Dr Tom Kerns
North Seattle Community College

 

Jenner On Trial

Tom Kerns

 

 

 

 

Chapter 5

 

The ethical review

 

If these application materials had been sent to an Ethics Review Committee in Jenner's time (had such committees existed) and if that ERC was guided by the same basic ethical principles that today govern the reflections of post-Nuremberg ERCs (which it might well have been), how would that committee have responded to this formal request for ethical review?

For readers who are familiar with the actual historical outcome of Jenner's experiment (which was favorable), it may be particularly difficult to judge the ethical propriety of the protocol without (subconsciously) taking into account the outcome of it, and the results to which it led. We should, however, keep in mind the fundamental principle that "A study is ethical or not at its inception. It does not become ethical merely because it turned up valuable data." That is to say, the design itself is either ethically appropriate or not ethically appropriate, regardless of the outcomes of the study, and regardless of whether the data from the study have been beneficial or not.

Let us turn, then, to the question of the ethical propriety of the experiment itself.

To simplify the structure of this discussion, we will consider four basic categories of questions that ERCs would ask, and then we will consider what the committee responses in Jenner's time would likely have been.

1) The first question the committee would ask is whether the proposed protocol is scientifically sound. Has it undergone a considered scientific review? Is the principal investigator competent to be directing the study? Is the design of the protocol sufficient to meet accepted scientific standards? Has the researcher adequately isolated the significant variables? Is the protocol sufficiently double-blinded and randomized? Is there a control group of adequate size and randomness? Is it clear how long the study will last, and are the reasons for choosing that time period sound? Are the endpoints of the study and the criteria of success adequately defined?

These questions about scientific methodology are important ethically as well as scientifically because for a sponsor to initiate a human subjects study without a sound scientific foundation is ipso facto a serious breach of ethical principles. If the protocol evidences inadequate methodology, it may be exposing subjects to hazard and inconvenience for no sound purpose at all. A poorly designed study could end up being all risk and no benefit to anyone.

2) The second kind of question the committee would ask is whether there is an acceptable and proportionate potential-harm to potential-benefit ratio for each individual research subject. They would also ask whether subjects will be paid for their trouble or given any free medical care, and if they will be, is the amount to be given to them so much that it could compromise their ability to make an authentically free choice without undue inducement?

3) A third set of questions an ERC would ask is whether the investigator will realistically be able to protect subjects from significant harm. Will the individual volunteers be adequately protected? Will their well-being take ultimate precedence over any social or scientific benefit that the investigator might want to achieve? Will the researcher be able to protect subjects against the kinds of hazards that might result from a failure of the experiment?

4) A fourth question the committee would be concerned with is whether the investigator will be able to obtain every subject's informed consent?

Let us now examine each of these four categories of ethical concern.

1) Is the proposed protocol scientifically sound?

Controls?

In Jenner's time, of course, there was as yet no notion of double-blind, placebo controlled studies, so a committee in his time would not have required anything in the nature of a control group. But they might have been concerned whether there was anything at all even resembling a control group in his study with which he might compare his test results. Of course, having a strictly defined control group would have required having an equal number of subjects who received some kind of "placebo vaccination," who would then have waited the same length of time that the test subjects waited, and who would then also have been deliberately challenged with a dose of virulent smallpox pus, as were the test subjects. This control procedure is exactly what the Nazi doctors did in their typhus vaccine experiments in Buchenwald and Natzweiler concentration camps during World War II. This practice was strongly condemned at the Nuremberg Trials as highly unethical, since the control subjects were put at maximally high risk for lethal typhus infection.

In Jenner's case, however, the practice of attempting such infection with smallpox (i.e., direct challenge) actually consisted of the exact same procedure as variolation, viz., scarification of the arm and infection with virulent smallpox pus from the sores of a person sick with smallpox.

