On the history of vaccination and anti-vaccination

I post this with some trepidation. Wanderlusting the Jemez is neither a medical blog nor a political blog. I don’t really want this to be a political post. But vaccination seems to have become a political issue, so while I’ll make my best efforts to keep my blog apolitical, someone is likely to loudly complain that I’ve hit him with a pellet or two. But I think this is an important topic, worth the risk.

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Vaccination is a preventive medical procedure in which the health practitioner “teaches” the immune system of a healthy patient to rapidly recognize and eradicate an infection from a specific virus or bacterium.

Our immune systems have many components, but they can be grouped into two parts. These are the innate immune system and the adaptive immune system.

The innate immune system is the older and more diverse part of the immune system. Almost every living organism has some kind of innate immune system to protect it from infection or intoxication. Innate immunity can be as simple as physical barriers, such as tree bark or animal skin, or it can be as elaborate as the complement cascade. The latter is a sophisticated and general mechanism for recognizing and killing bacterial cells that are posing a threat. The innate immune system includes a number of immune system cells that patrol the body, looking for things that don’t belong and removing them if possible.

The innate immune system does most of the heavy lifting of protecting us against the microorganisms that are always present in our environment. It provides first, second, and third of defense, with physical barriers such as the skin providing the first line of defense and local immune cells providing the second line of defense. The third line of defense is provided by the ability of local immune cells to call in additional immune cells to deal with a threat. These are the SWAT teams of the innate immune system.

However, the innate immune system is inadequate for the worst threats, because some viruses and bacteria have acquired the means to evade the innate immune system. Even its SWAT teams are trained and equipped only against general categories of threats, and are not specialized to deal with such sophisticated attacks. That is the job of the adaptive immune system.

The adaptive immune system is capable of developing highly specialized and extremely effective weapons against specific foreign substances. Usually these foreign substances are proteins that the immune system recognizes as not the body’s own proteins. An example is the spike protein of COVID, which allow the virus to latch onto our cells and pry their way inside. There’s nothing quite like it in the healthy human body. However, the adaptive immune system can also respond to unusual carbohydrate chains, lipid (fat) molecules, and other giant molecules that it recognizes as foreign.

The immune system is astonishingly good at spotting things that don’t belong. But it gets help from ordinary cells that have been infected with a virus. Many viruses, including COVID, carry their genetic information on a single strand of RNA. When a virus invades a cell, large numbers of this stand of RNA are duplicated in an attempt to hijack the cell’s machinery. We are just beginning to learn how a cell defends itself against a virus, but when a cell recognizes foreign RNA in its interior, it does at least three things: It begins shredding every strand of RNA it can find; it begins looking for foreign proteins coded by the RNA, and “presenting” strands of this protein on its cell membrane; and it begins turning out proteins called interferons. Interferons interfere with virus replication, but they also warn neighboring cells to crank up their virus defenses.

Turning on the RNA shredder is very hard on a cell, because the shredding machinery is indiscriminate and shreds the cell’s own RNA. But it is (so far as we presently know) the only way the individual cell has to try to rid itself of a virus. If RNA shredding fails, one of the immune system’s T cells may order the infected cell to take the drastic step of “falling on its sword”, killing itself to prevent further virus replication. This process of apopotosis works best with cells that are capable of being replaced, such as most of our skin and mucous membrane cells. Cells like heart cells or brain cells have little capability to replace themselves, so apoptosis is an act of desperation when these cells are infected. It may not be coincidence that the cells most likely to be infected by viruses have retained the ability to reproduce. This comes at the cost that these are also the cells most likely to become cancerous in old age.

Presentation of foreign proteins on a cell membrane is the first step in activating the adaptive immune system. The immune system includes antigen-presenting cells which gather up foreign protein strands or other foreign macromolecules (antigens) from the body’s tissues, transport them to lymph nodes, and present them for analysis. Many of these cells, such as dendritic cells, are stationed throughout the outer tissues of the body, waiting for an antigen to come along. They may spot the antigen when an infected cell presents it, or they may find the antigen themselves in the intercellular spaces and recognize it as foreign. Either way, the antigen-presenting cell heads for a lymph node and there presents the antigen to naive B cells.

Once an antigen is presented to B cells in a lymph node, the immune system verifies that it is a foreign antigen, and then determines which naive B cells most closely match it. The fit is likely very loose at this point. The most closely matching naive B cells begin rapidly multiplying. Some of the daughter cells are plasma cells, which begin immediately producing antibodies against the antigen. Antibodies are protein chains that include a variable region that is the right shape and charge to tightly bind to a particular antigen. The rest of the molecule is a “payload”, and there are several types. Some antibodies clump antigens together, which helps immune cells gather them up for disposal. Others are like a homing beacon that leads immune cells to the antigen. In the case of viruses, it is common for the antibody to inactivate the virus merely by binding to it, because the antigen is necessary for the virus to function and the antibody gums up the antigen and thereby neutralizes it.

The early batch of antibodies are a poor match to the antigen, so they are unlikely to be sterilizing antibodies that rapidly inactivate the virus. But they provide some mild immunity, helping the innate immune system hold the line while the adaptive immune system prepares something better — by adapting.

