the fetus in her uterus. This fetal infection can result in the development of severe abnormalities such as hearing impairment, congenital cataracts in the eyes, and the development of cardiovascular abnormalities.

Rubella vaccines In 1964, the Wistar Institute developed the RA 27/3 strain of rubella virus. This strain was isolated from the explanted kidney tissue of a fetus obtained at the therapeutic abortion of a mother who had been naturally infected with rubella virus (Liebhaber et al., 1972). The reason for the abortion was that her infected fetus was subject to the development of multiple birth defects and was

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not expected to survive. After the RA 27/3 strain was isolated, it was propagated on a human cell line. It was subsequently found that this strain, when used as a vaccine, induced superior antibody responses and was better tolerated compared to other rubella vaccine strains available at that time. The first rubella vaccines were licensed in 1969. Use of the RA 27/3 rubella vaccine strain has been considered by the National Catholic Bioethics Center as well as the Pontifical Academy for Life. They have argued that since the original abortion occurred over 55 years ago, was not performed in order to isolate the virus, and that no additional abortions were required; that the use of this vaccine is morally acceptable and is associated with parental duty. It is important to note that the use of this vaccine has prevented many cases of fetal death and congenital rubella syndrome (Fig. 18.3). During the 20th century rubella cases averaged 47,000 annually. Today there are less than 10. Congenital rubella syndrome averaged 152 cases annually. There were none in 2020. In 1991, the Institute of Medicine in the United States reported on the adverse consequences of pertussis and rubella vaccines (Howson et al., 1991). In the case of rubella, there was evidence of a link between one rubella vaccine and the development of arthritis.

Dr. Andrew Wakefield In February 1998, a British physician Dr. Andrew Wakefield and 12 coauthors published a study in a major medical journal The Lancet, which suggested that there existed a link between the use of the MMR vaccine, inflammatory bowel disease, and the development of developmental disorders in childrendmost

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notably autism. Clearly, the public fear of vaccines did not originate with Dr. Wakefield, but his claims tapped into a deep reservoir of doubt and suspicion. The Lancet paper was entitled “Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children” (Wakefield et al., 1998). Wakefield and his coauthors claimed to have investigated “a consecutive series” of 12 children that had been referred to the Royal Free Hospital School of Medicine with chronic enterocolitis and regressive developmental disorders. The authors reported that the parents of eight of the children associated their losses of acquired skills, including language skills, to MMR vaccination. The authors concluded that possible environmental triggers (namely the vaccine) were associated with the onset of the disease (Eggertson, 2010). They suggested that there were causative links between MMR vaccination, colitis, and autism spectrum disorder. The paper was clearly flawed as a result of the small numbers involved (only 12 children were studied) and any link to autism was entirely conjectural. The paper was evidently written by Wakefield himself, and formally stated that “no causal link had been established between MMR vaccine and autism as the data were insufficient.”

Conflicts of interest In 2004, 6 years after the paper was published, revelations in the Sunday Times newspaper first reported significant conflicts of interest affecting Wakefield’s paper. It was reported that Wakefield had been hired by a lawyer looking for an expert witnesses to start a planned class-action suit regarding “alleged” vaccine damage. Only after being recruited by the lawyer, did Wakefield begin the study on the 12 children. He had been paid £55,000 or more, from solicitors seeking evidence against vaccine manufacturers. The study had also failed to obtain approval from the Ethical Practices committee of the Royal Free Hospital. Finally, Wakefield also had a conflict-of-interest in that some months prior to the study, he had filed patent applications for a single measles vaccine as well as for various treatments and “cures” for inflammatory bowel disease and autism (Nuwarda et al., 2022). As a result of these revelations, the Lancet paper was partially retracted in February 2004. This retraction was only partial since the editors believed that the authors had not intended to deceive them. At that time, they declined to withdraw the paper citing “public interest in the issue.” The partial retraction involved 10 of the 12 coauthors.

Methodological problems Investigations continued and as a result, the British Medical Council ruled in January 2010 that in fact, the children that Wakefield studied were not randomly chosen but were carefully selected. Five of the 12 children had been previously diagnosed with developmental abnormalities. There was no control

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group of children thus preventing discrimination between causal and coincidental findings. The children were stated to be “healthy” when this was not the case. They all had relevant preexisting conditions. The council found that Wakefield had acted unethically and shown a “callous disregard” for the children in his study and who had been subjected to invasive procedures (colonoscopies, lumbar punctures, and biopsies). These procedures were not assessed in a “blind” manner.

Retraction As a result of these subsequent findings, Wakefield’s paper was fully retracted in 2010 (Eggertson, 2010). On February 2, 2010, the Lancet issued a statement saying that “several elements of the paper are incorrect contrary to the findings of an earlier investigation.”. On May 24, 2010, Andrew Wakefield was struckoff the Medical Register and as a result, was no longer permitted to practice as a medical doctor in the UK. In 2011, the British Medical Journal in issued a statement described the original paper as fraudulent (Godlee et al., 2011; Wikipedia Lancet). JABS (Justice, Awareness and Basic support) was an organization formed in 1994 and based in the UK, that serves as a support group for parents of children who believe that they became ill after receiving the MMR vaccine (Wikipedia JABS). A solicitor for this group, Richard Barr, formed the partnership with Andrew Wakefield in 1996. Wakefield was paid £150 per hour. JABS referred children to Wakefield and Wakefield admitted several of them to hospital for his study. Richard Barr is also alleged to have paid Wakefield to encourage him to discredit the MMR vaccine (Wikipedia Andrew Wakefield).

Autism spectrum disorder Autism (autism spectrum disorder) is a chronic neurodevelopmental disorder of children with a great diversity in clinical presentations. It has a strong genetic component. Its major manifestations are social communication difficulties, restricted interests, and repetitive activities. Its causes are unknown, but epidemiologic surveys have indicated that many affected individuals also have gastrointestinal disturbances. A survey in the United States found that children with autism were 47% more likely to be diagnosed with the chronic intestinal disease, Crohn’s disease, while they were 94% more likely to be diagnosed with a similar clinical syndrome, ulcerative colitis. These are both subtypes of inflammatory bowel disease associated with dysregulation of the intestinal immune system and an inappropriate immune response to the intestinal microbiota. Additional studies have demonstrated an association between inflammatory bowel disease in parents and the development of autism in their children (Sadik et al., 2022). There thus appears to be a link between maternal susceptibility to inflammatory bowel disease and the development of

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autism. The precise mechanisms behind such a link remain unclear. It has been suggested that they could involve immune system dysregulation as a result of dysbiosis in the microbiota, malabsorption of some essential micronutrients during pregnancy, or even an anemia. There are at least 100 genes apparently linked to the development of ASD and the diversity of symptom severity is attributed to the spectrum of genetic influences and the number and type of genes involved (Satterstrom et al., 2020). Thus, different ASD traits appear to be associated with different genetic contributions and the combinations of genetic factors they influence.

The response When unsubstantiated claims are made regarding the possible adverse events of vaccines, it often appears that the medical authorities are very slow to respond (Cabrera-Lalinde, 2022). This is true, but it reflects the time needed for concerned scientists to gather and reliably analyze safety data. Vaccine opponents, on the other hand, can merely announce claims with no data and possibly a few anecdotes. Multiple subsequent epidemiological studies have failed to find any link between the MMR vaccine, colitis, and autism. In 1998, a panel of experts established by the British Medical Research Council found “no evidence to indicate any link” between the MMR vaccine and colitis or autism in children. The Institute of Medicine in the United States has also published two extensive studies on the subject of vaccination and autism in 2001 and 2004 confirming an absence of any such linkage (Institute of Medicine, 2001, 2004). There is no increased risk of autism even among high-risk children whose older siblings had autism (DeStefano and Shimabukuro, 2019). There have been no associations found between any of the three individual components of the MMR vaccine and the development of inflammation or gastrointestinal disease. There is no evidence for the transfer of toxic products from the gastrointestinal tract to the brain (Immunization Action Coalition, 2019). Many autism advocacy groups continue to defend Wakefield (Vaccine epidemic). Conspiracy theorists suggest manufacturers are hiding the truth. These groups include Generation Rescue and The Autism Community in Action (Wikipedia).

