Dr Tom Kerns
North Seattle Community College


Jenner On Trial

Tom Kerns





Chapter 2


A bit of history


Smallpox, a disease probably as old as ancient Egypt, was the raging epidemic in 18th century England when Edward Jenner (1749­1823) began his medical training. "By the seventeenth century [smallpox] had replaced the plague as Europe's most devastating and feared disease." Its effects were dramatic and, since it was not limited to any particular risk group or risk behaviors, it threatened virtually everyone. No one was safe from its scourges. In fact, before the practice of vaccination became common, "almost everyone eventually contracted the disease." It was common enough that a proverb in Jenner's time declared that "From smallpox and love but few remain free."

Smallpox has a high morbidity and a high mortality as did the Black Death two centuries earlier, and this fact no doubt contributed to it being "the most universally feared of all diseases." A large percentage of people infected with smallpox died of it. I have seen estimates of mortality ranging from 25% to 50% to 70%. The higher estimate is probably an exaggeration, and the true mortality rate is probably closer to the lower end of that range, which is still quite high. By the end of the 18th century, when Jenner performed the famous cowpox experiment we will be examining below, smallpox killed over 400,000 people per year in Europe alone. Even for those who survived smallpox infection, many were blinded in one or both eyes, or made deaf, or developed severe and painful neuritis, or were visibly scarred for the rest of their lives.

The actual course of the disease varied from patient to patient.

Many died in the first few days of the rash, others soon after the first week of the rash, and some were carried to their graves even before the rash appeared. Once a person was infected, there was no effective treatment.

Some patients appeared exactly as if they had been severely scalded or burned, and even less seriously affected victims said the skin felt as though it were on fire. In addition to the skin, which sometimes sloughed off in large pieces, the virus attacked the throat, lungs, heart, liver, intestines, and other internal organs, and that is how it killed. Victims reeked of a peculiarly sickening odor. In some, the disease caused hemorrhaging internally and externally, the so-called black smallpox, which was almost always fatal.

Those who survived the first onslaughts of the disease, still might "die of complications such as pneumonia, heart failure or brain damage. Those recovering may be insane, paralyzed, deaf or subject to painful neuritis, as well as disfigured by the scars." Occasionally scarring was relatively mild - having fifty "pocks" was considered mild - but most were scarred quite severely. It was said of King Louis XV of France, for example, that he had been so badly scarred by smallpox that it looked as if he had two noses.

The disease was indeed a major scourge.

The smallpox was always present, filling the churchyard with corpses, tormenting with constant fears all whom it had not yet stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of a betrothed maiden objects of horror to the lover.

Although it was believed by some that "the negro suffered more severely than the white man," it was also recognized (as with HIV and AIDS) that people of every race, social class and economic position alike were at risk.

No effective cure was available for smallpox (as is also the case with AIDS). In addition, everyone who contracted the disease was known to be contagious, capable of infecting (and killing) anyone who came near them during its active stages. Consequently, people who were infected and sick with smallpox were much shunned because they represented the potential for infecting others and spreading epidemic sickness and death into other families.

Because the pathogenesis of the disease was not understood, since there was as yet no concept of disease-causing microbes, there was little hope of ever discovering a cure. Nor was there any hope that smallpox would somehow just "go away." It had, after all, plagued the world for millennia, and Europe for at least two centuries, and its incidence in England had greatly increased in Jenner's own century, the 18th.

It was commonly recognized that people who contracted smallpox and who then recovered from it did not seem to ever get the disease again. This notion, that getting the disease once protected a person from ever getting it again, led to the idea of trying to prevent serious cases of the disease by deliberately infecting people with mild cases of it. That is, went this suggestion, if we could deliberately infect people with a mild case of smallpox when they were young, then if they healed from that mild case they would be protected against ever contracting another case of smallpox, mild or serious, in the future.

This practice, called "buying the smallpox," "inoculation," or "variolation," was already a not uncommon folk practice in Turkey and on the European continent by the early 1700s, and had been practiced in China and Africa even earlier than that. It was, however, considered quite controversial. When Lady Mary Wortley Montagu, wife of the British ambassador to Turkey, wanted to introduce the practice to the upper classes in her native England (in 1716), she wrote a lengthy letter to her countrymen urging the introduction of this new practice. She was also able to persuade the royal family to undertake a public, life-threatening medical experiment using as subjects some prisoners in Newgate jail, in order to test the safety of this new practice. She hoped that the medical establishment would then be persuaded of the safety and utility of the practice of variolation. She concludes her letter thus, after describing the variolation procedure in some detail:

Every year thousands undergo this operation: and the French Ambassador says pleasantly that they take the small-pox here by way of diversion, as they take the waters in other countries. There is no example of anyone that had died in it [sic]; and you may believe I am well satisfied of the safety of this experiment, since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England.