Thus, perhaps Jenner did have something resembling a control group after all, viz., all those persons in the rest of the population who had not been vaccinated with his cowpox (and who had also had neither natural cowpox disease nor natural smallpox disease). If these "controls" were to be challenged with smallpox infection by the method of variolation, they would theoretically have an acute reaction to the procedure, just as did all other variolated persons. When Jenner's subjects who had been "vaccinated" (as Jenner's cowpox immunization came to be called) were challenged by the method of variolation, however, Jenner expected them to have no negative results from it at all. Therefore, although Jenner did not have a strictly defined control group of subjects who were like his test subjects in every variable except one, he did nevertheless have a theoretical group of controls in the general population of non-"vaccinated" persons who had been successfully variolated.

Preliminary evidence

Was there sufficient preliminary scientific evidence gathered prior to the experiment to suggest a good likelihood that the trials would be effective?

On the application form, Jenner details six kinds of supporting evidence:

i. The accepted notion that persons who have contracted smallpox once, whether by the practice of variolation or by a naturally acquired infection, did not seem to contract smallpox ever again. This evidence supported the notion that immunization against smallpox was at least possible.

ii. Substantial anecdotal evidence and local folk wisdom among dairymen and their families to the effect that anyone who had once contracted cowpox would not ever contract smallpox. This anecdotal evidence supported the notion that naturally acquired cowpox infection could immunize a person against naturally acquired smallpox infection.

iii. Jenner's attempts to variolate (i.e., challenge with infectious smallpox) persons who reported having already had natural cowpox infection in the past, but not having yet contracted any smallpox infection. These attempts at variolation led, as we saw earlier, to no acute reaction to the smallpox. This evidence supported the notion that naturally acquired cowpox infection could immunize a person against artificially induced smallpox infection.

iv. Jenner's experiment with his ten-month old son Edward, Jr in 1789, in which he inoculated the child with swinepox pus to see if an artificially induced swinepox infection would protect him against infection with smallpox. Several weeks later, after young Edward had healed from the mild swinepox disease, Jenner challenged him with smallpox pus (by means of variolation), and this attempt led to no reaction whatsoever. This evidence supported the notion that an artificially induced pox infection (even though it was swinepox rather than cowpox) could immunize a person against artificially induced smallpox infection.

v. The Newgate jail experiment with six variolated prisoners, which experiment was designed to prove the safety of the practice of variolation. Jenner used this evidence to argue for the safety of deliberately inoculating (challenging) with smallpox, and thus for the ethical propriety of deliberately infecting, or trying to infect, a person with a lethal disease.

vi. The longstanding practice of variolation throughout England for the previous sixty or seventy years. Jenner also used this evidence, as he used the Newgate jail evidence, to argue for the safety and the ethical propriety of deliberately challenging subjects with smallpox.

Whether the experiment with his son would itself have passed an ethical review seems to me rather questionable, particularly due to its serious lack of prior evidence that swinepox protected anyone against anything, let alone against smallpox. In light of the lack of any such evidence (anecdotal or otherwise), for Jenner to deliberately attempt infecting young Edward, Jr with smallpox - seven separate times - on the belief that he was protected against it by his prior infection with swinepox, seemed like a great leap of faith at best. It would seem that an application for scientific or ethical review of this experiment would have found serious fault with Jenner for attempting it.

This distinct possibility now raises the question of whether it is ever ethically permissible to use data discovered in an ethically improper experiment. Should data from unethical experiments be considered as inadmissible evidence, and therefore never to be used? Should such data perhaps even be completely destroyed? The concerns raised by these questions may apply as well to the Newgate jail experiment in 1721, an experiment which Jenner uses as evidence for the safety of the practice of variolation. (He could also have used it as evidence in support of the claim that artificial inoculations can produce efficacious immunity against smallpox, though with only one subject (the nineteen year old woman) involved in the efficacy portion of the experiment, it would be very weak evidence indeed.)

The Newgate jail experiment would also likely not have passed ethical review with an ERC for three reasons: a) the experiment used vulnerable subjects with limited capacity for free consent; b) the sponsors of the experiment offered such overwhelmingly strong inducement to participate, viz., freedom from incarceration, that it may have violated the principle of undue inducement; and c) there is doubt as to whether the young woman was given any choice at all in becoming a subject in the efficacy portion of the experiment. For these reasons, the Newgate jail experiment concerning the safety and efficacy of variolation may also not have passed ethical review in a modern ERC.

