Dr Tom Kerns
North Seattle Community College

 

Jenner On Trial

Tom Kerns

 

 

 

 

Chapter 7

 

Comparison of Dr Jenner's experiments with today's HIV vaccine experiments

 

And finally, what might we learn about today's HIV vaccine efficacy trials if we look at them in relation to what we now know about the ethical dimension of Edward Jenner's vaccine experiments? Without proposing any final judgments or dogmatic conclusions, it may still be valuable to make note of some few comparisons between Jenner's experiments with the cowpox vaccine and today's proposed trials with HIV vaccines, and perhaps even to hint at some small lessons we might learn from Jenner's efforts. What do we find when we compare the two sets of efficacy trials?

In answer to this question I propose the following fourteen insights, comparisons, and lessons.

a. The behavioral prevention standard did not stop spread

When we consider the potential harms and potential benefits to subjects in a vaccine efficacy trial, we must of course measure that harm/benefit ratio for the candidate vaccine against the harm/benefit ratio for the current standard of prevention for that disease.

In the case of Jenner's experiment, it was not entirely clear what should be considered the current standard of prevention; either prevention by isolation, or prevention by variolation, could be considered the current standard of practice. We thus compared his experimental vaccine to each practice separately.

When we compared the anticipated harm/benefit ratio of the cowpox vaccine to the known harm/benefit ratio of the variolation procedure, it seemed that the ratio of the candidate cowpox vaccine's harms and benefits was approximately comparable to that of variolation, or possibly even somewhat better. When we compared the anticipated harm/benefit ratio of the cowpox vaccine to the known harm/benefit ratio of the practice of prevention by isolation, we saw that prevention by isolation was actually attended by fairy high risk, since isolation as a way of preventing contagion was not very effective. We saw that in theory it should have worked well, and would have worked well if people had faithfully followed it, but that in practice it still allowed for a continuous large number of new infections.

When we look now at the anticipated harm/benefit ratio for today's candidate HIV vaccines and compare them to today's standard of HIV prevention, what do we find? The current standard of prevention for HIV infection today should probably be considered to be education and behavior modification (i.e., reducing or eliminating risk behaviors). Basic epidemiology, of course, shows us that, while this practice may work well for some individuals, it does not seem to work for a large number of others. A very large number of persons are still being infected. It may be protested that if all individuals were strictly faithful to their behavioral changes, the prevention would be effective and they would not become infected. In Jenner's time too, if people had been strictly faithful to their isolation procedures, they would probably not have become infected with smallpox. Unfortunately, however, despite the horror of the disease and the high likelihood of contracting the disease, many people were still unable, or almost unable, (or at least strongly disinclined) to stay away from persons they loved who were sick.

We see the same phenomenon today with HIV infection. Many persons are unable, or almost unable, or perhaps just very averse to the idea of staying away from persons they want to be close to. Obviously, today's situation with HIV requires sexual connection, or some sort of bodily fluid contact, in order for the infection to be transmitted, and smallpox did not require intimate sexual contact for transmission. The principle, however, is the same: behavioral separation between infected and uninfected persons was difficult and unlikely in Jenner's time, and it is difficult and unlikely today. For a large numbers of persons, the behavioral methods of prevention are simply not effective (if only because they are not able to follow them strictly, or are very averse to following them strictly).

Thus, when we consider the harm/benefit ratio for today's HIV candidate vaccines, that ratio must be compared to the harm/benefit ratio of the current standard of prevention, i.e., behavioral separation. This is not an easy or simple comparison, since it is not easy to determine what the harms or benefits of behavioral separation should be considered to be. Should we use as our base the harm/benefit ratio in those situations where the behavioral separation was rigorously maintained, and was therefore successful, or should we use as our base the harm/benefit ratio overall, across the entire spectrum of the human community, where it is sometimes successful but often not?