Despite Lady Mary's anecdotal protestations to the contrary, many would later object to the procedure because there were no guarantees that variolated persons would survive the disease they had been given. Some did die of it. "A supposedly mild exposure to the disease in effect might not be so mild after all, and could kill or mutilate rather than simply immunize." As many as three or four persons per hundred did die of the procedure.

Because of these grave misgivings about the practice, the royal experiment was undertaken, at the urging of Lady Mary, to test the safety of the practice. This experiment involved testing variolation on six prisoners, three men and three women, in Newgate jail in 1721, and the purpose of the test, at first, was solely to determine the safety of the practice of variolation. This experiment, performed of course with no control group, offered the six prisoners their full freedom on the sole condition that they submit to the experiment of variolation. Thus,

Three men and three women prisoners were inoculated on the morning of August 29, 1721, in front of twenty-five physicians, surgeons, and apothecaries, as well as representatives of the press.... All but one of the subjects developed mild symptoms of smallpox, and that person was later found to have had a slight case of smallpox the year before [and was thus already immune].... They all recovered, showing no ill effects of the inoculations and, true to the royal word, were pardoned on September 6.

This portion of the experiment had tested for safety only. Some people also wanted to know, however, whether the variolation procedure actually protected a person against contracting smallpox again. They wanted to know if it was efficacious. So, in order to test for efficacy, a Dr Charles Maitland

arranged for one of the survivors of the Newgate inoculations, a nineteen-year-old woman, to come to a small town near London to act as the nurse and lie in the same bed every night with a ten-year-old smallpox victim.... Fortunately, after six weeks of exposure, she still had not contracted the disease.

These two experiments together were intended to test for both safety and efficacy, the two primary facts that researchers want to establish about any drug or vaccine. Whether the Newgate prisoner experiments actually proved what they intended to prove is another question. There were, after all, only six subjects - only five if we except the one who was already immune to smallpox. If the practice of variolation had a 4% mortality rate, for example, there would have needed to be four times as many subjects for that one-in-twenty-five mortality to be made evident. Nevertheless, the experiment did seem to provide some fairly persuasive evidence, at least in the popular mind, that the practice appeared to be moderately safe.

Lady Mary did later have her six year old son variolated, and a few years after that, her four year old daughter, both with no resulting harmful complications. Lady Mary's efforts at introducing the practice of variolation to England were in fact quite successful, and by the middle of the 18th century the practice flourished.

Unfortunately, however, from a public health perspective, variolation would not turn out to be a very successful method for controlling smallpox epidemics. Variolated persons were, after all, at some considerable risk of contracting a serious case of smallpox from the procedure, and there was even a 1% to 4% risk of actually dying from the procedure. Furthermore, variolated persons were still contagious and fully capable of accidentally infecting healthy persons. In fact, when we read that "the rate of smallpox infection in England actually rose during the eighteenth century," we cannot help but wonder if the practice of variolation may have contributed to that increase by directly increasing the number of infected (and therefore infectious) persons in the population.

Smallpox, after all, no matter how mild it may be in a specific case, is still highly contagious, and those infected by someone with a mild case might still themselves develop a serious or fatal case. On the average, a given case of smallpox probably resulted in contagion to two to five other persons, usually family or friends. Furthermore, some people recognized that the practice of variolation not only increased the incidence and prevalence of the disease in England, but that the practice had also probably increased the severity of the disease. Because of these beliefs, variolation was made illegal for a time in mid-century, across the channel in France. It was also eventually made illegal in England in 1840 (well after Jenner's experiments), when it was enacted that any person who shall...produce in any Person, by Inoculating with Variolous Matter, or by willful exposure to Variolous Matter, or willfully by any other Means whatsoever produce the Disease of Smallpox in any person shall be liable to be proceeded against...and shall, upon Conviction, be imprisoned in the Common gaol, or House of Correction for a Time not exceeding one Month.