Those daughter cells that are not diverted to producing early, weak antibodies deliberately mutate the part of their genetic coding that determines what antigen is matched by the variable region of their antibodies. This is called somatic hypermutation. Some of the mutated daughters cells are no better a fit to the antigen than the original naive B cells; these cells are weeded out. Some may mutate to match one of the body’s own proteins; these are vigorously weeded out. But some daughters provide a tighter fit to the antigen. These continue multiplying, spinning off some plasma cells that produce increasingly effective antibodies, while further mutation and selection continues to tighten the fit. In time, a clone (cell line) is produced that is a nearly perfect match to the antigen. This clone then multiplies full blast to produce an army of plasma cells that produce vast quantities of sterilizing antibodies. These eliminate the virus from the body.

This assumes, of course, that the patient is still alive at this point. Somatic hypermutation takes time to develop full immunity: days to weeks. But once a large population of highly attuned plasma cells is pumping out antibodies, the virus is rapidly cleared from the system.

Once the virus has cleared, most of the plasma cells die off. A small number become memory B cells, which can remain in circulation for decades. These resemble naive B cells, but they are already attuned to a specific virus, and their mechanism of activation is modified to take advantage of this fact. The memory B cells continue producing small amounts of antibodies, which is why an antibody test can sometimes show years later that you were once infected. This low level of antibody is often enough to prevent a second infection from taking hold. But if a second exposure to the virus does get a foothold, the memory B cells can be rapidly activated and, because they already are attuned to the virus, they can immediately start turning out sterilizing antibodies. These stop the second infection in its tracks. You very likely will show no symptoms. If you do, they will be relatively mild symptoms. And you will generally shed a lot less virus than someone with a full-blown infection.

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We’ve known for millennia that many infectious diseases seem to hit an individual only once. If he survives, he never gets the disease again, even when he is heavily exposed to it. These include what we call the childhood diseases, which most people used to get in childhood exactly once and were done. Examples include measles, chickenpox, and mumps, usually considered mild when contracted at a young age — though all have potential serious complications, and we now routinely vaccinate against them. Other examples are less pleasant to think about: polio, smallpox, diphtheria, or whooping cough. Most polio patients survive without paralysis, and most whooping cough patients eventually fully recover, but a small percentage of patients are paralyzed or killed by these infections. And both smallpox and diphtheria are deadly.

The Chinese seem to have been the first to recognize that deliberately infecting a person with a mild strain of smallpox would produce lasting immunity. The Chinese version of variolation involved collecting scabs from smallpox sufferers who seemed to have a milder strain of the disease, possibly Variola minor . The scabs were dried for a few days (which likely reduced their virulence further) and then were ground up and … snorted up the nose. With luck, this produced a mild infection, which in turn elicited strong immunity.

It’s not clear when variolation first caught on in the West, but by 1721 it was being put into practice by Reverend Cotton Mather in New England. The procedure was to take virus from someone with a mild infection, then inoculate the recipient with a shallow skin scratch. Virus introduced this way was less likely to spread throughout the body and cause a dangerous infection. This was still a risky procedure: Variolation killed up to 1% of those treated. But smallpox epidemics killed up to 60% of those infected, so the risk was worth it.

Early opposition to variolation was, curiously enough, not a response to its risks but to its effectiveness. The English theologian, Reverend Edmund Massey, published The Dangerous and Sinful Practice of Inoculation in which he argued that diseases were God’s punishment of the wicked, and inoculation to prevent disease was thwarting the will of God. Other religious leaders, like Reverend Mather, were supportive of variolation, and were likely in the majority, but the antivaccination movement was born.

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In 1796, a country doctor by the name of Edward Jenner observed a curious thing. Milkmaids often acquired a mild skin disease, cowpox, from the cattle they milked. (Or, as a wag on the Internet put it: Cows sometimes acquired milkmaidpox from the milkmaids stealing their precious bodily fluids.) Once the disease ran its course, the milkmaids were immune to infection by smallpox. Jenner was not the first to make this observation, but he was the first to put it into practice and report his success to the wider public, and it has been said that he thereby saved more human lives than any other human who has ever lived.

This procedure of vaccination works because cowpox is closely related to smallpox, shares most of the same antigens, and the antibodies that the immune system produces against cowpox are sterilizing against smallpox. Vaccination was much safer than variolation, since there was almost no possibility of a “breakthrough” infection of full-blown smallpox in the person vaccinated. But very few medical procedures are absolutely safe, and it is estimated that even modern vaccines based on Jenner’s discovery killed perhaps one or two patients per million patients vaccinated. The safety in Jenner’s time was considerably lower; vaccination was done directly from one patient to another, and could accidentally transmit more serious diseases. The nascent anti-vaccination movement claimed, for example, that vaccination was transmitting syphilis, which is a very serious disease, and was particularly so prior to the development of modern antibiotics. The anti-vaccination movement also claimed, correctly, that Jenner was wrong in his assertion that vaccination produced permanent and total immunity. Some vaccinated individuals did come down with smallpox years later. This was infrequent and the infections generally much less deadly, but Jenner’s overselling of the benefits of vaccination eroded trust enough to allow the anti-vaccination movement to grossly undersell its benefits.

Smallpox is deadly, but it is a disease only of humans, with no animal reservoir, and vaccination is safe and effective by any reasonable measure. The odds of dying from smallpox vaccination are much less than your chances of someday being killed by a lightning bolt, and vastly lower than the odds of dying of smallpox in an area where the disease is endemic in the population. The vaccine is about 95% effective, meaning that a vaccinated individual is about 1/20th as likely to develop the disease on exposure to the smallpox virus as an unvaccinated individual, and the 5% who do come down with the infection are less than half as likely to die.