The consequences Wakefield’s paper had a huge impact. It tapped into a persistent reservoir of real concerns regarding autism, vaccines, and their safety. It attracted international media attention and as a result there was a significant decline in MMR vaccination, especially in the UK (Motta and Stecula, 2021). The MMR crisis led to a significant drop in vaccination rates (but nowhere as drastic as the pertussis crisis) (Hussain et al., 2018). Wakefield’s paper has been

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characterized as “perhaps the most damaging medical hoax of the 20th century” (Flaherty, 2011). As a result of the Lancet paper and subsequent newspaper articles, confidence in the MMR vaccine fell from 59% to 41% in the UK. Vaccination rates for MMR dropped from 92% in 1996 to 84% in 2002. Measles outbreaks that developed in the UK in 2003 and 2009 were attributed to the non-vaccination of children (Blume, 2005). Interestingly, in the wake of the MMR-autism controversy, vaccination rates in the US increased slightly when those in the UK were dropping (Hausman, 2019). The MMR debacle has also brought to the fore, the role of the media in manipulating public opinion. Certainly, anti-vaccination groups have used the media to great effect in publicizing and exaggerating the adverse effects of vaccines. This has been assisted by a general lack of vaccine literacy in some outlets, and the great attraction of sensational headlines and stories. Thus, single incidents can be reported as major disasters by some commentators, whereas the saving of thousands of lives in undramatic fashion is not newsworthy (Poland and Jacobson, 2001). Additionally, numerous perceived fears of vaccination are perpetuated by “expert” celebrities, and pundits who provide wide exposure for their views on the internet. These people have proven influential in espousing the false notion that vaccines are unreasonably dangerous and thus persuading people not to vaccinate their children. In 2016, Wakefield directed the anti-vaccination film, “Vaxxed: from cover-up to catastrophe” (Najera, 2016). A survey of British parents who were resistant to MMR vaccination indicated that they were unconvinced by the reassurances of the Ministry of Health that the vaccine is safe. In addition, they resent pressure from medical professionals to comply (Evans et al., 2001). Despite the above, during the 2020e21 school year in the United States, vaccination coverage nationally for two doses of MMR in kindergartners was 93.9%. That year 2.2% of kindergartners had exemption from at least one vaccine and an additional 3.9% were not up to date on their MMR shots (Seither et al., 2022).

Thiomerosal Throughout the 1990s, there was a growing concern regarding the presence of mercury in contaminated environments. Methylmercury is especially toxic and can cause neurologic disease. Methylmercury is a serious environmental toxin (especially since it accumulates in some fish species such as tuna and salmon). This environmental concern eventually spilled over to vaccines and their preservative thiomerosal. Thiomerosal contains an ethyl mercury compound together with thiosalicylate. It was added to vaccines at a concentration of 0.003%e0.01%, as a preservative since the late 1920s (Hausman, 2019). Ethyl mercury is rapidly cleared from the body and blood mercury levels do not rise above safe levels (Nuwarda et al., 2022).

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There is no evidence that thiomerosal does any harm to vaccinated individuals, and it is effective in preventing the growth of microbial contaminants such as the tetanus bacillus. Nevertheless, as a result of this becoming an issue of vaccine safety, in 1999, the US Food and Drug Administration (FDA) and vaccine manufacturers agreed that thiomerosal should be reduced or eliminated from single-dose vaccines. This caused significant confusion since it was still present in multi-dose vaccine vials, and why remove it if it was actually safe. In 2001, the Institute of Medicine Safety Review Committee issued another report concluding that there was no evidence to suggest that thiomerosal caused autism, ADHD, or delayed development in children. In fact, autism rates have continued to rise even after thiomersal use was discontinued. Today, thiomerosal is no longer used in the common childhood vaccines, but it is present in some multidose influenza vaccines given to adults. In 2004, a review by the Institute of Medicine concluded that “the evidence favors rejection of a causal relationship between thiomerosal-containing vaccines and autism.” The decision to remove thiomerosal from most vaccines clearly sent a mixed message on vaccine safety, confusing physicians and frightening parents. Parents blamed vaccine thiomerosal for their children’s autism. Politicians exploited the controversy. For example, in 2004, California Governor Arnold Schwarzeneger prohibited thiomerosal-containing influenza vaccines in that state. Other states such as Delaware, Illinois, Missouri, New York, and Washington followed his example (Nuwarda et al., 2022). In 2007, a hearing was convened under the National Vaccine Injury Compensation Program in the United States to examine a possible MMR/ thiomerosal-autism link. In the case of Michelle Cedillo v Secretary of Health and Human Services, the family of Michelle Cedillo, an autistic girl, sued the government claiming that her autism was caused by receiving MMR as well as by thimerosal-containing vaccines. They sought compensation under the National Childhood Vaccine Injury Act. The court determined in February 2009 that the plaintiff had “failed to demonstrate that thimerosal-containing vaccines could contribute to immune dysfunction, or that the MMR vaccine could either cause autism or gastrointestinal dysfunction.” They therefore ruled that parents of autistic children were not entitled to compensation under the program (Wikipedia Cedillo).

Foreign intervention One reason why vaccination skepticism has flourished is through the use of social media, where anti-vaccination messages flourish. In 2015, DARPA (the US Defense Advanced Research Products Agency) asked researchers to seek to identify the source of these “influence bots” on twitter (Benecke and DeYoung, 2019). Researchers found that #VaccinateUS was a Twitter hashtag linked directly to Russian troll accounts connected to the Internet Research

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Agencyda company backed by the Russian government that specializes in online influence projects. One of the most important tactics used by these influence bots is to exploit the vaccine debates to exacerbate socioeconomic tensions within the United States. For example, these Russian tweets will often blame the elite for forcing the vaccine on low-income subjects. DARPA studies also indicated that 93% of tweets about vaccines was generated by accounts that could not be verified a either bots or human users, yet they exhibited malicious behavior. Thus, in effect, amplifying the misinformation that parents are exposed to and fuel the belief that the science behind vaccine use is questionable and incomplete.

References Benecke O, DeYoung SE. Anti-vaccine decision-making and measles resurgence in the United States. Humanit Crisis Res 2019;6:1e5. https://doi.org/10.1177/2333794X19862949. Blume S. Anti-vaccination movements and their interpretations. Soc Sci Med 2005;62:628e42. Cabrera-Lalinde I. The online information environment. How misinformation affected the perception of vaccines in the 20th century based on the examples of the polio, pertussis and MMR vaccines. The Royal Society; 2022, ISBN 978-1-78252-567-7. Conis E. Vaccination resistance in historical perspective. Organization of American historians; 2015. https://www.oah.org/issues/2015/august/vaccination - resistance. DeStefano F, Shimabukuro TT. The MMR vaccine and autism. Annu Rev Virol 2019;6:585e600. https://doi.org/10.1146/annurev-virology-092818-015515. Eggertson L. Lancet retracts 12-year-old article linking autism to MMR vaccines. Can Med Assoc J 2010;182(4):e199e200. Evans MH, Stoddart L, Condon E, Freeman M, Grizzell M, Mullen R. Parent’s perspectives on the MMR immunization: a focus group study. Br J Gen Pract 2001;51:904e10. Flaherty DK. The vaccine-autism connection. A public health crisis caused by unethical medical practices and fraudulent science. Ann Pharm (Poznan) 2011;45(10):1302e4. Gastanaduy P, Haber P, Rota PA, Patel M. Chapter 13. Measles. In: Epidemiology and prevention of vaccine-preventable diseases. 14th ed. Centers for Disease Control and Prevention; 2021. Godlee F, Smith J, Marcovitch H. Wakefield’s article linking MMR vaccine and autism was fraudulent. Br Med J 2011;342:c7452. Hausman BL. Anti/vax: reframing the controversy. Cornell University Press; 2019. eISBN: 978-15017-3563-3569. Howson CP, Howe CJ, Fineberg HV, editors. Adverse effects of pertussis and rubella vaccines: a report of the committee to review the adverse consequences of pertussis and rubella vaccines. Washington DC: National Academies Press; 1991. Hussain A, Ali S, Ahmed M, Hussain S. The anti-vaccination movement: a regression in modern medicine. Cureus 2018. https://doi.org/10.7759/cureus.2919. Immunization Action Coalition. MMR vaccine does not cause autism: examine the evidence!. 2019. www.immunize.org. Institute of Medicine. Immunization safety review: measles-mumps-rubella vaccine and autism. Washington DC: The National Academies Press; 2001. https://doi.org/10.17226/10101. Institute of Medicine. Immunization safety review: vaccines and autism. Washington DC: The National Academies Press; 2004. https://doi.org/10.17226/10997.

