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