Given these facts, it was proper to attempt complete eradication of smallpox, and the virus is now extinct in the wild. But here’s something to keep in mind: A point was reached, when smallpox was on the verge of extinction, where your odds of dying of the vaccine became greater than your odds of dying of smallpox. Vaccination continued, because the benefit to future generations of complete eradication was judged worth the immediate risk to those being vaccinated. It seems clear to me that this was the ethical choice. Now that smallpox is extinct in the wild, we no longer vaccinate anyone but a few laboratory researchers against smallpox, and that is also the correct choice.

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Although the word vaccination originally referred to preventative inoculation with cowpox (Vaccinia), the term is now applied to all forms of preventative inoculation with antigens to train the immune system to resist a future infection.

Vaccination, together with public health measures, was the best medical science had to offer through the 19th and early 20th centuries. Sulfa drugs, which could snuff out a bacterial infection that was already established, were not discovered until 1932. Once discovered, sulfa was so effective against pneumonia, the leading cause of death in the elderly, that it was said to have “dethroned the captain of the men of death.” Other antibiotics followed.

Antibiotics work by blocking biochemical processes that are unique to bacteria. Sulfa inhibits production of folic acid in bacteria. We humans get this essential vitamin through our diet, but bacteria had never acquired the ability to absorb folic acid from their environment. When a human patient with a bacterial infection is treated with sulfa, the invading bacteria are starved of folic acid, and their growth slows to a crawl. The human host is essentially unaffected. Penicillin sabotages the production of bacterial cell walls, killing the bacteria outright. Human cells have no such wall, and penicillin is so nontoxic that the level of overdose for some formulations has never been established. Severe allergic reactions to penicillin do sometimes occur, because the immune system of a few patients spots the penicillin as foreign to the body, and overreacts to it. Fortunately, this is rare.

But antibiotics are almost useless against viral diseases. Viruses rely on very few biochemical reactions of their own; they mostly commandeer the host cell’s machinery, and knocking out this machinery kills the cell along with the virus. As a result, vaccination continues to play a crucial role in protecting us from viral infections.

Louis Pasteur discovered the next round of vaccines after smallpox. He developed vaccines against chicken cholera and anthrax, but his most famous was the rabies vaccine.

Rabies is a terrible disease. It is not highly contagious, generally requiring the bite of an infected animal, but once the infection takes hold, death is all but 100% certain. And it is a most unpleasant death. Fever and headache progress to mental disturbance, delirium, and coma. A particularly unpleasant symptom is spasms of the throat muscles when attempting to drink fluids, which can progress to uncontrollable and excruciating painful throat spasms at the mere mention of water. It is because of this symptom that the name hydrophobia is sometimes applied to rabies.

The disease develops slowly. The usual time from infection to first symptoms is one to three months, though it can be as little as a few days or as long as six years. The virus enters muscle cells, where it quietly replicates without alerting the immune system. It then jumps to nerve cells and migrates towards the brain. Once in the brain, the virus moves back down the nerves towards the salivary glands, where it rapidly replicates and is released into the saliva to infect the next victim.

The rabies vaccine is one of the very few vaccines that is typically administered only after exposure. Pasteur’s original version used Infected spinal tissue from a rabbit, which was thoroughly dried, inactivating the virus. This was ground and injected into the patient’s abdomen, where the dead virus particles were fully exposed to the immune system. The spinal tissue was irritating and caused local inflammation, which actually increased the immune response to the virus and made the vaccine more effective — it was an example of an adjuvant. A long series of vaccinations with increasingly virulent infected spinal tissue, traditionally 14 in number, allowed the immune system to gradually build up a strong response to the virus. This procedure was effective but was both painful and dangerous. The injected spinal tissue could occasionally trigger a severe autoimmune response. But since the alternative was a high risk of a very unpleasant death, vaccination was universally considered the best option.

Modern rabies vaccines contain no complete virus particles and have proven safe and effective. They also require fewer doses and are much less painful. When given to a patient who is already exposed to rabies, the vaccine is generally used in combination with rabies gamma globulin, which is rich in sterilizing antibodies against the virus. The gamma globulin provides a measure of temporary but immediate protection.

By law, rabies vaccines are required for rabies-susceptible pets in virtually every Western legal jurisdiction. However, only those humans who are likely to come into contact with the virus, such as veterinarians, are routinely vaccinated against rabies. For others, vaccination after exposure is almost always effective, rabies exposure in areas with pet vaccination laws are rare, and preventative vaccination is not worth even the small risk involved.

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Polio is a surprisingly modern disease. The virus has been around for a long time, but until the 20th century, most humans were exposed to it in infancy, developed a mild case of the disease, and acquired lasting immunity. Perversely, modern public health measures reduced the likelihood of exposure to the point where many persons were first exposed as teenagers or young adults, and they were more likely to develop the paralytic form of the disease.

Polio is an enterovirus, whose normal target is the digestive tract. It is spread by food or water contaminated with human feces. In about 75% of childhood cases, an infection causes no obvious symptoms. In most of the remaining cases, it causes flu-like symptoms which resolve without complications. But in about 1% of cases, the virus invades the central nervous system, causing meningitis. About 1 to 5 out of every 1000 patients develops permanent muscle weakness, or worse.

Development of a vaccine posed some serious technical challenges, because of the variety of different strains and the difficulty of growing polio in the laboratory. The Salk vaccine combined three strains of polio, which were inactivated with formaldehyde. The vaccine proved 60% effective or better against the most common strains of polio.