But of course Jenner was not advocating variolation. He was advocating a much safer (i.e., a much less lethal, less contagious, and less likely to produce dangerous sequelae) alternative to variolation.

However, the ERC would certainly have had to struggle with the question of whether it would allow Jenner to use results from experiments that violated ethical norms as support for his own proposed experiment. If the committee chose to not allow any data from these two ethically questionable experiments because of the principle that using data gathered from unethical experiments is itself ethically untenable, then the committee would have to face another question, viz., whether, without those two pieces of evidence, Jenner has enough supporting evidence to justify his experiment.

I think he does, for the following reasons: The experiment of inoculating his ten-month-old son with swinepox was of questionable relevance in any case. Swinepox and cowpox would seem to be two entirely different diseases. Inclusion of the swinepox experiment in the application materials may not have been necessary or even important. As for the Newgate jail experiment, it was probably also not necessary to Jenner's argument, since the subsequent 50 years of variolation throughout England was even stronger evidence for the relative safety (with the emphasis on "relative") of smallpox inoculation.

Therefore, in my opinion, the committee may well have disallowed Jenner's inclusion of those two experiments in his research proposal. They would probably at least have admonished him to never again do experiments similar to the swinepox experiment on his son.

Nevertheless, in spite of such admonishments (or exclusions), the committee would probably find that Jenner had presented enough preliminary evidence to render a favorable outcome of the cowpox experiment at least possible, and perhaps even probable. They would probably not disallow his proposed experiment on any of these grounds.

Is the principal investigator competent?

Was the principle investigator competent to undertake such efficacy trials?

Colleagues in the two medical clubs to which Jenner belonged may well have had questions about Jenner's competence, in light of his constant harping on the illogical notion that having contracted one disease (cowpox) could protect a person against infection with another disease (smallpox). Members of the Royal Society may also have questioned Jenner's competence to undertake this sort of experiment. After all, he had been voted in as a Fellow of the Royal Society (FRS), not on the basis of any medical work or researches, but purely on the basis of his observations of the nesting behaviors of cuckoo birds. A distinguished career observing the natural history of birds and other animals would hardly qualify one as a researcher in the prevention of infectious diseases.

However, Jenner was also a well trained, highly educated, and certified medical practitioner who, in addition to his nine years of medical apprenticeship, had spent two additional years studying under the tutelage of the most famous surgeon and teacher of his time, Dr John Hunter, in London. Jenner had earned his master's high commendation and even his friendship. In fact it was from John Hunter that Jenner had learned the principle: "Why speculate, why not try the experiment?" Thus, it would be difficult to consider a physician as well trained as Jenner to not also be a competent investigator. His belief in "vaccination," of course, was considered quite unorthodox by the medical establishment, but belief in the efficacy of unorthodox protocols does not in itself make an investigator incompetent. Nor does the seeming rashness of Jenner's willingness to inoculate his son with swinepox and then attempt to intentionally infect him with smallpox pus, though that experiment may have led some people to question his good sense. Still, Jenner had been fully and appropriately trained, according to the standards of his day, as a medical practitioner and medical investigator. Furthermore, he had done as much preliminary research on the notion of inoculation with cowpox as could have been expected of any investigator before undertaking studies using human beings.

Animal research?

There was at the time no concept of using animal models for the study of infectious diseases so there is no likelihood that an ERC would have asked for such evidence. However, even if it had been common practice to do preliminary research with animal models, no animals seemed to get sick with smallpox, so it would probably have been difficult (as it is today with AIDS research) to find or develop any adequate animal model.