As an aside, coming back to the 20th century and AIDS for a moment, some researchers have expressed the same fears about HIV vaccination programs, viz., that a vaccine might actually worsen the epidemic by spreading the disease even more rapidly than it is being spread now. This could happen by any or all of three separate mechanisms:

a) It could happen as a result of people who have been vaccinated feeling safer, and thereby relaxing their safe sex practices and engaging in more risky behaviors than they had before. If an HIV vaccine were able to completely prevent infection with the virus, rather than simply preventing disease, and if it were 100% effective in every vaccinee (though no vaccine is 100% effective; 80 - 90% efficacy is considered exceptionally high), then there would be little danger that an HIV vaccine would make the epidemic worse. But lacking either of these two conditions, an increased confidence on the part of people at risk could be a real danger.

b) If an HIV vaccine was not able to meet the high standard of completely preventing infection, but instead only prevented the development of disease, then HIV+ persons would be able to live much longer and, remaining contagious, would continue to be able to pass the disease to others for many more years.

c) Finally, if the vaccine that was being used was a live, attenuated virus vaccine, there would then be the possibility that vaccinated persons could also pass that attenuated virus on to others by the same routes that they can today pass HIV itself on to others. That would be a good thing if the attenuated virus they were passing were indeed fully benign, but if that attenuated virus ever mutated back to virulence, then the vaccination program would only have made the epidemic worse.

These three possible mechanisms for worsening the HIV/AIDS pandemic via a vaccination program are in some ways different and in some ways similar to the ways that variolation worked to worsen the smallpox epidemics in England and elsewhere.

We now return to 18th century England:

Edward Jenner himself was inoculated by variolation in 1757 at the age of eight. The procedure was elaborate and most unpleasant. In Jenner's case, the preparatory period alone (of fastings and bleedings) lasted six weeks. The process of his variolation is described thus:

He [Edward Jenner] was bled until pale, then purged and fasted repeatedly, until he wasted to a skeleton. He was denied solid food in favor of a vegetable drink that was supposed to sweeten the blood; after the inoculation itself - the least traumatic event of the entire experience - he was removed to an "inoculation stable," and, according to an early biographer, "haltered up with others in a terrible state of disease, although none died." His recovery, amidst the moaning and crying of other inoculated children, took another three weeks, and he was sickly for some time thereafter.

In summary, the variolation process, in addition to being highly unpleasant (some called it cruel) and without any guarantees of success, also increased the risk of spreading the disease and making the epidemic worse. Clearly, something better was desperately needed.


Legend has it that Edward Jenner, while still a teenager in the beginning of a seven year apprenticeship with Abraham Ludlow, a local surgeon, was once examining sores on the hands of a Gloucestershire milkmaid who had cowpox. It was in this situation that the young milkmaid spoke to Jenner the words that would later change his life and the future practice of medicine: "Now I'll never take the Small pox, for I have had the Cow pox."

Most educated medical men considered this piece of local folk wisdom, i.e., the notion that a case of cowpox served as a protection against smallpox, to have absolutely no merit at all. They considered it just another of the comforting, but silly, beliefs that some country folk have about medical matters. A few years later, when Jenner discussed this idea with colleagues in his local medical clubs, his ideas were roundly dismissed. Still, he could not let go the idea that inoculation with cowpox might somehow immunize persons against infection with smallpox.

Much as he believed in this theory, however, he did recognize that there were still some instances that counted against his hypothesis, i.e., instances in which persons who had had cowpox did, in spite of that infection, later contract a case of smallpox. Jenner was aware of these cases, and aware that they did count against his theory. He writes:

There were not wanting instances to prove that when the Cow pox broke out among the cattle at a dairy, a person who had milked an infected animal and had thereby apparently gone through the disease in common with others, was [still] liable to receive the Small pox afterwards. This...gave a painful check to my fond and aspiring hopes.

However, he redoubled his investigations and discovered that at certain stages of the cowpox infection the pus from the sores was not able to induce any immunity to smallpox, but that at other stages of infection, it was fully able to induce immunity to smallpox. He also hypothesized that some dairy cattle diseases that appeared to be cowpox were actually spurious cowpox infections, and not the true cowpox disease. Jenner continued to assiduously record his observations.