However, the early vaccines were not always safe. Salk developed a protocol for vaccine production that was approved by the FDA. Experienced vaccine manufacturers enhanced the protocol to ensure that no live virus remained. Their vaccines were safe and effective. Cutter Pharmaceuticals, which was less experienced with vaccine production, followed the Salk protocol to the letter — and some lots of their vaccine contained virus that was not fully inactivated. The Cutter vaccine caused 40,000 cases of polio, including ten deaths.

At this point, bad vaccine collided with mutating law.

Cutter was sued by Melvin Belli, the “King of Torts”, on behalf of two children who developed polio as a result of being vaccinated with the Cutter vaccine. The evidence presented in court showed that Cutter had strictly followed the protocol approved by the FDA and that the lots of vaccine that were tested passed the the safety tests. Based on this evidence, the jury found that Cutter had not been negligent. However, Cutter was held to have violated an implied warranty on its product, a finding at odds with much of the case law of the time. But the trial came at a time when a great deal of American consumer law was changing. Strict liability was becoming more prominent — the idea that a defendant could be held liable even with no showing of malice or negligence.

It’s hard for me to find any villains in this story. Cutter had manufactured vaccine according to instructions, approved by an arm of the government, and its vaccine had passed the prescribed safety tests. Many Cutter employees, including Cutter executives, had had their children vaccinated with the company’s vaccine. (And some had developed polio.) But I also sympathize with the plaintiffs, who had contracted polio from the vaccine. I’m not much of a Melvin Belli fan, but as a lawyer, he was vigorously arguing his client’s case, which was his job.

The court case, and others like it, had three consequences. First, Cutter was driven out of the vaccine business. Second, public confidence in the Salk vaccine was shaken, even when further testing showing that other manufacturers were making a safe vaccine. This opened the door to the Sabin oral vaccine, which uses a mutated strain of polio that multiplies well in the gut (producing a strong immune response) but has lost the ability to invade the nervous system. The Sabin vaccine was arguably cheaper, safer, and more effective.

Third, the Cutter incident began to bring the antivaccination movement out of the fringes.

An attempt has been made to eradicate polio in the way smallpox was eradicated, but polio is still infecting persons in Afghanistan and Pakistan. Islamist extremists have denounced polio vaccination as a conspiracy to sterilize Muslims, and it has not helped that the CIA ran a vaccination clinic as a front during its search for Osama bin Laden. Unfounded rumors circulated for a time that the polio vaccine was responsible for AIDS. This was disinformation; but it is true that here are now more polio cases from virus in the oral vaccine reverting to a virulent form that from wild strains. Vaccination against polio is considered still ethical, because of the rise of wild cases that would follow if it ceased.

But this represents yet another ethical quandary. Polio vaccination poses more immediate risk to its individual recipients than wild polio. But the end of polio vaccinations would pose a much greater long-term risk to humanity as a whole. We must not play God, and yet we are playing God either way we choose.

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In 1949, the DTP vaccine was approved.

DTP is a trivalent vaccine. “D” stands for diptheria, “T” for tetanus, and “P” for pertussis. The D and T components are actually toxoids, inactivated forms of protein toxins produced by diphtheria and tetanus. The toxoids teach the active immune system to generate neutralizing antibodies against the toxins, and with their toxins neutralized, neither diphtheria nor tetanus can take hold. The P component is a more conventional vaccine, producing sterilizing antibodies against the pertussis bacterium itself.

Diphtheria produces a severe throat infection that destroys the lining of the throat. The dead tissue forms a characteristic black membrane, and untreated individuals often choke to death on their own dead throat lining. Even with treatment to keep the airway open, victims may die of heart damage from the potent toxin produced by the bacteria. The death rate is around 5% to 10% even with treatment.

Tetanus is also known as lockjaw. It can take hold in a deep wound that is poorly oxygenated. The bacterium produces a toxin that attacks the nervous system, causing spastic paralysis. Muscles involuntarily tighten and will not relax. In the early stages, the jaw muscles are most affected, which is the basis for the common name. As the infection progresses, larger muscles become involved, and spasms can become so severe that broken bones result. The spasms are excruciatingly painful. Have you ever had a calf muscle cramp up? Imagine all your large muscles doing that, for hours at a time. Death follows in about 10% of cases, even with treatment, due basically to exhaustion. The disease essentially tortures its victims to death.

Pertussis is less awful mainly by contrast. It produces cold-like symptoms, then begins severely irritating the lining of the lungs. This produces a horrendous cough that leaves the victim gasping for air (hence the common name for the disease, “whooping cough”.) A coughing spell can break ribs or induce vomiting and the the cough can persist for three months. The disease is highly contagious, and while it rarely kills adults or older children, it can kill up to 0.5% of infants who are infected.

In the 1970s, a claim began to circulate that the pertussis component of the vaccine was responsible for a rare condition labeled pertussis vaccine encephalopathy. The incidence was low, around one per 310,000 immunizations, and much less than the rate of death from pertussis itself, which was in the thousands per year before the development of the vaccine. Officials continued to recommend vaccination.

Then the lawyers came into the act. There is nothing that draws our sympathy more than an injured child, and juries returned verdicts accordingly. In the new legal climate, it did not matter that the vaccine was prepared properly and that the risks were known and explained. Under strict liability, the manufacturers could still be made to pay damages. These skyrocketed in 1982, when reporter Lea Thompson produced the TV documentary, DTP: Vaccine Roulette. By the end of 1985, only one pertussis vaccine manufacturer remained in operation in the U.S., and the cost of the vaccine had skyrocketed.