In any case, the harm/benefit comparison we are faced with today is very similar to (and just as complex as) the harm/benefit question faced in Jenner's experiment, and an ERC dealing with the harm/benefit ratio in either case may have a difficult time answering the question.

b. Protecting vulnerable subjects

Just as Jenner's cowpox vaccine experiment needed to be done on vulnerable subjects (small children) because children were the ones at disproportionately high risk for contracting the disease, so today's HIV vaccine experiments need to be done on vulnerable populations (e.g., socially marginalized groups, or groups in developing nations) because these persons belong to communities at some of the highest risk for HIV infection. More specifically, vulnerable populations which will be considered for HIV vaccine efficacy trials will probably include some of the following: injection drug users; commercial sex workers; women in developing nations who do not have the degree of freedom and autonomy available to some women in industrialized nations; persons in developing nations who have not had the opportunity for education that would make it easier for them to understand the necessary elements of informed consent; children, in both developing and industrialized nations; military recruits; persons in parts of the developing world who might be in any way vulnerable to manipulations (intentional or not) of scientists from the industrialized world; and perhaps other vulnerable groups. Any of these subpopulations, some of which are more vulnerable than others, may be subjects in HIV vaccine experiments.

Therefore, whatever special protections and precautions Jenner took (and should have taken) for protecting the interests of his vulnerable subjects should also be taken to protect the vulnerable subjects in HIV vaccine trials.

Care must be taken, furthermore, to insure that vulnerable groups are not discriminated against in their desire to participate in biomedical research. If they wish to participate, they must be allowed the same opportunities as other less vulnerable groups.

c. Plentiful preliminary evidence

Probably because there was so much skepticism among his colleagues about the likelihood of cowpox infection being able to protect against smallpox infection, Jenner waited until he had plentiful preliminary research to help validate the likelihood of success in his experiments.
Similar (healthy) skepticism with regard to the likely success of today's HIV candidate vaccines will also require today's researchers to have plentiful preliminary evidence to support the probability of success of candidate HIV vaccines (evidence that will probably be in the form of animal studies, and phase I and II human trials).

d. Protection against artificially induced vs. naturally acquired disease

Jenner seemed to believe that the only necessary criterion of success in his cowpox vaccination experiment was the almost immediately (after several days) visible result of his subjects having had no adverse reaction to the smallpox variolation challenge. He did not seem to realize, at least not initially, that there may be a difference between a person's reaction to artificially induced smallpox (i.e., variolation) and a person's reaction to naturally acquired smallpox, i.e., smallpox which has been acquired as a result of being in proximity to an infected person. Jenner did not think there would be any significant immunological difference between an artificially induced smallpox challenge and a naturally acquired smallpox challenge. That is, he did not seem to realize that it would not be scientifically justifiable, based on the discovery that a person is no longer susceptible to variolation, to conclude with certitude that his subjects would then also be protected against contracting naturally acquired smallpox disease. Although it seemed like a logical assumption at the time, today's more practiced designers of research protocols (and most of today's ERCs too) would remind Jenner that he would need to test his vaccine for efficacy on both artificially induced and naturally acquired smallpox infection. Today Jenner would be reminded that, in order to be certain that his subjects were protected against naturally occurring smallpox disease, he would need to follow them for some years, probably through at least one local smallpox epidemic, and maybe even for the rest of their lives, to assure himself that they were indeed protected against naturally occurring smallpox infection. In actuality, Jenner probably did continue to monitor his subjects for as many years as he could, if only because, as a sympathetic country doctor, he continued to care about the well-being of his subjects (who were probably also sometimes his patients).

Today's HIV vaccine researchers, unable to be the country doctors to their subjects, who will probably live in nations and cultures different than those of the persons who initiate, sponsor and design the trials, will need to build into the structure of the trials the planning for long-term followup.

e. Having your theories vindicated

Jenner's ideas for a prophylactic vaccine were very much disparaged by his colleagues before he performed the experiments, but were applauded later when the experiments were found to be roundly successful. Today's researchers, particularly those with unorthodox approaches to vaccine development, will probably also be hoping for a similar vindication of their ideas and theories.

f. Caring about your volunteers

Jenner cared deeply about his subjects. He knew them personally, and their individual lives and well-being were important to him. He genuinely cared about them as persons (i.e., as valuable in themselves, and not merely as a means to accomplishing his own scientific ends). He was, after all, in addition to his role as a researcher, also the family physician for most of his subjects and their families. It was quite natural for him to care about them as persons. In addition, his cowpox experiments were conducted using only ten or twenty subjects. It is entirely possible to know and genuinely care about such a small number of subjects.

Today's researchers, however, conducting protocols with thousands, perhaps tens of thousands of subjects, will find it much more difficult to see that each subject is personally known and personally cared about by investigators and staff who are part of the on-site team. Difficult as this will be, however, it should be considered an essential part of a well-designed and well-conducted trial.

g. The Other

Jenner was probably not tempted to think of his subjects as in any way Other than himself . They were, after all, British subjects just as he was, most were children very like his own children, all were of the same Caucasian racial heritage as himself, all had virtually the same cultural, linguistic, and religious heritage as he did, and all even lived in the same region of the country (i.e., in Gloucestershire) as he did.