280 A History of Vaccines and their Opponents Lanzieri T, Haber P, Icenogle JP, Patel M. Chapter 20. Rubella. In: Epidemiology and prevention of vaccine-preventable diseases. 14th ed. Centers for Disease Control and Prevention; 2021. Liebhaber H, Ingalls TH, LeBouvuer GL, Hortsmann DM. Vaccination with RA27/3 rubella vaccine. Am J Dis Child 1972;123(2):133e6. https://doi.org/10.1001/archpedi.1972.02110080111011. Marlow M, Haber P, Hickman C, Patel M. Chapter 15. Mumps. In: Epidemiology and prevention of vaccine-preventable diseases. 14th ed. Centers for Disease Control and Prevention; 2021. Misin A, Antonello RM, DiBella S, Campisciano G, Zanotta N, Giacobbe DR, et al. Measles: an overview of a re-emerging disease in children and immunocompromised patients. Microorganisms 2020;8(2):276e92. https://doi.org/10.3390/microorganisms8020276. Motta A, Stecula D. Quantifying the effect of Wakefield et al. (1998) on skepticism about MMR safety in the US. PLoS One 2021. https://doi.org/10.1371/journal.pone.0256395. Najera RF. Andrew Wakefield’s Vaxxed; scary music and specious claims. https://cpp-hov.netify. app/blog/andrew-wakefields-vaxxed-scary-music-specious-claims. Nuwarda RF, Ramzan I, Kayser V. Vaccine hesitancy: contemporary issues and historical background. Vaccines 2022;10:1595e615. Poland GA, Jacobson RM. Understanding those who do not understand: a brief review of the antivaccination movement. Vaccine 2001;19:24405. Sadik A, Dardani C, Pagoni P, Havdahl A, Stergiakouli E, et al. Parental inflammatory bowel disease and autism in children. Nat Med 2022;28:1406e11. https://doi.org/10.1038/s41591022-01845-9. Salmon DA, Haber M, Gangarosa EJ, Phillips L, Smith NJ, Chen RT. Health consequences of religious and philosophical exemptions from immunization laws. JAMA 1999;281(1):47e53. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 2020;180:568e84. https://doi.org/10.1016/j.cell.2019.12.036. Seither R, Laury J, Mugerwa-Kasujja A, Knighton CL, Black CL. Vaccination coverage with selected vaccines and exemption rates among children in kindergartendUnited States, 2020e21 school year. MMWR (Morb Mortal Wkly Rep) 2022;71(16):561e8. Tolley K. School vaccination wars: the rise of anti-science in the American anti-vaccination societies, 1879e1929. Hist Educ Q 2019;59(2):161e94. https://doi.org/10.1017/heq.2019.3. Wakefield A, Murch S, Anthony A, Linnell J, Casson D, Malik M, et al. Ileal-lymphoid-nodularhyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351(9103):637e41 [Retracted]. Wikipedia. Andrew Wakefield. https://en.wikipedia.org/wiki/Andrew-Wakefield. Wikipedia. Cedillo v. secretary of health and human services. https://en.wikipedia.org/wiki/ Cedillo0-v.-secretary-of-Health-and-Human-services. Wikipedia. Generation rescue. https://en.wikipedia.org/wiki/Generation-Rescue. Wikipedia. JABS. https://en.wikipedia.org/wiki/JABS. Wikipedia. Lancet MMR autism fraud. https://en.wikipedia.org/wiki/Lancet-MMR-autism-fraud.

Chapter 19

Safety and sexual promiscuity: hepatitis B, human papilloma virus, and influenza vaccines Many of the adverse events attributed to vaccines are simply coincidental. Because two events occur one after the other, is no proof that one causes the other. This has been a significant cause of vaccine hesitancy with regard to the administration of vaccines to young children. The ideal timing of vaccinations is first determined by the state of development of a child’s immune system. Thus, a vaccine should not be administered to a child before their immune system can respond optimally to it. On the other hand, vaccines should be given as early as possible to provide a child with protection. Unfortunately, this results in vaccines being administered at an age that coincides with the appearance of certain developmental problems in young children: problems such as autism, colitis, diabetes mellitus, and some neurologic diseases. As a result, there has been a tendency to attribute these problems to recent vaccination without any other evidence of causality. This coincidence has had major adverse effects on vaccine usage as demonstrated by the Wakefield affair described in the previous chapter. It is important therefore to investigate these coincidental occurrences and seek to discriminate between causation and coincidence in order to maintain confidence in vaccine safety (Heininger, 1983). An excellent example of the exploitation of coincidental events is the “Death by Gardasil” story promoted by opponents of vaccination against human papillomavirus (HPV). Given that this vaccine, Gardasil, has been administered to huge numbers of teenage girls, it is unsurprising that occasional cases have occurred when a girl dies for other reasons, subsequent to the vaccination procedure. These reports use tenuous connections between HPV vaccination and the unexpected death of a child to exploit the grief of the parents and their understandable desire to find a rational explanation for their child’s death. As a result, the theory has been promoted that the HPV vaccine, Gardasil, is lethal (Gorski, 2018). Similar claims have linked the vaccination of young children to sudden infant death syndrome and even to “Shaken baby syndrome.” Anti-vaccinationists claim that the labels given to such deaths are actually a cover-up for vaccine-induced lethality. Thus, in the case of shaken A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00013-9 Copyright © 2023 Elsevier Inc. All rights reserved.

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baby syndrome, the cause of death is misdiagnosed. It was the vaccine that killed the babydnot the child abuser. Two virus-like particle-based vaccines are currently used in humans, one against hepatitis B virus and the other against human papilloma virus. The hepatitis B vaccine uses an adjuvant to induce a cell-mediated immune response and cytotoxic T cells. This human hepatitis B vaccine was the first to use these particles, and it was also the first anticancer vaccine, since hepatitis B can also cause liver cancer. Both vaccines have engendered hostility from anti-vaccinators despite their effectiveness and lack of significant adverse effects.

Hepatitis B Hepatitis B (formerly called serum hepatitis) is caused by a small DNA virus belonging to the Hepadnaviridae family (Haber and Schillie, 2021). It specifically infects liver cells and causes liver inflammation-hepatitis. The clinical signs of infection may be inapparent in children, but the disease is more clinically obvious in adults. It is transmitted either orally or across mucosal surfaces (sexually). High risk groups include healthcare workers, intravenous drug abusers, homosexual men, and individuals with multiple sexual partners. About half of the adults who become infected are asymptomatic. Symptomatic victims develop a fever, malaise, loss of appetite, nausea, and abdominal discomfort before developing jaundice. The acute illness lasts for 1e3 weeks, but recovery may take weeks to months. Most adults recover although infants can develop chronic infection. It has been estimated that between 3% and 6% of the global population carry the virus and about one in three are infected by it at some point in their lives. Most adults eliminate the virus spontaneously, but about 10% develop a persistent infection and become chronic viral carriers. Chronic virus carriers have a high risk of developing cirrhosis or even liver cancer. Several different vaccines against hepatitis B (HBV) have been available in the United States since 1981. They contain isolated recombinant proteins synthesized in yeast that can form virus-like particles. Thus, the currently available vaccine consists of pure, non-infectious viral subunits that spontaneously assemble into these particles. Because they contain no DNA, they cannot replicate or transmit the disease. The current vaccines are available either as single vaccines or in combination with DTaP and inactivated polio vaccine. They are available in adult and pediatric doses (Haber and Schillie, 2021). The vaccine is given routinely to children and adults at risk in a threedose series. It is 80%e90% effective.