Congress hammered out a political compromise to deal with the situation. The 1986 National Childhood Vaccine Injury Act relieved manufacturers of strict liability for their vaccines, so that children harmed by a vaccine that was manufactured according to FDA guidelines were compensated from a permanent fund. Only manufacturers who were demonstrably negligent could be directly sued. Other cases were to be brought to a Vaccine Court for adjudication, and any claims upheld by the Court would be paid out of the permanent fund. This removed a powerful disincentive to the manufacture of vaccines. The act also required doctors to give patients an information sheet with each vaccination, outlining the benefits and risks of the vaccine.

NCVIA also established the Vaccine Adverse Event Reporting System, or VAERS. This required all health care providers to report certain adverse events that followed vaccination. These had to be reported whether or not the healthcare worker believed there was any connection between the adverse event and the vaccination. And the system was open to non-healthcare workers, including parents and their lawyers, who could make their own reports and did not have to provide verification.

One of the things that makes us human is our capacity to connect cause and effect. Other animals have this ability to a limited degree. A border collie can learn a new command in under five repetitions from a skilled trainer. But humans often can connect cause and effect in a single trial. This has obvious survival advantages, but it also leads to a lot of false positives. A false positive is when a test or trial of some kind reports something that isn’t there. The tendency of humans to make false connections is troublesome enough that it is one of the classical formal logical fallacies, the post hoc, ergo propter hoc fallacy. “B followed A; therefore A caused B.” Yes, sometimes. But sometimes not, and the mere fact B followed A does not logically establish that A caused B. The crowing of the rooster does not make the sun rise.

VAERS is an exercise of the post hoc, ergo propter hoc fallacy on a global scale. I will come back to this point later.

Ironically, it is now known, with about as much certainty as science can muster, that pertussis vaccine encephalopathy does not exist. The condition being reported was infantile epilepsy. It occurs spontaneously, and because it first presents itself at about the same age that young children are vaccinated against pertussis, about one child in 350,000 will develop infantile epilepsy shortly after being vaccinated, purely by chance.

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In February 1998, the respected British medical journal The Lancet published a paper by Andrew Wakefield and twelve coauthors claiming that there was a possible link between vaccination with the MMR vaccine and autism. At the same time, Wakefield held a press conference further promoting the possible link, and recommending an alternate vaccination schedule using monovalent vaccines.

Like DTP, MMR is a trivalent vaccine, targeted against measles, mumps, and rubella. These are classical childhood diseases, and most children infected with these diseases recover uneventfully. But measles occasionally attacks the central nervous system, and about 0.2% of measles patients in Western countries die of the disease. In vulnerable populations, such as in Africa, the death rate is sometimes as high as 10%. Vaccination reduced the worldwide death rate from 2.6 million in 1980 to 73,000 in 2014. The rates have now begun to rise again because of resistance to vaccination.

Mumps can produce deafness and sterility, though it rarely kills. Rubella is usually a mild infection in adults, but when a pregnant woman is infected, her child may be born with severe birth defects.

Autism is a poorly understood but devastating developmental disorder that appears to be present from birth. Patients show severe cognitive defects in the area of social interactions and communications and are prone to repetitive behavior. Although autistic children sometimes show remarkable ability in mathematics or other narrow interests, they are severely handicapped in picking up social cues or correctly understanding the mental state of others.*

It remains unclear what causes autism. The available evidence suggests a genetic predisposition: If one twin is autistic, the other twin is usually autistic as well. Siblings of autistic children are 25 times as likely to be autistic as the general population. But autism is uncommon, and most siblings of autistic children are not autistic. Thus the genetics are not straightforward. Environmental factors may be involved as well. It is likely that autism is actually a set of closely related conditions with different causes.

But one thing we are sure of, because of the extensive research that followed Wakefield’s announcement, is that vaccination does not cause autism.

The breakthrough cases of smallpox occurring as a result of variolation were real, though the benefits generally outweighted the risks. The occasional transmission of other dangerous diseases as a result of early vaccination were also real, though, again, the benefits outweighed the risk. The polio cases from the Cutter vaccine were real, though vaccines were later developed that were much safer and more effective, and their benefits outweigh the risks. The rare cases of pertussis vaccine encephalopathy were not real, or at least they were not caused by the vaccine, but I have seen no suggestions that any bad faith was involved. It was an honest mistake. Abundant evidence has been published that the claim that vaccines cause autism was not an honest mistake. On the contrary, it was described in The Annals of Pharmacotherapy as “perhaps the most damaging medical hoax of the 20th Century”.

British journalist Brian Deer of the Sunday Times published an expose on Wakefield, disclosing that he had been approached by a personal-injury lawyer who was interested in opening a class-action suit for “vaccine damage”. Wakefield accepted undisclosed payments from the lawyer, and only then began carefully recruiting children for his study. Also undisclosed was that Wakefield had a patent on his own monovalent measles vaccine, another serious conflict of interest: Wakefield had advocated for substituting a monovalent measles vaccine for the trivalent measles vaccine in his original press conference.

Lancet retracted Wakefield’s paper, and a formal investigation by the UK General Medical Council found the study shot through with fabrication of evidence and other ethical violations. Wakefield was stripped of his license to practice medicine in the UK. He now lives in Texas and is a darling of the antivaccination movement.

Further studies have failed to find any link between the DDM vaccine and autism.

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A similar story played out shortly after, in which an excess of caution by regulators led to a panic and played into the hand of the antivaccination movement.