Endpoints and criteria of success

Were the endpoints and criteria of success for Jenner's experiments adequately defined? Even though this issue is not formally addressed in his application for ethical review, we do see evidence that he had considered the question. One endpoint was clearly defined, viz., if the first subject, James Phipps, were to get seriously ill, either from the cowpox inoculation or from the smallpox challenge. If that were to happen, Jenner said, that would have been the end (an unsuccessful end) of that series of experiments.

But what would have constituted a successful endpoint of the experiment? One successful endpoint, the one that Jenner accurately expected, is that after being vaccinated with cowpox matter, and upon being challenged with smallpox pus (i.e., upon being variolated), the subject would have absolutely no untoward reaction whatsoever. The site of the challenge would not redden, swell, form a pustule, or show any sign of infection whatsoever. Jenner would then see this as evidence that the cowpox vaccination had "taken," i.e., had protected the subject against infection with smallpox, and therefore that it was a successful procedure for protecting persons against smallpox disease.

The assumption he made, and a seemingly logical assumption it was, was that if the subject showed no reaction to the smallpox challenge, then that subject was therefore protected against naturally acquired smallpox infection as well and therefore protected against naturally acquired smallpox disease. That seemed like a perfectly logical assumption, so he did not question it.
But he should have questioned it. Artificially induced smallpox and naturally acquired smallpox were, after all, acquired by two different routes of infection (scarification and inhalation), and it could not be certain that protection against one route of infection also conferred protection against another route of infection (as we have seen with AIDS vaccine research in some animal models).

Any of today's more practiced designers of biomedical research protocols - Jenner was, I believe, the first medical investigator to do scientifically designed medical research with human subjects - would doubtless have reminded Jenner that this was still an assumption, i.e., an hypothesis, and that as an hypothesis it should probably not just be accepted a priori, but should rather be tested.
So how could the hypothesis that cowpox inoculation protects subjects against naturally acquired smallpox infection be tested? The only way to adequately test whether subjects would contract naturally acquired smallpox disease would be to monitor and observe them for a number of years, at least through one or two local smallpox epidemics, and perhaps even for the rest of their lives, to see if they ever contracted smallpox after being naturally exposed to it.

If it indeed turned out that none of his vaccinated subjects ever had any adverse reactions to direct smallpox challenge, and it also turned out that none of them ever contracted a naturally occurring smallpox infection, in spite of having been exposed to persons with smallpox disease, then at that point Jenner could finally conclude that cowpox vaccination did indeed protect people against contracting smallpox disease.

He would also, at this point, know one other valuable piece of information: He would know that failure to react to smallpox challenge (i.e., to variolation) was one of the "correlates of protection;" i.e., he would know that people who do not react to variolation also do not contract naturally acquired smallpox disease. From that point on Jenner would then know that in order to determine whether a vaccination procedure had been effective he would only need to determine whether the subject reacted to smallpox challenge by way of variolation. If the subject(s) showed no reaction to that challenge, then that would be a successful endpoint in future studies, because that had been discovered to be a significant correlate of protection.

To say it simply, it would probably have been necessary, as part of the study design, especially in his first trials, for Jenner to observe his subjects for some years following vaccination to determine whether or not they were also protected against naturally acquired smallpox disease, as well as against challenge by variolation. An ERC would probably have recommended that Jenner add this as one of the endpoints of the study. The three endpoints would therefore be: a) subjects become seriously ill, so the study ends (unsuccessfully); b) subjects have no adverse reaction to challenge by variolation, so the study gives promise of being successful; and c) subjects also do not contract any naturally occurring smallpox disease for many years into the future. This endpoint would mean that the cowpox vaccination procedure had definitely been successful, i.e., it had accomplished what was wanted: protection against naturally acquired smallpox disease with no untoward side-effects.

An ERC would probably have recommended that Jenner clarify these three endpoints, and the two criteria of success, and Jenner would probably have been happy to comply with this request. He probably expected to informally monitor his subjects for the remainder of their lives in any event.

In sum, it would seem that Dr Jenner's proposed experiment met, or with minor modifications would meet, as many of the scientific demands as it could be expected to meet in his day. It would probably not be faulted on scientific grounds.