Multiple sclerosis France has been a very vaccine hesitant country. Even before COVID-19, 41% of French citizens expressed doubts about vaccine safety. Despite their

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skepticism, the anti-vaccination movement in France has not had a high profile. All that changed with the introduction of a vaccine against hepatitis B. Between December 1998 and July 1999, a French man, called “W” by the courts, received three recommended doses of a hepatitis B vaccine. One month after the last dose, in August 1999, “W” first developed symptoms of multiple sclerosis (MS). Multiple sclerosis is a chronic, slowly developing, autoimmune disease in which the immune system attacks the myelin sheaths surrounding the nerves within the brain. As a result of this “demyelination,” the nerves eventually fail to function properly, resulting in pain and paralysis. While its initiating cause is unknown, MS is linked to a genetic predisposition in association with infection by the human herpesvirus, EpsteineBarr virus. EpsteineBarr virus is totally unrelated to hepatitis B. There is no known association between HBV and MS and no evidence that HBV makes MS more severe. Nevertheless, in 2006, “W” and his family sued Sanofi Pasteur, the company that had manufactured the hepatitis vaccine, claiming that it had caused his multiple sclerosis. “W” died in 2011 from MS-related complications. “W” initially won his case. The French regional court in which the case was heard ruled that since he had no previous health issues and no family history of MS, then the development of symptoms after he received the third dose of hepatitis vaccine was sufficient to conclude that the vaccination was the probable cause. In 2011, the Court of Appeals overturned this ruling stating that while the vaccine may have caused his MS, there was no reason to believe that the vaccine was “defective” in any way. Eventually the case made its way to a higher appeal court who ruled that in the absence of any evidence of a connection between the vaccine and MS, and the fact that MS is known to begin to develop many years before clinical disease presents itself, then it almost certainly began long before “W” was vaccinated. The family appealed to the European Court of Justice who ruled in 2017 that vaccines can be blamed for illness without scientific proof (Vogel, 2017)! In May 2000, the French Ministry of Health decided to award financial compensation to the families of individuals who claimed to have been harmed by a hepatitis B vaccine. The ministry claimed a link with no apparent evidence, but the media believed it to be true. Subsequent epidemiologic investigations in children have failed to show any link between the development of demyelinating diseases and vaccination in European or North America children (INSERM, 2003). Multiple studies on demyelinating diseases in adults have also failed to establish any causal or even an epidemiological link with hepatitis B vaccination. Likewise, there is no experimental evidence from animal studies showing any possible mechanisms. Hundreds of millions of people worldwide have received the hepatitis B vaccine without untoward effect. Clearly, with that number of vaccinated individuals, some will most certainly coincidentally develop MS (CDC).

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In 2016, it was also reported that a steep loss of confidence in hepatitis B vaccines had resulted from media reports of infant deaths following vaccination in China (Yu et al., 2016). The media reported in December 2013 that there had been 17 sudden deaths and one case of anaphylactic shock in patients following HBV vaccination. Before these reports, 85% of survey respondents regarded these domestic vaccines as safe. After these reports, this figure dropped to 26.7%. Even when it was demonstrated that these sudden deaths were not caused by HBV vaccination, 18.4% of respondents reported that they would still refuse HBV vaccines for their children. Thus, a safe and effective vaccine was suspended as a result of a decline in parental confidence and vaccination refusal. This also emphasizes the need for timely credible investigations to examine these vaccine coincidences.

SIDS and HBV vaccine In another example of exploitation of the coincidence between vaccination and disease, some anti-vaccinationists have claimed that Hepatitis B vaccine is a cause of sudden infant death syndrome (SIDS). The claimants report a story regarding an infant that died within 16 hours after receiving a second dose of hepatitis B vaccine. The figures show otherwise. Thus, when the hepatitis B vaccine was first introduced, about 5000 children in the United States died annually from what was classified as SIDS. Within 10 years, vaccine coverage had increased to about 90%. However, the incidence of SIDS had dropped to about 1600 cases annually. This decrease was a result of a program called “Back to Sleep” mounted by the American Academy of Pediatrics. Statistically, it can be calculated that about 50 cases of SIDS will occur annually within 24 hours of a child receiving a vaccine. However, the incidence of SIDS is the same in children who do and do not receive HBV vaccine (Eriksen et al., 2004).

Human papilloma virus The major Christian and Muslim religious denominations are proponents of sexual propriety. As a result, there have been multiple objections to hepatitis B and human papillomavirus vaccination based on the fact that these can be, or are, sexually transmitted (Grabenstein, 2013). These negative opinions are not considered theological nor medical but are largely based on parental responsibility and views as to what is regarded as acceptable sexual behavior and timing. In the case of hepatitis B, sexual transmission is only one of several transmission routes. HPVs are members of a large family of at least 120 small, double-stranded DNA viruses that infect epithelial cells and can cause common skin warts. Several of these strains can also infect mucosal epithelium and so cause genital warts and, in some cases, cervical cancer. As a result, HPV is the commonest sexually transmitted infection in the United States and worldwide. An

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estimated, 79 million persons are infected in the United States, with 14 million new infections occurring annually. The prevalence of HPV infection is estimated to be greater than 10% among 15e49-year-olds in the USA. Most individuals clear the virus infection within a year, but a small proportion become persistently infected. There are more than 40 identified mucosal strains of HPV and immunity to one strain does not ensure protection against the others. About 90% of all genital wart cases are caused by HPV types 6 and 11. However, more than 20 HPV types can cause genital warts and in addition cause proliferation of the cervical epithelium that may eventually progress to cervical cancer. These viruses may also cause some vulvar, genital, and even some head and neck cancers. Cervical cancer is the second most common cancer and the fifth leading cause of death among women worldwide. HPV types 16 and 18 are associated with 70% of cervical cancers. Three HPV vaccines are licensed in the United States that differ in the specific virus strains they contain. They are directed against the strains of HPV that cause genital warts and cervical cancer. They contain a mixture of purified recombinant viral capsid proteins that can self-assemble into virus-like particles. The immune system therefore responds to these particles as if they were viruses. Like the HepB vaccine, the HPV vaccines do not contain any live virus nor viral DNA and as a result are not infectious and cannot cause cancer. They also contain an adjuvant to boost the level of protective immunity. Based on its high effectiveness, the FDA approved Gardasil, the first vaccine to be directed against HPV in June 2006. The newest version of this vaccine, Gardasil 9, protects against multiple cancers caused by HPV types, 16, 18, 31, 33, 45, 52, and 58; against precancerous lesions caused by HPV types 6, 11, 18, 31, 33, 45, 52, and 58; and against genital warts caused by HPY types 6 and 11. More than 135 million doses had been administered in the United States alone by 2021. It does not contain any preservatives or antibiotics (Osazuwa-Peters et al., 2021). The recommended regimen is three intramuscular doses administered to individuals aged 9 through 45 years given at 0, 2, and 6 months. For individuals 9 through 14 years of age, a two- or three-dose regimen is recommended. In this case, the second dose may be administered 6e12 months after the first. Gardasil has also been approved by the FDA for the prevention of genital warts and anal cancer in males. Thus, it protects against five different types of cancer: cervical, anal, throat, penile, vaginal, and vulvar. It has the potential to eliminate cervical cancer as a Public Health problem. Despite its proven effectiveness, vaccination rates against HPV in the United States are low. Thus, in 2020, only 59% of 13- to 17-yearolds were fully vaccinated.