In 1999, the FDA was ordered to review all mercury-containing food and drugs in the United States. Mercury is a potent and cumulative nerve poison, it sometimes turns up in measurable quantities in seafood (such as tuna), and it was a component of a number of drugs. People my age likely remember having cuts and scrapes painted with Mercurochrome, an antiseptic containing mercury, which was effective but was also left a spectacular red stain that only time would remove. More to the present point, many vaccines were contained a mercury-based preservative, thimerosal.

You may be wondering why any mercury would be present in any food or drug, if it is a cumulative nerve poison. In the case of tuna, it was not put there deliberately; mercury is found naturally in the environment, as a result of volcanic activity, and this is aggravated by releases of toxic waste from mining and industry. The latter sources are declining as stricter environmental regulations come into force and alternatives to mercury-bearing compounds are found.

The presence of mercury in drugs is deliberate and is based on one of the most fundamental of pharmacological sayings: “The dose makes the poison.” Most drugs are poisonous if overdosed. There have even been recorded cases of persons dying of water poisoning, and I’m not talking about drownings. If you drink enough water all at once, it can dilute your bloodstream enough to have lethal consequences. At the other extreme, curare is a very potent inhibitor of respiration, used in traditional cultures as a poison for poison-tipped arrows; but in small doses, it is a muscle relaxant vital for certain kinds of surgery. It is also a drug of last resort for reducing the severe muscle spasms associated with tetanus.

Mercury in Mercurochrome is little absorbed by the body, and in an age when antibiotics were still fairly new, its use was judged worth the small risk to prevent potentially dangerous infections. Nowadays, triple antibiotic cream fills that niche, and Mercurochrome was banned by the FDA in 1998.

Thimerosal is used as a preservative in vaccines to prevent them from being contaminated by bacteria and to allow them to be stored at room temperature. Such preservatives are mandatory for multi-dose vials of vaccine, since each time a dose is taken from the vial, there is risk of contamination by harmful bacteria. Preservatives eliminate this risk. In 1928, the lack of such preservatives in an early diphtheria vaccine resulted in Staphylococcus contamination that killed twelve children.

In the 1999 FDA review, vaccines containing thimerosal were among the drugs scrutinized. Prior to 1998, there was no evidence that thimerosal in vaccines was dangerous. There was not even a suggestion that thimerosal in vaccines was dangerous. But the review noted that thimerosal in vaccines was converted in the body to a substance called ethyl mercury. The toxicity of ethyl mercury was not well understood, but the substance is somewhat similar to methyl mercury, a viciously toxic form of mercury whose risks were well known. Out of an excess of caution, the FDA panel based its risk assessment for thimerosal preservatives on the toxicity of methyl mercury. And, by that measure, there was concern that the amount of thimerosal in routine childhood vaccinations might give a child a cumulative dose in excess of the safety limit. FDA accordingly recommended removing thimerosal from such vaccines.

It turns out that the toxicity of mercury depends a great deal on its form. Methyl mercury is about as bad as it gets, particularly as the body has a hard time eliminating it. Ethyl mercury is now known to be much less toxic and to be much more easily eliminated from the body, disappearing in a few weeks. As a result, a more up-to-date calculation shows that there is no discernible risk to children from thimerosal preservatives in vaccines. Nevertheless, out of an excess of caution, thimerosal is no longer permitted in childhood vaccines in the U.S.. It is still used in some vaccines for adults or for rare conditions, and it is used in the developing world, where the cost of single-dose vials and the lack of refrigeration continue to make thimerosal-preserved multidose vials the best option.

But the announcement by FDA produced something of a moral panic. Mercury is a nerve poison; autistic children suffer from a disorder of the nervous system; and autistic children begin showing obvious signs of their condition at about the same age that children receive their first childhood vaccinations. People made a connection: Post hoc, ergo propter hoc. Lawyers came into the act, and thousands of lawsuits were filed in the Vaccine Court on the basis that mercury in vaccines had given these children autism. A market grew up for chelation therapy to remove the supposedly toxic levels of mercury from autistic children; these were dangerous, and did no good, because mercury was not the problem.

I should probably make a full disclosure of my attitude towards lawyers. I have enormous respect for my friends who are lawyers. It is an inherently ethical profession that serves a vital role in maintaining the system of rules that allow us all to live together in relative peace. Anyone who believes he has been unlawfully wronged, or who has been accused of wrongdoing, is entitled to a lawyer who will vigorously make his case in court. But I see an important divide between the lawyer who puts out a shingle and waits for clients to come to him, and the lawyer who goes out looking for clients. There may be rare cases where the interests of society are promoted by such a thing, but as a general rule, I don’t think much of ambulance chasers, of lawyers who use mass advertising or who send out mass mailings trying to get me to join a class action. My impression is that my lawyer friends agree.

The rate of diagnosed autism was rising sharply in the 1990s, and since there was a plausible mechanism for mercury in vaccines to cause autism, the vaccine-autism theory was very thoroughly studied. In the end, no evidence of a link was found. Children in Scandinavia, which never used thimerosal in childhood vaccinations, showed the same rise in autism cases as children in countries that did. The ban on thimerosal in childhood vaccinations has not reversed the rise in diagnosed autism. There is no link between vaccinations and autism, and the Vaccine Court has ruled in favor of an autistic plaintiff just once, for a patient with an exceedingly rare genetic condition that might plausibly have played poorly with vaccination.