2) Is there is an acceptable ratio of potential-harm to potential-benefit for each individual research subject?

The risks in the experimental procedure must be compared to the risks in the current standard of treatment, but it is not entirely clear what should be considered the "current standard of treatment," the practice of variolation, or the practice of simply isolating persons infected with smallpox. Let us compare the experimental risks and benefits to each of these practices separately.

Harm/benefit ratio compared to variolation

If variolation is to be considered the current standard of treatment, then inoculation with cowpox did not seem to present any greater risk than inoculation with virulent smallpox. In fact it probably could be expected to present a much lesser risk. After all, almost all the risks that Jenner lists in his ERC application are risks that would also accrue to anyone undergoing the process of variolation. Therefore, the risks of Jenner's procedure do not seem to be any greater than the risks of variolation, and may even be less.

As for the benefits from being variolated, viz., protection from future infection with smallpox (if the variolated person survives), these seem to be relatively certain. Benefits from vaccination with cowpox were uncertain, even though there was anecdotal evidence that persons who had had naturally acquired cowpox did not seem to ever contract smallpox. And in any case, when the cowpox subjects are challenged with actual smallpox, that process will be virtually identical to being variolated, so the subjects will, even if they receive no benefit from cowpox vaccination, at least receive the benefits (and perhaps the risks) of variolation.

Harm/benefit ratio compared to isolation

On the other hand, if simply staying away from persons sick with smallpox is to be considered the current standard of treatment, then there is almost no risk at all in that practice, at least as long as it is physically possible to accomplish it. So if that is to be considered the current standard of treatment, then the risks of being infected with cowpox, and then challenged with smallpox, would certainly outweigh the risks of the current standard of practice. The benefits of vaccination, on the other hand, if they did successfully came to pass, would be much greater than the highly uncertain effectiveness of simply staying away from persons sick with smallpox.

In sum, the potential-harm to potential-benefit ratio does not seem to be outside the bounds of reason in either case. The protocol would probably not be faulted on that account.

Inducement?

What about Jenner's promise to provide subjects with free medical care during the course of the experiment, and even to include medical care for non-experiment-related sickness or injury? (I do not know that Jenner did in fact offer this to his subjects; I am only surmising that he was the sort of physician who would have offered it.) This practice would seem to be ethically acceptable, particularly if Jenner was the only, or one of the only, physicians in local practice, and especially if he was already the family physician for the families of his subjects.

However, the provision of free medical care for the remainder of their lives, while probably motivated by compassionate feelings on Jenner's part, may raise eyebrows in an Ethics Review Committee. The question would be whether the amount of medical care promised to subjects would be so great that it might limit their ability to make a free and authentic choice about participating in the experiment without undue inducement. This, it seems to me, would be a difficult judgment call on the part of committee members.

3) Will the investigator be able to protect subjects against significant harm?

There was, of course, serious question as to whether Jenner would be able to protect his subjects against the harm of smallpox to the same degree, or greater, as did the current standard of treatment. That question was what the whole experiment was designed to ascertain. The more crucial question would actually seem to be whether Jenner had good reason - in the form of material evidence - to believe that the vaccination would protect his subjects. As we have seen in response to the question about appropriate scientific methodology, Jenner seems to have had as much preliminary evidence as would have seemed reasonable at the time for proceeding with the experiment.

As far as caring for and compensating any subjects who might be harmed by the experiment, i.e., who might contract smallpox as a result of the experiment, Jenner seemed anxious to do all he was capable of doing. In the event of the death of any subject who was the breadwinner in a family, Jenner offered to look after the family personally, using his own financial resources. An ERC might applaud Jenner's obvious good will in this detail, but may also suggest care and compensation measures that did not rely solely on Jenner's own personal financial fortunes, his good will, and his ability to practice medicine. His heart does seem to be in the right place, however, and he would probably welcome any committee suggestions.

4) Will the investigator be able to obtain each subject's properly informed and freely given consent?