Then in 1789, when Jenner was 40 years old and married only a little more than a year, there was in Gloucestershire an outbreak of swinepox, a disease very like cowpox except that it attacked pigs rather than cows. Jenner decided (just after he had been elected as a Fellow of the Royal Society) to try immunizing his ten month old son, Edward, Jr, and two of his neighbor's servants, by inoculating them with swinepox. He had learned well from his famous teacher, Dr John Hunter, that one will learn more by "trying the experiment" rather than by just speculating about it. So Jenner performed the experiment by making a small scratch on the servants' and the baby's arms with a lancet and then infecting the scratch "with matter from a pustule of the baby's nurse, who had caught the swinepox infection." Eight days later baby Edward took sick and developed sores, but then (as anticipated) later recovered. Some months after that his father attempted to deliberately infect him (and the nurse also) with smallpox itself, not just once, but five times, in order to test the efficacy of the immunization. No smallpox symptoms of any sort ever developed. The porcination - dare we call it - "took." The protection was effective. Then, two years later, Jenner again challenged his son with smallpox, this time, however, with unhappy results.

This time there was a reaction, and a severe one, but not [probably] from the smallpox. The inoculation material turned out to be contaminated - a constant danger that later threatened to undermine Jenner's work altogether. Young Edward contracted a fever and his arm swelled all the way to the armpit. But he quickly recovered, and a year later Jenner inoculated him with smallpox once again. And once more there was no reaction. Apparently, the Swine-pox protected against smallpox.

Unfortunately, however, in the years following these experiments, young Edward "became a sickly child and exhibited signs of mild mental retardation," though there is no direct evidence that these sequelae were related to the inoculation experiments. Young Edward unfortunately died at the age of 21 from tuberculosis. His father's grief was severe.


Jenner considered the swinepox inoculation experiment a success, and so began to bolster his experimental evidence with anecdotal evidence gathered from dairy families whom he visited during the following years. Many of these families claimed that since they had had cowpox, they were now immune to smallpox. Jenner asked if he could try to infect them with pus from smallpox sores to see if they actually were immune. Fortunately, they were.

For example, Joseph Merret had cow pox in 1770. Jenner inoculated him with smallpox in 1795 and it had no effect on him.... But might Joseph have had smallpox many years before [and become immune because of that infection]? Jenner's answer was, in effect, that in a village everybody knew everyone else's business and that records were kept. The second example was Sarah Portlock who had cow pox twenty-seven years before her negative result to smallpox inoculation. Another example was John Phillips, who had had cow pox when he was nine. At the age of fifty-two he was inoculated, without effect, with virulent smallpox. Mary Barge could even nurse smallpox patients without catching the disease because she had had cow pox thirty-one years before.

These were direct challenge experiments to test the efficacy of naturally acquired cowpox disease in protecting against smallpox. These experiments were all done using adult subjects. Jenner would later use these data to argue that artificially induced cowpox infection would also have the same prophylactic effect in protecting against smallpox.

Jenner recognized that this evidence, though strong, was not foolproof, because it relied on the accuracy of people's recollections and claims that they had only had cowpox and had never had smallpox. Still, it seemed to Jenner that these additional experiments - successfully challenging previous cowpox sufferers with virulent smallpox - did add one more bit of evidence to support his hypothesis.

Then, in 1796 there was another outbreak of cowpox in Gloucestershire, and Jenner decided to test his theories again, this time using artificial inoculation with cowpox. There was also, in 1796, a serious smallpox epidemic in London, only a day's journey from Jenner's village of Berkeley in Gloucestershire. This smallpox epidemic was serious and would eventually kill 3500 persons in that one year alone, so Jenner must have felt some sense of urgency to prove the efficacy of his cowpox inoculation, and to do so sooner rather than later.

He must also have felt an urgency to prove that it would be safe and efficacious in young children, since they were the group most at risk for smallpox infection.

Thus, he now needed some experimental subjects on whom to do the same kind of testing that he had done with young Edward, Jr seven years earlier. Whom might he use as research subjects for such an experiment, one we would today call an efficacy trial?

It is at this point (if not before!) that Jenner would have had to submit his proposed research protocol to an Ethics Review Committee (ERC), had such bodies existed at the time.

It is also at this point in time, in the Spring of 1796, that I have brought Edward Jenner back to life.


Jenner homepage and Table of Contents
preface | Introduction | chp 1 | chp 2 | chp 3 | chp 4
cchp 5 | chp 6 | chp 7 | chp 8 | App I | App II
Ethical Issues in HIV Vaccine Trials