Initial problems As soon as the HPV vaccine was released in 2006, it met with a storm of criticism. Conservative religious groups rallied against the vaccine arguing

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that it would encourage promiscuity. Thus, this vaccine encountered considerably more opposition and hesitancy than any of the childhood vaccines produced previously. Objections to the vaccine are linked to sexual politics. These are objections based on the fact that HPV is a sexually transmitted infection and concerns over the recommended age at vaccination. Social conservatives have countered vaccine mandates on the grounds that they infringe on the rights of parents to discuss sexual topics with their children. Pro-abstinence activists have expressed concerns that HPV vaccination may encourage teenage promiscuity. (There is no evidence for this.) Suggestions have been made that the FDA approved the vaccine despite proper safety testing. In addition, many parents seriously underestimate the seriousness of HPV infections (Intlekofer et al., 2012). In January 2007, Texas Governor Rick Perry, a Republican, signed an executive order requiring girls of 11 and 12 to be vaccinated with Gardasil (Tanne, 2007). Under the order, unvaccinated girls would not be allowed to enter the sixth grade at school unless their parent’s claimed objections on the basis of religion or conscience. At that time, Perry argued that the HPV vaccine was no different from vaccinating children against polio. As a result, Perry was seriously criticized by religious conservatives. Subsequently, when running as a candidate for President in 2008, Perry reversed his decision and called it a mistake. In his backing of the vaccine in 2007, Perry felt obliged to characterize the vaccine as “pro-life.” On September 12, 2011, controversy regarding the HPV vaccine was reignited by remarks by a Republican presidential candidate Michele Bachman, during a debate, when she denounced Perry’s role in mandating HPV vaccination in Texas. Bachman stated that she had encountered a woman who believed that her daughter had developed mental retardation following HPV vaccination. She reasserted claims about the dangers of this vaccine several times (Intlekofer et al., 2012). California Bill AB499 which mandates HPV vaccination of all 6th grade girls in the state also triggered strong opposition from religious conservatives.

Current problems Problems have continued to follow HPV vaccines since its introduction. These are associated with ongoing opposition from anti-vaxxers as well as parental hesitancy and even fear of needles. Denmark introduced HPV vaccine for teenage girls in 2009. It was initially well received with >90% vaccination coverage in girls born between 1998 and 2000. However, the Danish media began to report alleged adverse events in vaccinated individuals. As a result, the HPV vaccination rate declined to 54% for girls born in 2003. A study of Facebook pages dealing with the HPV vaccine in Denmark (Agergaard and Neilsen, 2020) has shown that there are three forms of adverse comments regarding the vaccine. One claims a loss of

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quality-of-life following vaccine usage. A second expresses doubt regarding the evidence behind the consequences of HPV infection. The third generally accuses the Health authorities of betraying those that have suffered losses as a result of using the vaccine. Basically, “us” who have been affected by adverse events or are critical of the vaccine versus “them”dthe health authorities, the drug companies, and the Danish Cancer Society. HPV vaccine opponents are not, in general, minimizing its effectiveness. However, its opponents are minimizing the frequency and severity of the diseases that it protects against. They suggest that HPV infection is rare, and that cervical cancer is very rare. Surveys of HPV vaccine hesitant parents have also shown that safety concerns figure prominently among their reasons for not ensuring that their adolescent children receive appropriate additional doses (Clark et al., 2016). HPV vaccine opponents continue to exaggerate its adverse effects. It does have some adverse effects. As with all vaccines that trigger an early innate immune response, the most commonly reported adverse effects of Gardasil include pain, swelling, redness, itching, and bruising at the injection site, as well as some systemic effects such as headache, fever, nausea, dizziness, tiredness, diarrhea, abdominal pain, sore throat, and occasional fainting. Some yeastallergic individuals may develop severe reactions to the vaccine. Despite this relatively short list of possible adverse events, over the years since its introduction, concerns about the safety of the HPV have not diminished. Thus, concerns about its safety among parents increased by 80% between 2015 and 2018 (from 13% to 23%) (Osazuwa-Peters et al., 2021). The parents of many eligible teens have, as a result, either delayed vaccination or decided not to vaccinate them at all. The fact that there has been a decrease in reported adverse effects associated with HPV vaccine raises the question, why is concern regarding possible adverse events rising (Osazuwa-Peters et al., 2021)? In addition to the moral issues, Gardasil is expensive ($350 for a threedose course) and is not generally covered by insurance policies. Much of this reluctance also relates to racial, ethnic, and poverty disparities among the US population. Resistance to Gardasil has also focused on its alleged injuries (Hausman, 2019). One article suggested that the aluminum from adjuvants was identified as being present in nipple fluid from some breast cancer patients (Hausman, 2019). Thus, this links the adverse effects of vaccines to contaminants such as aluminum and the mercury in thiomersal. However, the paper involved suggested that the aluminum actually came from antiperspirants. Other claims are that Gardasil causes sudden death in teens or even that it causes premature ovarian failure and infertility (Gorski, 2018). Robert F. Kennedy Jr, a leading opponent of vaccination, has published articles discouraging use of the HPV vaccine. He has also produced an anti-vaccine documentary “Vaxxed 2: The people’s truth” which focuses on HPV vaccine. Kennedy is a leader of a prominent anti-vaccine group called “Children’s Health Defense” (CHD). In

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August 2022, CHD was suspended from Instagram and Facebook for violating their policies on COVID-19 misinformation (The Guardian, Aug 18, 2022). The Global Advisory Committee on Vaccine Safety of the World Health Organization has reviewed the safety data from HPV vaccines since 2007 and considers them to be extremely safe. They have looked at possible links between Gullain-Barre´ syndrome, complex regional pain syndrome, postural orthostatic tachycardia syndrome, premature ovarian insufficiency, primary ovarian failure and venous thromboembolism, and the administration of the HPV vaccine. They report that there is no evidence for any causal relationship between HPV vaccination and these conditions. Thus, after more than 15 years of experience with the HPV vaccine, parental concerns are rising, while the actual safety data shows that reports of adverse events are actually falling. Currently nonserious events range from 43 to 28 per 100,000 vaccine doses. Serious events are around 1.8 per 100,000 doses or 0.0018%. The growing hesitancy is also associated with the search for information online where there has been an increase in the number of sites reporting negative and incorrect information.

Encouragement of immorality The initial opposition to HPV vaccination resulted from questions regarding the morality of producing a vaccine against viruses that can be sexually transmitted. The initial marketing of the HPV vaccine was not helped by its association with sexually transmitted disease. This would, as a result, require parents to talk about sexual issues and disease with young children who were not sexually active. There were also concerns raised about young teens believing that, since they had been vaccinated, then it was OK to experiment with sex. The Catholic Medical Association has issued a position paper on HPV immunization (CMA, 2007). Among their statements are: First, the fact that HPV is spread primarily by sexual contact does not render vaccination against it unethical. Healing and preventing diseases, no matter what their source, are acts of mercy and a moral good. The CMA does however oppose the mandating of vaccines.

Heavy marketing/mistrust Although there has been a gradual increase in HPV vaccine usage over the years, it is also speculated that the growing mistrust of government and medical authority in recent years has played a role in developing these safety concerns. Disinformation about some vaccines can also have an adverse effect on the use of vaccines in general. In effect this may be fallout from the COVID-19 experience. As discussed in the next chapter, all vaccine coverage has dropped significantly since the onset of the COVID-19 pandemic.

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Heavy marketing by the government and the manufacturer has also raised suspicions regarding the product. In many cases, physician recommendation is a major driver of vaccination decisions. The decline in HPV coverage appears to reflect a lack of discussion with family physicians in addition to increased coverage of anti-vaccine efforts by the press (Smith, 2019). A major reason why adolescents do not receive their appropriate booster shots is a lack of awareness of the need for them (Clark et al., 2016). In the later half of the 20th century, there was a growing tendency to engage the patient in decision making by physicians. While welcome, it contrasted sharply with mandated vaccination. Respect for medical knowledge and expertise has been replaced by skepticism. Also, concerns about corrupt relationships between medical practitioners and the pharmaceutical industry persist. This is especially important respecting claims regarding the HPV vaccine Gardasil. Merck lobbied to have the vaccine made mandatory for middle-school aged girls. However, this is a sexually transmitted disease, and some argued that Merck was facilitating a girl’s early entry into sexual relations. Parents did see the HPV vaccine development and promotion as corrupted by politicians and funded by the pharmaceutical industry. Thus, they lost trust in the science as well.

