A History of Vaccines and their Opponents

By Ian R Tizard

The coronavirus pandemic that began in 2019 brought to the fore the presence of a significant minority of individuals who strongly oppose vaccination. This opposition is by no means recent. Ever since the very first attempts to immunize individuals, opposition has been intense in some societies. The reasons for this opposition range from religious to political to medical. Although vaccines have eliminated smallpox and largely eliminated polio and measles, opposition to vaccination persists and, in some countries, has grown stronger.A History of Vaccines and Their Opponents seeks to describe the history of this opposition as well as its changing rationale over the years and in different societies. The discussion may ultimately provide some suggestions for reducing hesitancy in the future.

• Demonstrates vaccine hesitancy is not new and is widespread around the world
• Presents the history of the opposition to immunization
• Provides counterarguments to the opposition today

• Language: English
• Publisher: Academic Press
• Release date: Apr 21, 2023
• ISBN: 9780443134333

Ian R Tizard

Ian Tizard, BVMS, BSc, PhD, DSc (Hons), DACVM, is a Diplomate of the American College of Veterinary Microbiologists and a University Distinguished Professor Emeritus of Immunology, Department of Veterinary Pathobiology, The Texas Veterinary Medical Center at Texas A &M University (TAMU), College Station, Texas, USA. Dr. Tizard earned his Bachelor of Veterinary Medicine and Surgery from the University of Edinburgh, Scotland in 1965. He then completed a Bachelor of Science in Pathology and a PhD in Immunology. After completing his studies, Dr. Tizard became a Post-Doctoral Fellow at the University of Guelph, where he remained on as a professor until 1982 when he moved to TAMU. Dr. Tizard wrote the first standardized textbook on Veterinary Immunology in 1977. This text, now in its 10th edition, is used worldwide, and has played a major role in establishing Immunology among the key disciplines of Veterinary Science.

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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 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.

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 inescapable—vaccines work. Infectious agents and their anti-vaccination allies are the inevitable losers.

Ian R. Tizard

Chapter 1: How vaccines work

Abstract

Living in a world dominated by microbes, animals such as humans require potent defensive systems in order to survive. These defense systems ensure resistance to infections and can be triggered by vaccination. There are two major forms of immunity. Fast developing but temporary innate immunity, and slowly developing but prolonged and potent adaptive immunity. Adaptive immunity itself also occurs in two forms. Antibody-mediated immunity directed against extracellular invaders such as bacteria and cell-mediated immunity directed against intracellular invaders such as viruses. In both cases, resistance to infection may persist for many years as a result of the production of large numbers of rapidly responding memory cells. Vaccines can trigger both forms of immune response as well as triggering memory cell formation and hence prolonged resistance to specific infectious diseases.

Keywords

Adaptive immunity; Antibodies; Antigens; B cells; Innate immunity; Memory cells; T cells

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 immunology—the science of the defense of the body—the 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 everywhere—in 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.

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 bacteria—our normal microbiota—do 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 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.

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 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 fatigue—an 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 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 price—the 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.

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.

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 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 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.

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.

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 cells—extracellular 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 cells—the 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).

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, their levels climb to reach a peak by 10–20 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.

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.

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 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.

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.

Note that antibodies and T cells have quite different functions. Thus, antibodies are optimized to deal with the organism itself, such as free virus 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 cell–mediated 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 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