In the case of minors, Jenner would need to inform both the individual minor subjects and their parents or guardians. He would need to explain to them, probably orally, all the risks of the experiment, the potential benefits of the experiment, and the purpose the experiment was trying to achieve. He would also need to inform them that they were free to quit the experiment at any time. James Phipps would need to be made aware that he could refuse attempted infection with smallpox any of the times it would be tried in the following twenty or twenty-five years.
In Jenner's attached informed consent form, he does seem to address all these issues. The committee would probably find little or no fault with his consent form.

Most ERC's today rarely simply approve or disapprove protocol applications. Instead, they most often approve requests conditionally. That is, they give their conditional approval based on the principal investigator's willingness to modify the protocol in certain ways to insure that it meets ethical requirements. I have indicated some of the probable recommendations that the committee might have made to Dr Jenner, and which he would be required to implement before he undertook the experiment. I do not see that any of these recommendations would have been unacceptable to Jenner.

Therefore, I believe the experiment would ultimately have been considered ethically acceptable.

In actuality, Dr Jenner did inoculate eight-year-old James Phipps with cowpox on May 14, 1796 (three days before Jenner's 47th birthday). Thus the date of the first efficacy trial for a "vaccine" involving human subjects, just 200 years ago, corresponds with the planned initiation of WHO's first approved efficacy trials for an HIV vaccine. Whether the WHO trials will be as successful as Jenner's remains to be seen.

James Phipps did get mildly sick from the cowpox, as expected, and he did recover within two weeks. He was subsequently directly challenged with virulent smallpox, but there were no negative effects at all. He was completely protected against artificially induced smallpox infection. Jenner continued to challenge Phipps with smallpox infection almost yearly for the following twenty or twenty-five years, in order to see how long Phipps' immunity would last. In effect, however, Jenner was actually giving Phipps vaccination "boosters" and probably strengthening his immune response with each challenge.

Jenner published the report of his experiments in 1798 under the title An Inquiry into the Causes and Effects of the Variolae Vaccinae, a Disease Discovered in Some of the Western Counties of England, particularly Gloucestershire, and Known by the Name of the Cow Pox. This publication initiated a lengthy debate in the medical community and in the public arena about the safety, efficacy, and social desirability of the cowpox vaccine, a debate that engaged Jenner deeply for the remainder of his life, and in which Jenner's position ultimately triumphed.

An editor of one of today's prestigious scholarly journals has ironically suggested a set of "authors' guidelines" which, if followed, would increase the probability that the author's work will be accepted for publication.

Authors should (1) not pick an important problem, (2) not challenge existing beliefs, (3) not obtain surprising results, (4) not use simple methods, (5) not use full disclosure, (6) not write clearly.

Edward Jenner violated each one of these rules fully, and that may be the reason that his book was at first refused publication by the Royal Society. It may also be the reason that his writing generated so much controversy, enough that it kept Jenner busy defending and promoting vaccination for the remaining 25 years of his life. (As one would expect, the practice of variolation eventually fell into almost complete disfavor, practiced only irregularly here and there for the next century or so, the last vestiges of the practice being found as recently as the 1960s and 1970s in Ethiopia, western Africa, Afghanistan, and Pakistan. )

 

Another debate, contemporaneous with the publication of Jenner's book, began with the publication of a book, also in 1798, by Thomas Robert Malthus, entitled An Essay on Population. This debate was about the patterns, methods, and social effects of human population increase and decrease. A small part of this debate, at least in the public mind, concerned itself with the practice of immunizing large numbers of the poor against smallpox disease. This debate did not concern itself at all with questions about the efficacy of the vaccine method of preventing the smallpox. It, in fact, assumed that the vaccine method of preventing smallpox would probably be quite effective. This debate, instead, focused on whether human beings should intervene at all in the prevention of large-scale, lethal epidemic diseases, since such diseases served the natural function (according to some believers) of keeping human population growth under control and within certain "natural" bounds. Though a discussion of this debate is outside the scope of this book, one does sometimes hear similar opinions voiced even today, opposing those who work to prevent the spread of AIDS.

 

 

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