We do not know what accounts for the rise in diagnosed autism. We are not even certain that the rise is real. Autism is easily misdiagnosed as mental retardation, schizophrenia, or other forms of cognitive impairment that were more familiar to physicians in the late 20th century. Diagnostic criteria have improved considerably in recent decades. Also, and I am sorry to say it: There is evidence that autism has become something of a fad diagnosis. More cases that would previously have been diagnosed as something else are now being diagnosed as autism, and in some cases, this may be because that is what the parents want to hear.

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And now we come to COVID.

COVID is caused by a strain of coronavirus, part of a family of respiratory viruses that causes a good share of cases of the common cold. But just as the mild cowpox virus and the deadly smallpox virus are closely related, so the various strains of coronavirus show different levels of virulence and transmissibility. The strain responsible for COVID-19, as it is more precisely called, is particularly nasty.

Coronaviruses get their name for the spike proteins that cover their surfaces. These have a fancied resemblance to spikes on a crown. The spike proteins consist of two functional parts; one latches the virus onto a human cell, and the other allows the virus to then penetrate the cell membrane and infect the cell. The spike proteins are essential to the functioning of the virus, and they must have the right shape to perform their functions effectively.

The origins of COVID remain uncertain, but it first emerged in Wuhan, China, in November 2019. The virus spread rapidly, arriving in the U.S. in January 2020, and infections peaked in April 2021. As of September 10, 2021, there have been over 40 million confirmed cases in the United States, and there have been over 650,000 deaths. As with seasonal influenza, the death rate is highest among the elderly, but the mortality rate of 1.6% for coronavirus averaged across all age groups is considerably higher than the 0.5% mortality rate for influenza in those over 65 years of age. The disease is highly infectious, with each patient estimated to infect around three other patients under conditions of normal social interactions. That’s an explosive rate of growth.

Roughly a third of those infected show no symptoms. Of the remainder, about 81% develop nothing worse than mild peumonia, treatable at home. The other 14% develop severe symptoms, such as difficulty breathing, and 5% become critically ill. The virus has a particular affinity for the lungs, and most deaths are from respiratory failure. Do the math: Of those who end up hospitalized with COVID, almost one in five will never leave the hospital alive.

The disease is transmitted by airborne droplets containing the virus, which are produced when an infected person coughs, speaks, or simply breathes. An infected person is shedding the most virus at about the time he first notices symptoms. This means an infected person can spread the virus before he even knows he is ill. The droplets containing the virus range from relatively large droplets that carry a high virus load, but rapidly settle to the ground, to aerosols that can remain suspended for hours in poorly ventilated areas.

Because a patient is contagious before he even knows he is ill, and some never show symptoms, quarantine only of the sick is an inadequate control measure. Ideally, each case can be tracked to determine who has been exposed, so that exposed persons can be put in quarantine as a precaution. Because aerosols are most concentrated immediately around the person carrying the virus, social distancing has real value in reducing transmission. The virus is relatively delicate, and is destroyed by sunlight or by desiccation (drying out). For this reason, transmission in outdoor settings is very unlikely. Indoor settings are another matter. Transmission by contact is not an important route compared with airborne transmission, and hand sanitizer, or any other alcohol-based disinfectant, destroys the virus on contact.

The value of face masks is hard to quantify. They will not stop individual virus particles, which are less than a millionth of an inch in diameter. But they do not need to: The disease is not transmitted by individual virus particles, which are rapidly destroyed by drying out in air. The disease is transmitted by much larger aerosol droplets, and masks are effective at blocking larger droplets. Their greatest weakness is at blocking the smaller aerosol droplets, which are large enough to keep the virus alive but small enough to get around the edges of the mask or through its pore spaces. But blocking only some of the droplets is still blocking some of the droplets.

The most effective protection against coronavirus, responsible for the steep decline in cases after April 2021, is vaccination. All other control measures pale in significance.

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There are three COVID vaccines currently approved for use in the United States. The Pfizer and Moderna vaccines are mRNA vaccines, while the Johnson & Johnson vaccine is a viral vector vaccine.

The Johnson & Johnson vaccine is the more established technology. The vaccine consists of an adenovirus — basically, a common cold virus — that has been genetically modified in two ways. First, the virus has had crucial genes removed so that it is incapable of multiplying. Second, it contains genetic coding for spike proteins of COVID. When the modified virus is injected into the body, it latches onto cells and passes through their membranes, and the coding for spike protein is translated and expressed. The spike protein moves to the cell membrane, where it is detected by the immune system, triggering a strong adaptive immune response. But the virus is incapable of completing its life cycle, so its code is soon cleared from the body without causing disease.

The mRNA virus is something new. The techniques involved have been studied for many years, but reached the point where they could be used to make a safe and effective vaccine just in time for COVID. (I am religious enough to regard this as something of a miracle.) The virus consists of strands of messenger RNA. This is the form of genetic coding that transmits genetic information from a cell nucleus to the ribosomes, the structures that translate the genetic code into protein. As with the Johnson & Johnson vaccine, the mRNA vaccines code for spike proteins.

The mRNA is combined with lipids (fat molecules) that perform three functions. First, they stabilize the fragile mRNA. Second, they help the mRNA cross the cell membrane, where the mRNA is translated by ribosomes to spike proteins. Third, the lipid molecules are adjuvants — they are a big red flag to the immune system that something foreign has entered the body. The immune system goes on full alert, and when it spots spike protein on cell surfaces, it goes into full freakout mode and develops strong adaptive immunity against the spike protein.

Spike protein is absolutely essential to the virus, and its shape can change only so much while remaining effective. This gives us hope that the vaccines will have reasonable effectiveness against future mutations of the virus, though molecular biology is such a complicated field that we can make no promises.