Trypanophobia Sometimes, of course, the reasons for vaccine hesitancy can be relatively simple. Thus, a survey of American parents conducted in 2012 found that the most common reason for adolescents to forgo their second dose of HPV was a fear of the pain caused by injections! Other reasons listed were a lack of awareness about additional doses and a concern regarding safety issues (Clark et al., 2016). It has been estimated that one in six adults has avoided receiving the influenza vaccine due to needle fear. This fear of needles, also called trypanophobia, is a significant contributor to vaccine hesitancy. While most people dislike injections, some develop overwhelming extreme fear of them. This often follows a negative or traumatic experience with an injection. It can also be related to hypochondria or other anxiety disorders. It has been estimated that up to 10% of adults avoid vaccination as a result of a fear of injections. Many have visceral responses such as suddenly hot and sweaty, accelerated heart rate, shaking, and lightheadedness. This may have multiple reasons including hypersensitivity to pain, fear of being restrained, and may extend to vasovagal reactions triggered on seeing a needle including syncope (passing out). (Rowello, 2021). An analysis of multiple databases analyzing needle fear, parents and their children in the general population report prevalence rates for needle pain fear run from 5% to 13% in the general population and 8%e28% in an under vaccinated population. The overall prevalence of fear in the general population is 8% in the general population and 18.3% in the under vaccinated

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population. This is clearly a significant impediment to vaccination (Taddio et al., 2022).

Influenza vaccine hesitancy Influenza is one of the commonest infectious diseases. It causes millions of cases in the United States and the rest of the world every year. However, it is almost totally preventable by vaccinationdflu shots. According to the CDC, it is estimated that in the United States alone flu shots prevent about 7.65 million illnesses (Richmond, 2022). Influenza viruses are RNA viruses that are genetically unstable. As a result, they change progressively over time. As a consequence, their surface antigens also changeda feature called antigenic drift. This means that influenza vaccines have to be changed each year and boosted annually. Notwithstanding their known effectiveness, many individuals refuse to be vaccinated against the flu. Some school districts mandate influenza vaccination in children in the fall before school reopens. This, of course, often triggers pushback from parents and others who oppose vaccine mandates (Deliso, 2020). The reasons for vaccine refusal are multiple and, in general, are similar to those affecting other vaccines. For example, many believe that the vaccine can actually give you influenza. There are both live and inactivated influenza A vaccines currently marketed in the United States. The injectable vaccine is inactivated and has not the slightest chance of causing influenza. It is also available as a modified live intranasal spray vaccine (Flumist). It is highly attenuated and while it can temporarily colonize the nose it cannot cause the disease. Some believe that the vaccines cause significant adverse effects. Like many vaccines they can cause soreness and tenderness at the injection site. There is a remote chance that they may trigger Gullain-Barre´ syndrome, but this chance is very much lower than that caused by a virulent flu infection (Chapter 22). Another ill-founded belief is that annual revaccination is unnecessary. However, as pointed out above, antigenic drift is inexorable, and vaccinating one year carries with it no assurance that you will be protected against the next variant that appears. It is also important to receive the vaccine well before the flu season starts, generally in September if possible. As pointed out in Chapter 1, vaccines do not provide instantaneous protection and waiting until flu strikes the neighborhood is often too late. Waiting too long is also one reason for the mistaken perception that the vaccine causes the flu. A feature of resistance to flu shots, as in many vaccine hesitancy cases, is a claim that flu shots are ineffective. The data shows otherwise. Not only do flu shots give about 60% protection, but they have a material effect in minimizing the need for flu-related hospitalization and death. Thus, they may turn a lifethreatening disease episode into a mild, transient febrile disease. This is especially important in the elderly, the very young, and pregnant women. As

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with COVID-19 vaccines, people should not expect the Nirvana effect with total protection in all cases (Richmond, 2022). It is also important to point out that even the young and healthy can get seriously ill with influenzadit is not just a bad cold.

References Agergaard TE, Nielsen KH. Loss, doubt, and betrayal: strands of vaccination skepticism on three Facebook pages involved in the controversy over human papillomavirus (HPV) vaccination. Front Commun 2020. https://doi.org/10.3389/fcomm.2020.557424. Catholic medical association position paper on HPV immunization. January 2007. www.cathmed. org. Center for Disease Control and Prevention. Hepatitis B vaccine and multiple sclerosis FAQs. https://www.cdc.gov/vaccinesafety/concerns/history/hepb-faqs.html. Clark SJ, Cowan AE, Filipp SL, Fisher AJ, Stokley S. Understanding non-completion of the human papillomavirus vaccine series: parent-reported reasons for why adolescents might not receive additional doses, United States, 2012. Publ Health Rep 2016;131:391e5. Deliso M. Hundreds of protesters gather against new flu vaccine mandate in Massachusetts; 2020. https://abcnews.go.com/US/hundreds-protesters-gather-flu-vaccine. Eriksen EM, Perlman JA, Miller A, Marcy SM, et al. Lack of association between hepatitis B birth immunization snd neonatal death: A population-based study from the vaccine safety datalink project. Pediatr. Inf. Dis J. 2004;23(7):656e62. Gorski D. Death by Gardasil? Not so fast there.. 2018. https://sciencebasedmedicine.org/deathgardasil-not-so-fast. Grabenstein JD. What the world’s religions teach, applied to vaccines and immune globulins. Vaccine 2013;31:2011e23. https://doi.org/10.1016/j.vaccine.2013.02.026. Haber P, Schillie S. Chapter 10, hepatitis B. In: Epidemiology and prevention of vaccinepreventable diseases. 14th ed. Centers for Disease Control and prevention; 2021. Hausman BL. Anti/vax: reframing the controversy. Cornell University Press; 2019. eISBN: 978-15017-3563-3569. Heininger U. Coincidence is not causalityda principle which needs regular rediscovery. Br Med J 1983. http://doi/101136/adc.83.4.355. INSERM. Consensus conference: vaccination against the hepatitis B virus. 2003. Intlekofer KA, Cunningham MJ, Caplan AL. The HPV vaccine controversy. Virtual Mentor 2012;14(1):39e49. https://doi.org/10.1001/virtualmentor.2012.14.1.msoc1-1201. Osazuwa-Peters N, Rhode RL, Boakye EA. HPV vaccination is safedyou don’t have to whisper it. JAMA Netw Open 2021;4(9):e2125124. https://doi.org/10.1001/jamanetworkopen.2021.25124. Richmond L. Flu shot myths and realities: the facts about flu vaccine safety, effectiveness and more. 2022. https://www.healthpartners.com/blog/flu-shot-myths. Rowello L. Needle phobia may be contributing to vaccine hesitancy more than we realize. 2021. https://www.verywellmind.com/needle-phobia-covid-vaccine-5197629. Smith TC. The HPV vaccine is on trial as anti-vaxxers mobilize against effective cancer prevention. 2019. https://nbcnews.com/think/opinion/hpv-vaccine-trial-anti-vaxxers. Taddio A, McMurtry M, Logeman C, Gudzak V, de Boer A, Constantin, et al. Prevalence of pain and fear as barriers to vaccination in childrendsystematic review and meta-analysis. Vaccine 2022. https://doi.org/10.1016/j,vaccine.2022.10.026.

292 A History of Vaccines and their Opponents Tanne JH. Texas governor is criticized for decision to vaccinate all girls against HPV. Br Med J 2007;334:337. https://doi.org/10.1136/bmj.39122.403044.DB. Vogel G. Decision by Europe’s top court alarms vaccine experts. Science 2017. https://doi.org/ 10.1126/science/aan7019. Yu W, Liu D, Zheng J, Liu Y, An Z, Rodewald L, et al. Loss of confidence in vaccines after hepatitis B vaccination in China. Int J Epidemiol 2016;45(2):441e9. https://doi.org/10.1093/ ije/dyv349.