Today's researchers may face temptations in this regard that Jenner did not face, viz., the temptation to think of their subjects as Other. Many subjects in developing nations, for example, may be of a different racial heritage than that of the researchers themselves, will probably be from quite different cultural, linguistic, and religious traditions, will probably live in different parts of the world than those who sponsor and design the trials, will probably be subject to quite different laws, will probably have quite different educational and social backgrounds, different manners of living, and perhaps even different expectations about what constitutes "normal human behavior." Because of these differences, researchers may be tempted to think of the subjects in their trials as Other, and may therefore be tempted to treat them as Other, and therefore to care about them less than they would care about someone who was more like themselves.

This temptation may lead researchers to care less about the health and well-being of their subjects than Jenner did, which could be a serious danger. Such an attitude toward subjects could indicate a higher risk of breaches of ethical conduct in the trial.

h. Financial gain

The anticipation, if any, of financial gain (if his experiments proved to be successful) seemed to not have been a significant motivating factor for Jenner. He seems to have been more concerned to discover a method of preventing human suffering. If he did anticipate any financial reward, it was clear that that was not the primary motivator. In fact, in later years he almost spent himself into penury in the process of promoting the good will use and distribution of his vaccine around the world.

Financial gain may, on the other hand, be one of the more central motivators in some of today's vaccine research. Today's research, after all, is in large part sponsored by incorporated business entities (corporations) whose primary raison d'etre is financial gain; i.e., they are for-profit corporations. These entities would probably not be sponsoring research at all if it did not entail the probability of financial gain. This may mean that the kind of motivation that leads to vaccine research today is quite different than it was for Jenner and his research. If that is true, then it may be the case that insensitivity to the needs and concerns of the volunteers is more a danger in today's research climate than it was for Jenner. It may also mean that today's research will therefore need to be monitored more closely by ERCs than it might have been in experiments done by an individual country physician who personally knew and cared about each of his subjects.

i. Corporations and agencies can't care

Jenner's research was conceived, initiated, sponsored and carried out by an individual human person, which probably made it more likely that the research sponsor would care about and wish to protect his subjects from possible harms.

Today's vaccine research is initiated, sponsored, executed, and monitored by agencies, companies, incorporated entities, committees, and (in the worst case) by bureaucracies. Individual human persons, of course, are the ones who carry out the work of these entities, but the agencies, companies, and incorporated entities themselves do not, by their nature, have any feelings for people or care about people. We need only be reminded of Martin Buber's analysis of the I-You and I-It relationships in today's world to understand this phenomenon. Therefore, any caring about individual subjects will have to be deliberately and consciously planned into the protocols, i.e., designed into their basic structure. The very design of the trials, in other words, should be arranged so that the caring about subjects - which is essential to an ethical trial (and is probably also essential to keeping subjects motivated enough to continue their participation in the trial during the long months and years) - will be likely to follow from the basic structure of the study.

j. Treatment and compensation

Jenner made it clear that he would take care of his subjects if anything untoward happened to them as a result of the experiment. He made it clear that he would treat them for smallpox if they contracted it, and that he would personally provide financial support for any family that lost a breadwinner to one of his experiments.

In today's research designs, this is referred to as treatment and compensation for research-related injuries, and is one of the ethical requirements for any biomedical research. Today's vaccine researchers are fully aware of these requirements.

k. No just-try-it experiments

Jenner's inoculation of his ten-month old son with swinepox pus seemed to be, according to my analysis, ethically questionable. Since it was an experiment that had virtually no supporting preliminary evidence, it could probably be classified as an experiment of the "we'll-never-know-till-we-try-it" variety.

This was one element that made that experiment ethically dubious. Even though there may be a passing temptation, with some of today's candidate vaccines, to "just try it," today's investigators are much more careful to not do any research involving human subjects without a great deal of supporting preliminary evidence.

l. Informed consent

Jenner's informed consent procedure was of course much less complex and much easier to accomplish than the informed consent procedure will be for today's HIV vaccine investigators. In Jenner's time there was little, if any, expectation of the formal necessity for a structured informed consent process. Furthermore, the concepts and data that needed to be explained to (and understood by) his subjects were not difficult concepts, and the data was simple. In addition, he had so few subjects that it would not be an overwhelming task to explain the necessary information to each one of them.