All three vaccines are highly effective against current strains. They reduce the chances of catching COVID by about a factor of ten, and even if you are infected, they cut the chance of serious illness in half. This is true even of the Delta variant that is now the major concern.

In practical terms, this means that instead of an infected person spreading the disease to three others during normal social interactions, an infected person in a vaccinated population has only a 1 in 3 chance of infecting anyone else. This is enough to stop an epidemic cold. Vaccination should have been the key to allowing us all to return to normal life.

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That hasn’t happened, because not enough of us have been vaccinated.

Ending the epidemic means reducing transmission to less than one new case per infected patient. This means that the epidemic will begin to die out as soon as a high enough percentage of the population are vaccinated (or are immune as a result of recovering from COVID). The precise percentage depends on what assumptions go into the models. Regardless, we can’t seem to quite reach the magic number.

This is frustrating. I received my two doses of the Moderna vaccine in April. This left me feeling comfortable attending my mother’s 90th birthday party, no small thing. At this point, with the protection the vaccination has given me, my chances of dying of a COVID infection are very much smaller than my chances of dying of a heart attack in the next year. It irks me that I am still required to wear a mask at work or while shopping, in effect, to protect those who refused to take the vaccine.

But irk is not constructive.

I think refusal to take the vaccine comes down to three issues: lack of good information, lack of motivation, and lack of trust in institutions. None of these are going to be helped by an angry or heavy-handed approach.

I have taken pains to give good information in this post. I would add only this, in regard to the issue of safety: No vaccine is absolutely safe. But no human activity whatsoever is absolutely safe. You can kill yourself getting out of bed in the morning. Pretty much everything in life is a gamble — but, unlike a game at a cassino, a lot of gambles in life are heavily weighted in your favor. The odds of taking serious harm from a COVID vaccination are vastly smaller than the chances of dying of COVID in a pandemic. If the incidence of COVID ever becomes so small that that changes, we can come back to this conversation. Meanwhile, there is no scientific justification for refusing COVID vaccination on the basis to safety concerns.

By lack of motivation I mean the belief that, sure, the vaccine may reduce your chances of getting seriously ill — but the small chance of that doesn’t seem so bad, particularly since you’re young and healthy. And you hate needles, and you don’t want to lose a day because the vaccine made you feel sick. I can understand that. My first dose made my arm ferociously sore, and the second cost me a couple of hours of severe chills and a day of work. Those reactions happen.

I’m still glad I got the vaccination the first chance I had.

I’m thinking most in this group are young men. So, as an experienced older man, let me put an arm around your shoulder and level with you. I didn’t make my final plans to attend my mother’s 90th birthday party until I knew I’d be fully vaccinated, because the thought that I might be responsible for giving her COVID, or for giving COVID to my nephew-in-law who was undergoing treatment for cancer, was unbearable. Look around you — you’ll find lots of people you don’t really want to be responsible for infecting. Part of being a real man is making some sacrifices to protect the weak and vulnerable. And a sore arm and a day of feeling crummy is a small sacrifice.

I know: Why don’t they just get vaccinated? A few can’t, but the better answer is: A real man doesn’t leave the dirty work to others.

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That leaves those whose reason for rejecting vaccination comes down to a lack of trust in institutions. I suspect this is the largest group among those who have refused vaccination. And what I have to say to this group is: I hear you, brother. But getting the vaccine is still the right thing to do.

I have gone in circles trying to figure out how to elaborate on this without getting political. I’ve decided it mostly can’t be done, and so I’m not going to elaborate much. I have a lot of sympathy for this essay, but I think it is too heavy-handed. Perhaps this one better expresses my own feelings. The short version: Both those stubbornly refusing to get vaccinated, because they don’t trust our scientific and political institutions; and those trying to weaponize those institutions to force the unvaccinated to get the jab, are putting more strain on those institutions than they may be able to bear.

Haven’t been vaccinated? Do it. Do it of your own free choice because it’s the right thing to do.

Angry at those who haven’t been vaccinated? Take a minute to listen, and hear the distrust of institutions behind what looks like an irrational stance. Then consider how you might act to lessen that distrust, rather than inflame it further.

There is one aspect to this that I think is reasonably apolitical, and which I will therefore comment a bit more on. Bedside manner has historically been a major part of the art of medicine. When doctors often had little to offer medically or surgically, they could at least provide psychological comfort to the ailing or dying patient and his family. We have seen remarkable advances in medicine in the last two centuries, and I think there has been some tendency for bedside manner to be neglected as a result. I think this may be particularly true of our best research physicians, who are understandably less focused on clinical medicine. I think some of those physicians have seriously neglected their bedside manner in their public pronouncements on COVID, because they have assumed it was sufficient that they had good science behind them.

Good science isn’t enough. You also need the bedside manner. And in our increasingly divided society, where more aspects of life are becoming politicized, lack of good bedside manner in approaching the public leaves the door open for quacks and frauds. The fringe practitioners may not have good science behind them, but they are exquisitely skilled at bedside manner. I believe this is one explanation for why so much of the public can reject CDC recommendations while putting deep trust in the lone researcher touting a quack alternative.

In any con game, part of the con is that the mark wants to believe. But another part of the con is that the con man knows that he has to win hearts before he wins minds, and his skills at doing so are remarkably polished.

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*It seems appropriate to disclose here that I have an autistic son, three autistic nephews, an autistic cousin, and my daughter and I may be borderline autistic.