Chapter 20

COVID-19: politics and disinformation Vaccines have been the victims of their own success. They have changed once deadly and terrifying diseases into a distant memory. Few modern parents in North America or Western Europe have experienced the devastation caused by a vaccine-preventable death in a child. The repeated successes of vaccination have meant that fewer laypersons and health professionals have had first-hand experience of the severity and dangers associated with vaccine-preventable diseases. Fear of infectious diseases has largely dissipated in developed western countries. As a result, many parents now tend to focus their attention on the perceived risks of available vaccines with little awareness or regard for the suffering caused by the diseases they prevent. Vaccines are only administered as preventatives to healthy individuals. Their benefits can only be estimated by population level studies, whereas risks, both real and imagined, are seen at the individual level. Unless exterminated like smallpox, infectious diseases never really go away. There are plenty of viruses out there that may, on occasion, jump into human populations and potentially cause lethal pandemics. In recent years, we have seen Ebola, SARS-1, Zika, Chikungunya, and Mpox causing temporary panics in the United States. By far, the most important of these recent emerging infections has been COVID-19 caused by SARS coronavirus 2. This is a severe respiratory disease that can only be prevented by effective vaccination. Unfortunately, in an age where there has been a radical change in the way people communicate, where vaccine literacy is low, and online sources of information are available without any effective fact-checking, it is unsurprising that misinformation, disinformation, and conspiracy theories regarding CIVID-19 and its vaccines have spread as never before. Patients increasingly rely on the internet for current health information. While health literacy has proven to be an effective way to convey Public Health information, it has also greatly increased the ability of damaging misinformation to spread. No longer dependent on pamphlets, the modern anti-vaccination movement has used the internet very effectively to spread disinformation in the form of distortions, exaggerations, and lies. The net effect has been that while the medical and scientific establishments have few doubts about the efficacy and safety of COVID-19 vaccines, there has been a A History of Vaccines and their Opponents. https://doi.org/10.1016/B978-0-443-13434-0.00012-7 Copyright © 2023 Elsevier Inc. All rights reserved.

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loud and persistent public debate that has had negative effects on vaccine uptake. As always, attempts to mandate COVID-19 vaccination have met with vigorous opposition. Likewise, attempts to regulate disinformation spread on social media platforms have proven to be largely inadequate. As a result, confidence in COVID-19 vaccines was eroded before the first ones were even made available to the public.

The origins of COVID-19 The origins of the SARS-2 Coronavirus are unclear. The first “official” case of SARS-2 respiratory infection, the index case, reportedly developed in midNovember 2019, in Wuhan, China. On December 1, this patient was admitted to a hospital with severe breathing difficulty caused by a pneumonia due to a previously unknown coronavirus. By December 27, there were more than 180 such cases. About two thirds of these early cases were reportedly linked to the Huanan Seafood Wholesale Market in Wuhan. These, so-called, “wet” markets are popular in China. They sell fresh fish and meat as well as assorted live reptiles and wild mammals, and house large numbers of creatures in close proximity. These live animals may be sold as pets or for food. Viruses can spread readily within these dense populations of stressed animals. From captive animals, they can also easily jump to humans, a phenomenon called zoonotic spillover. The SARS-2 coronavirus most likely originated in bats. While many of the original cases were associated with the “seafood” market it soon became obvious that the virus was also readily transmitted among humans. A similar event had occurred in 2002 when the SARS-1 coronavirus escaped from another Chinese wet market and infected thousands of people. Within a few weeks of the onset of the outbreak in Wuhan, the offending virus was identified, isolated, and its genome sequenceddsomething that could not have happened in prior pandemics. On January 7, 2020, the Chinese health authorities announced that the disease was caused by a novel alphacoronavirus. Its complete genome was published on January 10 and development of the first diagnostic polymerase chain reaction (PCR) assay was reported on January 15. This was an incredibly rapid scientific response. The virus was eventually named SARS-CoV-2. The disease that it causes was named Corona Virus Disease (COVID)-19 by the World Health Organization. Retrospective analysis of donated blood samples found antibodies to SARS-CoV-2 in samples from Illinois donated on January 7, 2020. Since it takes about 2 weeks for these antibodies to develop, those infections were probably acquired around Christmas 2019. The first confirmed COVID-19 death in the United States occurred in California on February 6, 2020. Subsequent analyses also indicate that the virus had also reached New York City sometime in February by way of tourists returning from California, Iran, and France.

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COVID-19 vaccines It was obvious, almost from the beginning of the COVID-19 pandemic, that the only long-term solution to this disease was the development of effective vaccines. Funding for vaccine production infrastructure has rarely been available in the absence of an imminent disease threat. As a result, coronavirus vaccine development started belatedly and from scratch. Eventually, however, massive funds were made available in an effort to accelerate the vaccine development process. The first human trial of a vaccine began on March 17, 2020, with the Moderna Vaccine being tested at Kaiser Permanente in Seattle, WA. Vaccines are tested through a multistage process. For example, a trial batch of vaccine must first be tested in a small group of individuals (Phase 1 trials). If safe and successful, it can then be tested in a small number of human volunteers to assure their safety. This group should have the same characteristics such as age and health as the proposed target population (Phase 2 trials). If all appears well and no significant adverse events have occurred, then the vaccine undergoes large scale clinical trials involving thousands of people (Phase 3 trials). The recipients are monitored looking for adverse events and to determine whether their antibody levels indicate that they are protected against the naturally acquired disease. These trials normally take many months or even years. Once developed, any vaccine will then have to be manufactured in huge amounts and this itself may be difficult to achieve. Despite these constraints, the vaccine industry took up the challenge and developed several different, and remarkably effective COVID19 vaccines in an incredibly short time. On May 15, the US government launched “Operation Warp Speed,” a national private/public partnership program to accelerate the development, manufacture, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. The aim of the program was to deliver 300 million doses of a safe, effective vaccine to the US public by January 2021. This program worked well. As a result, on December 11, 2020, the FDA issued an emergency use authorization for the first COVID-19 vaccine produced by Pfizer-BioNTech. Three days later, on December 14, Sandra Lindsay a nurse in New York became the first American outside a clinical trial to receive the vaccine. On December 18, the FDA issued an emergency authorization for a second RNA vaccine made by Moderna. Demand for these vaccines was high, especially among health-care professionals. By December 24, it was estimated that more than a million Americans had been vaccinated. Other vaccines followed in rapid succession. By December 2022, it was estimated that the vaccines had prevented more than 18 million hospitalizations and 3 million deaths in the United States alone (Fitzpatrick et al., 2022).

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RNA vaccines Studies on the use of messenger RNA technology in vaccines had been underway for at least 15 years. Many of these studies were triggered by the first outbreak of severe respiratory disease caused by the SARS 1 coronavirus in 2002. These initial studies had demonstrated that the best protective antigen in the virus was the spike protein; this protein forms the spikes on the viral surface and binds the virus to its target cell prior to invading it. Antibodies to the spike protein block this binding so that the virus is unable to invade cells (Box 20.1). Thus, once the COVID-19 virus was completely sequenced and the results published in early 2020, work could proceed immediately on the development of the vaccine. Development proceeded very rapidly for such a novel approach. The first two COVID-19 vaccines, one produced by PfizerBioNTech and one by Moderna, were approved by the FDA for emergency use in late November 2020. These two vaccines contained messenger RNA (mRNA) encoding the SARS-2 coronavirus spike protein incorporated in fat droplets. Once injected, these droplets are readily taken up by cells, their enclosed mRNA is then translated into the viral spike protein. This foreign

BOX 20.1 RNA vaccines The flow of information within a cell proceeds from DNA to RNA to protein. The protein molecules will trigger an immune response if they are foreign. Recently, most notably with the vaccines against COVID-19, it has proved possible to make highly effective RNA vaccines. The RNA encoding the antigenic protein of interest (in the case of COVID, this is the viral spike protein) can be readily synthesized. It can then be incorporated into fat droplets. When these are injected in the body, the fat droplets containing the RNA are readily taken up by nearby cells. Once inside the cell, the RNA can be translated into protein. Hence, the cell will begin to synthesize and express the viral spike protein on its surface. There it will be recognized by T cells and so trigger a cell-mediated immune response. These vaccines are relatively simple consisting of only the RNA of the specific gene sequence together with the lipid droplet. Different manufacturers employ slightly different formulations of the oil droplets. While conventional vaccines require large and expensive production facilities, RNA synthesis is relatively simple. It can be readily produced by a standardized process reducing both cost and time. Only information about the RNA sequence is required and there is no need to handle dangerous pathogens. RNA is also relatively stable as long as it is not exposed to a degrading enzyme such as RNase. RNA is also self-adjuvanting in that it is a potent stimulator of interferon production. It should also be pointed out that RNA, unlike DNA, does not need to get into the cell nucleus. It is sufficient for it to simply cross the cell membrane into the cytoplasm. In fact, naked mRNA is spontaneously taken up by many cell types and expressed within minutes.