With today's HIV vaccine trials none of those simpler situations will obtain:

i) The standards for informed consent are high standards (as they should be), and will therefore be more difficult to meet. A quick perusal of the WHO/CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects - nine of the fifteen guidelines are devoted to questions of informed consent - will give some indication of just how demanding today's informed consent requirements actually are.

ii) The complexity and quantity of the scientific, medical, social, legal, and ethical concepts that are necessary for adequately informed consent (placebo, control group, double-blind, immune system, autoimmune disorder, enhanced infectivity, social discrimination, legal requirements for compensation, etc) will all make the informing of subjects much more difficult.

iii) These difficulties will be all the more severe if the concepts are not familiar concepts in the subcultures of the subjects who are being tested. Furthermore,

iv) the data that underlie and support some of these concepts may be even more complex and difficult to understand than the concepts themselves. And finally,

v) today's researchers will have quite large numbers of subjects (perhaps in the tens of thousands) who will need to be adequately informed, and these numbers alone will make the informed consent process much more problematic and complicated.

Therefore the informed consent process for today's vaccine trials will probably be several orders of magnitude more complex and more challenging than was the informed consent process in Jenner's trials.

m. Harm/benefit ratios

Jenner's harm/benefit analysis was much simpler than the harm/benefit analysis that today's researchers (and ERCs) will need to consider. On the risks side, the number of known risks was significantly smaller for Jenner's subjects, partly owing to simple scientific ignorance. And on the benefits side, Jenner had accumulated some rather promising data that the likelihood of protective benefits for his subjects would be quite high. Jenner had already done some quasi-efficacy experiments before he ever inoculated anyone with cowpox; i.e., he had performed direct challenge experiments (by means of variolation) on some persons who had had naturally acquired cowpox infections, and he found that they were not susceptible to being artificially infected with smallpox. So the likelihood of protective benefit for subjects, as indicated by his preliminary research, was quite high.

Today's researchers, of course, do not have the conceptual (but immoral) luxury of being able to deliberately challenge vaccinated subjects. Jenner did have that luxury because the challenge was identical to one of the standard practices of prevention, viz., variolation. Since direct challenge testing is impossible today (except in some animal models whose relevance has been questioned), today's researchers do not have access to any of the kinds of strong preliminary human research data that Jenner had access to.

To say it more simply, today's researchers will not be able to directly challenge any persons they might discover who seem to have a naturally occurring immunity to HIV infection. This difficulty makes today's harm/benefit analysis much trickier and much more speculative.

n. Honest ignorance does not prevent discovery

One of the most valuable lessons we can learn from Jenner's success with his experiments, it seems to me, is the following: It is not always necessary to fully understand the inner workings of a process in order to make significant discoveries about that process. Jenner, for example, knew nothing about the etiologic agent for smallpox, he had no understanding at all about the pathogenesis of the disease in the body's organ and tissue systems, and he had no understanding of the immunologic mechanisms that explained why persons were protected against future disease. In fact, Jenner even seems to have based part of the reasoning for the validity of his experiments on a completely false theory, viz., his teacher John Hunter's erroneous belief that two separate systemic diseases could not coexist simultaneously in the same body. This theory, completely erroneous as it was, may have been part of Jenner's explanation for why persons who had contracted cowpox could not ever contract smallpox. And yet, in spite of these great ignorances, and even in spite of holding some false theories about his researches, he was still able to do an ethically and scientifically proper research protocol that had the ultimately beneficial effect of entirely eradicating from the planet one of humanity's most feared infectious diseases.

Today's researchers often feel that, despite enormous gains in our understanding of this disease and this virus, still far too little is known about the pathogenesis of AIDS and all its processes, too little is known about HIV itself, and even too little is known about the intricacies of the human immune system and how it operates. Small wonder, then, that so many researchers have been skeptical of ever finding a successful vaccine to protect against HIV and AIDS.

And yet, despite these very humbling and painful ignorances, today's discouraged researchers might still take heart from the slow, conscientious and deliberate efforts of Edward Jenner who knew far less about his disease in the 18th century than we know about our disease today in the 20th century, and yet who, in spite of that ignorance, was still able to find the first, the most successful, and certainly the most ultimately effective vaccine ever devised.

 

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