Eugene Robin, M.D.

Active Professor Emeritus Stanford University School of Medicine

Stanford, CA

I want to thank the organizers for assembling this meeting. I apologize for my inability to attend personally. However, I will be pleased to answer any questions that might arise and, in particular, to include in the final draft of this discussion any opposite views to my (perhaps controversial) presentation. I plan to emphasize some aspects of the vaccine problem which have little or nothing to do with the formal science involved in vaccine development but which are critical to assessing the balance between risks and benefits of specific vaccines. I also intend to emphasize some societal factors that are critical to the success or failure of even highly effective vaccines. I will also emphasize the point that current approaches to evaluating the risks versus benefits of vaccines are generally inadequate and are not optimal, either statically or dynamically, particularly with the passage of time.

Successful vaccine programs for specific diseases require mass education and participation by a substantial portion of the population for optimal results. This requirement can be illustrated by two examples. The eradication of smallpox by an effective vaccine is one of the most dramatic stories in medicine. An effective vaccine was first introduced in the early 19th century. The final fatal case of smallpox in Asia occurred in October 1975. In May, 1982, the World Health Assembly declared that "the world and all its people have won freedom from smallpox." Why did it take over 150 years for the disease to be eradicated, despite the existence of an effective vaccine?

We can learn from the experience in India and Asia. It became apparent that a program to eliminate smallpox must include the elements of "surveillance and containment." Beginning in 1973, a new strategy was developed which depended on the education of masses of people throughout India. Health care workers visited every village in India one week per month and, later, every house, to find cases. Villagers became mobilized for case findings and case isolation. Rigid control measures were adopted that depended on the participation of the public. These steps were effective and were adopted throughout Asia. And finally, smallpox was eliminated from Asia. It was the education, energizing and mobilization of broad masses of people that finally accomplished eradication of smallpox. The availability of the vaccine alone was not sufficient to eliminate the disease.

The second example comes from the island of Martinique in the Atlantic. There was a dramatically high incidence of rheumatic fever, acute glomerulonephritis and rheumatic carditis. A ten year program of education was instituted, targeting the public and public health workers. Knowledge of the relationship between pharyngitis and rheumatic fever led to a dramatic reduction in the incidence of acute rheumatic fever and its complications Although not a success story for vaccines the sequence of events represents a triumph for the education of the public.

Obviously, a program of participation by the public must be modified to fit the political, economic and cultural characteristics of a given society. For example, our society is involved in a major economic transition from fee for service to so-called managed care economics. Given an effective vaccine it will be required to convince the managers of managed care that the use of the vaccine is not only medically sound but economically sound as well. But the principles of public education and public participation can facilitate the application of effective vaccines and the abandonment of those with unfavorable risk/benefit ratios. This, then, leads to the next imperative. How can the benefit of a vaccine be demonstrated and how can its risks be accurately quantified - information that is a key part of the educational process?

The scientific approach to such quantification is the performance of an adequate, prospective, randomized, controlled clinical trial in which one half of a carefully defined group receives the vaccine and the other half receives a placebo. Such a trial not only measures the degree of protection provided by the treatment but also measures the adverse events associated with the use of the vaccine. Sad to say, such trials have not been performed for most commonly used vaccines and precise knowledge, particularly of the risks, is lacking. So, what can we "teach" the public if we ourselves, the medical scientific community, have not done the proper and required studies?

In addition, in the case of vaccines, there is another problem, the shifting of the ratio of number of cases of the given disease to the complications caused by the vaccine. This process can be called the cross-over point and can be illustrated as follows. Consider that a highly effective vaccine becomes available and as a result, with the passage oftime, there is a progressive decrease in the incidence of the disease and, thus, in the mortality and other complications associated with the disease. However, all things being equal, the percent of adverse events (complications) associated with the vaccine remains constant.

A point will be reached, the cross over point, where the complication rate of the vaccine for individual patients will be higher than the adverse effects of the disease. At this point, for individuals, the wise thing might be to refuse the vaccine. However, for society, it might be useful to continue vaccination to prevent recrudescence of the disease in the general population. Of course, without the data obtained from a prospective, randomized, controlled clinical trial, it is not possible to define the cross-over point. And, indeed, the cross-over point will shift with time so that new epidemiological studies may have to be performed.

But recall we have resolved to be honest and accurate and forthcoming with the members of our society. If so, we are required to inform them of the position of the cross-over point at any time. This, of course, raises the question of who should decide whether the vaccine is to be used. It may be that it is beneficial to society to continue using the vaccine so that there is no recrudescense of the disease. But doing so may be bad for individuals even though it may be good for society. And what if that individual is a young child? Shall we tell the parents that the use of the vaccine is not in the best interest of the child but is good for society? Hence. we recommend exposing the child to an unfavorable risk/benefit.

The final question to discuss is the issue of informed choice. I believe that the term "informed consent" is fundamentally patronizing and suggests that the health care provider is in a superior scientific position to suggest a given action to individual members of society. We have seen that in the case of vaccines this is often not the case. Informed choice is a less patronizing term than informed consent and deals with the subject as an equal. The process of informed choice should include transmission of precise and accurate information about areas of uncertainty and ignorance. A true process of informed choice would, for example, raise grave questions about the vaccination of young children for hepatitis B. But this is not the time or place for that discussion. In any case, the scientists who develop vaccines should be given great credit and respect for their pioneering work.

But it must be recognized that once a promising vaccine is available, that should be the beginning and not the end of the process. Accurate assessment of the risk/benefit ratio of the vaccine by means of a prospective, randomized, controlled clinical trial should be obligatory. For some pressing problems (e.g., AIDS) it might be useful to curtail this step. However, such a decision should not be undertaken lightly. An educational process involving the public should be mandatory in which the risks and uncertainties are described as well as the potential benefits.

Suspension of the right of informed choice should be only done in truly compelling circumstances and by a group that represents society broadly and not merely one composed of scientists, physicians and bureaucrats. We must be honest and admit that we do not know the impact of administering multiple, different vaccines on very young children or, indeed, on anyone. Finally, continued, rigorous clinical evaluation of a given vaccine should be mandatory.