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protein is then processed and presented on the cell surface where it is recognized as foreign by the recipient’s immune system. As a result, the spike protein triggers a protective immune response involving both T and B cells. Initial trials showed, and follow-up studies confirmed, that both these vaccines were 94%e95% effective after two doses. They prevented severe COVID-19 disease and death and had remarkably few adverse side effects. As manufacturing ramped up, initial vaccine shortages were overcome, and the vaccine became available to a second priority group; those over 65 and those with a predisposing medical condition. On February 27, 2021, the FDA permitted emergency authorization of a third vaccine produced by Johnson and Johnson (J&J). This was a single dose vaccine that used a very different technology from the previous RNA vaccines. Instead, it contained a harmless adenovirus into which, DNA encoding the gene for the coronavirus spike protein has been inserted. When this “recombinant” adenovirus enters cells, the infected cells use this DNA to make coronavirus spike protein that in turn triggers a protective immune response. The J&J vaccine is reported to be 85% effective against severe COVID-19. On April 13, however, use of the J&J vaccine was paused because of what appeared to be a high prevalence of blood clot complications. On December 30, 2020, a recombinant vaccine produced by AstraZenica was also approved in the United Kingdom. It also contained a genetically modified, harmless recombinant adenovirus that expressed the coronavirus spike protein. It has been reported to be 65%e85% effective. However, it too has been linked to rare cases of vaccine-associated blood clotting. Similar vaccines were also developed in Russia, India, and China around this time and employed in their respective countries. The use of the term “Operation Warp Speed” by american politicians was unfortunate since it gave the public the impression that vaccine development was a rushed job and that shortcuts were taken in the process. It is often the case that people are unwilling to go first with a novel vaccine. Much of the initial hesitancy therefore focused on the apparent haste with which the vaccine was produced. This was based on a belief that it had not been adequately and completely tested. This was not the case, the vaccine had been fully tested, and as a result, adverse events following vaccination were extremely rare.

Vaccination mandates The World Health Organization has argued that if vaccine mandates are to be used, they should be both proportional to the threat and the magnitude of the problem. They should also be used only as a last resort when other methods such as vaccine education have failed. Given the international nature, rapid onset, and severity of the COVID-19 pandemic, it is unsurprising that initially, many governments felt obliged to establish and enforce vaccine mandates for healthcare workers. This was especially the case where their healthcare

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systems were in danger of collapsing under the load of a huge number of coronaviral respiratory disease patients requiring intensive care. Once governments began to impose vaccine mandates, the protests began. Demonstrations took place in the streets of many cities in the summer of 2021. The mandates differed between countries. For example, in France, beginning in October 2021, people had to present evidence of vaccination to enter cinemas, museums, cafes, and trains. Around 200,000 protesters, it is estimated, took to the streets of France. In the United Kingdom, COVID-19 vaccination was mandated for healthcare workers in November 2021 but was revoked after protests in March 2022. Austria also imposed a vaccine mandate in February 2022, but then suspended it. Italy introduced a mandatory healthcare worker vaccination in April 2021, and Greece introduced mandatory vaccination for the over-60s. The downsides of mandates, as discussed in this book, are clearly evident. Nevertheless, they must be judged by whether or not they worked. This analysis must include just what to require and how seriously should it be enforced. Thus, most countries adopted a process similar to France where health passes proving vaccination were required in order to get access to certain public spaces such as restaurants and theaters. Some countries such as Ecuador introduced these passes as soon as the vaccines became available, others introduced them progressively as the wave of infections by the delta variant of COVID-19 grew. These health passes were much less restrictive than mandated vaccination and permitted the unvaccinated to participate in some civic activities. In other countries, governments made vaccination a condition of employment. This was the case in the United States where vaccination was initially required for health care or federal jobs. Many private employers did the same. Some used the old-fashioned method of requiring COVID-19 vaccination for enrollment at school. The government of Singapore ruled that unvaccinated COVID-19 victims would have to pay for their own healthcare. Studies have been conducted on the effects of these mandates. Thus, Lithuania mandated vaccination while adjacent Poland did not. Following the mandate, Lithuanian’s vaccine coverage rose 12% above Poland’s where previously they had been almost identical. In Canada, the introduction of certificate-based policies increased the pace of vaccination by 66% on average, although the effect differed greatly among different communities. In France, even the unpopular mandate likely resulted in the uptake of an additional 8.6 million doses of vaccine. Within 2 months, 91.4% of French citizens had received their first shot of a COVID vaccine compared to 76.6% in the EU as a whole (Nuwarda et al., 2022). It has been calculated that this increase in vaccine uptake resulted in the prevention of 4000 deaths in France. These results also effectively reduced the pressure on the French hospital system and thus prevented another lockdown. In Greece, the mandate resulted in 42% of the unvaccinated over-60s received the vaccine. Mandates worked!

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Enforcement of a vaccine requirement for healthcare workers is a highly ethical matter. Besides protecting the vaccine, vaccinated individuals also protect their colleagues and patients. It minimizes staff absences enabling organizations to continue functioning. A study in New York City by Dr. James Lee found that in areas where mandates were in place, 90.5% of healthcare workers were vaccinated. In locations where vaccines were not mandated, only 73.3% were. These differences were also a result of improved access to vaccination. Thus, where mandates were not in place there was a 26.7% gap in coverage between staff earning more than $75,000 (Doctors and senior managers) (79.6%) and those earning below the federal poverty line (cleaners and manual laborers) (52.9%). In locations where mandates were in place this gap dropped to 11.9% (Lee et al., 2022). Once the vaccines were readily available and distributed across the United States, some states and cities also began to issue mandates to their employees. Thus, starting on August 22, 2021, healthcare workers in NYC were required to be vaccinated or else undergo weekly COVID-19 testing. On July 26, the Veterans Administration required the same for its health workers. Moving on, California and NYC required the vaccine for all state workers. On July 29, President Joe Biden called for all federal workers to be vaccinated. On August 6, California mandated vaccination for all healthcare workers. Given the huge number of individuals vaccinated and the relative absence of serious adverse vaccine-associated events, the Pfizer/BioNTech vaccine received full FDA approval on August 23, 2021. This was a significant stimulus for vaccination uptake since many of the vaccine hesitant had previously been reluctant to receive a vaccine that had only received emergency authorization from the FDA. On August 24, several employers such as the Walt Disney Company mandated vaccines for its employees. Two days later, on August 26, the Pentagon required vaccination for all active-duty service members. On September 9, President Biden announced that all companies with over 100 employees must require vaccination or undergo weekly testing. On September 10, the Los Angeles Board of Education required all schoolchildren over 12 to be vaccinated. On September 27, United Airlines announced a vaccine mandate deadline for its employees. In January 2022, Boston and Chicago announced that proof of vaccination would be required to enter indoor spaces such as gymnasiums, restaurants, and theaters. New York City and Los Angeles already had similar rules. Now the pushback started. Many conservative groups filed lawsuits opposing these mandates. However, the courts, with the Jacobson v Massachusetts ruling in mind, ruled in most cases that the mandates were lawful. For example, on January 13 the US Supreme Court upheld the health care worker mandate. It should be pointed out that mandates can have different effects on different subjects. Thus, although vaccine passport requirements have an

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overall positive effect on vaccination uptake, they are polarizing. Generally, it makes those who intend to take the vaccine even more positive about it. However, it has an opposite effect on those who have concerns. (These effects are most negative among some ethnic communities based on their historical experiences and their level of trust in the medical community.) (Pertwee et al., 2022).

Political partisanship Political partisanship also became a major predictor of COVID-19 vaccination status in the United States and as a result, the pandemic has been more serious than it otherwise would have been (Gadarian et al., 2022). Across the United States, there has been a clear link between social identity, political party affiliation, and views on vaccination. Studies on vaccination rates and mortalities in US counties have demonstrated that vaccination rates were lower, and mortality was higher, in counties that had supported the Republican party in the previous election when compared to those that had voted for the Democrats (Fig. 20.1). It was estimated that Americans in counties that voted 60% or higher for the Republican presidential candidate, Donald Trump, were 2.26 times more likely to die from COVID-19 than those living in counties that voted for his opponent, the Democratic candidate, Joe Biden (Papenfuss, 2022). These death rates closely followed the lack of vaccination protection.

300 COVID deaths per 100,000 people

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Counties where Trump received >70% of the vote All US adults eligible for vaccine

Counties where Trump received