AIDSWEEKLY Plus; Monday, April 13 & 20, 1998
Daniel J. DeNoon, Senior Editor

The escalating intensity of the debate became apparent in Jonathan M. Mann's March 15, 1998 presentation to the Presidential Advisory Council on AIDS. Mann, a long-time leader in the worldwide battle against the epidemic, left a position at Harvard University to become the founding director of the World Health Organization (WHO) Global Program on AIDS. He is now dean of the School of Public Health at Allegheny University, Philadelphia, Pennsylvania.

Mann blasted the so-called rational approach to HIV vaccine development as "unethical practice" that "violates human rights of Americans."

The prevailing opinion of U.S. policymakers is that there is simply no good evidence that current candidate AIDS vaccines stimulate the kinds of immunity that correlate with disease protection. Exactly what these correlates are, however, remain unknown.

The current U.S. HIV vaccine development strategy, as outlined by David Baltimore, chair of the National Institutes of Health AIDS Vaccine Research Committee, is to quickly conduct small trials of candidate vaccines as they become available. Information gleaned from these small trials will be used to developed improved vaccines, and the process would be repeated until researchers arrive at a vaccine considered to have a good chance of efficacy. Only at that point will large-scale trials be conducted.

Not everyone agrees with this assessment. For example, the firm VaxGen - spun off from parent Genentech - is about to implement a Phase III trial of its combination peptide HIV subunit vaccine in Thailand. VaxGen researchers - including AIDS pioneer Donald Francis - vehemently argue that such time-tested, empirical approach is the best way to obtain a working vaccine.

While virtually all current vaccines have been developed by such empiric methods, proponents of the rational approach argue that all the easy vaccine targets are gone, and that vaccines for complex pathogens such as HIV require application of the most recent advances in immunology.

Mann takes serious issue with this idea, stating that "it creates an unreasonable barrier to progress." He further argues that there would be no delay in testing AIDS vaccines if the disease did not strike "already marginalized populations, thereby exacerbating pre- existing patterns of societal discrimination."

AIDS Weekly Plus has obtained a copy of Dr. Mann's remarks. They appear below in their entirety:

"There is increasing worldwide consensus that a preventive vaccine will be essential for controlling the expanding and intensifying global HIV/AIDS epidemic.

"There are several AIDS vaccine candidates which have been shown to be safe in humans, and some produce a variety of immune responses, including those possibly associated with protection against HIV, in a majority of recipients. If the process of vaccine development was proceeding normally - traditionally - this would lead to prompt initiation of field trials to determine protective efficacy of vaccine candidates. Yet years later, field trials of AIDS vaccine candidates are still not underway.

"Three reasons have been put forward to explain this unusual deviation from standard vaccine development practice. First, it has been alleged that special ethical problems exist regarding conduct of AIDS vaccine field trials. While important, none of these ethical issues are insurmountable. Secondly, the fear has been expressed that if the first vaccine trial is not highly successful, it would be impossible to conduct further trials; the global urgency and need for an AIDS vaccine make this fear groundless.

"The third issue involves disagreement within the scientific community about whether current candidate vaccines will protect. This controversy, inherent in development of all vaccines, has been allowed unreasonably to paralyze progress towards AIDS vaccine development. Something has gone wrong with the process, because the history of successful vaccine development, including recent vaccines such as against rotavirus and whooping cough (pertussis) unequivocally shows that the immune correlates of protection are very often unknown, both prior to field testing and even after approval for licensure.

"Some vaccines (such as against Lyme disease) have been found to be highly effective in field trials without identifying a human correlate of immunity. And smallpox was eradicated using a vaccine whose exact mode of action and protection was unknown!

"This raises a series of ethical and human rights issues. For the failure to proceed expeditiously with field trials of available AIDS vaccine candidates constitutes unethical practice and violates human rights of Americans.

"The key ethical concept of concern is the duty to help people in need, and the central human rights violations involve the right 'to share in scientific advancement and its benefits', and the rights to non-discrimination and to life.

"The ethical duty to help involves a balance of benefits to another and the risk to self. For example, if you do not know how to swim and you see a person being swept away in a raging river, failure to jump in and try to save the person is not unethical. However, if you are a trained lifeguard and see someone drowning in a calm lake, you have an ethical duty to help.

"The failure to mount field trials of available AIDS vaccine candidates, in a manner consistent with traditional and current good vaccine development practice, violates the duty to help and is patently unethical. Requiring certainty about immune correlates of protection before starting field trials of AIDS vaccine candidates is unethical because it creates an unreasonable barrier to progress.

"To illustrate: the immune correlates of protection against rotavirus, a major cause of death in childhood worldwide, were unclear when field trials of candidate rotavirus vaccines were initiated. Field trials were started once candidate rotavirus vaccines were shown to be safe and to induce some immune responses. In a series of field trials, rotavirus vaccine proved its effectiveness and today, even while the vaccine was recently approved by the FDA advisory committee and recommended for universal childhood immunization by the federal government's Advisory Committee on Immunization Practices, the immune correlates of protection are still unknown. Proceeding to field tests of rotavirus vaccine was highly ethical, while delaying testing until all the scientific answers were available would have been unethical, and detrimental to public health.

"It is unrealistic and illusory to wait for universal consensus within the scientific community about when a vaccine candidate is ready for field trials. There has never been universal consensus about vaccines: to cite just one example, the names of those prominent scientists who declaimed vigorously against polio vaccine testing have been forgotten, while Enders, Salk and Sabin made public health history. The decision about how and when to proceed to field trials, bearing its own burden of responsibility and accountability, is best placed in the hands of those experienced with vaccine development, including its public health dimensions.

"Human rights are also particularly relevant because the US government has invested so heavily and several of its institutions, including NIH, the Department of Defense, CDC and FDA, are involved in AIDS vaccine research and development. In this context, federal governmental failure to proceed to AIDS vaccine field trials, while contributing institutionally and financially to field trials of other vaccines which met essentially similar criteria vaccine development criteria (human safety and immunogenicity without clear knowledge about correlates of immunity) represents a clear violation of the human rights of American citizens.

"This human rights violation is underscored by the fact that the vulnerable population for HIV infection in the United States, the estimated 40,000 new HIV infections in 1998, will occur predominantly in already marginalized populations, thereby exacerbating pre-existing patterns of societal discrimination. It is as if the US government had decided that the AIDS epidemic could be controlled in this country without a vaccine. In contrast, progress towards Lyme vaccine development, to protect against a disease affecting middle and upper- class populations in this country, has proceeded rapidly. Very simply, if 40,000 college students were becoming HIV infected each year, it is obvious that field trials of AIDS vaccine candidates would have long been underway.

"Thus, the failure to proceed to field trials, in the context not of an ideal world but in the real world of successful vaccine development, is unethical and violates human rights. The failure to act, like silence, has moral consequences.

"At an institutional level, this failure stems from decisions and recommendations made by NIH and its AIDS vaccine advisory committee, both of which are headed by notable scientists who nevertheless lack experience with vaccine development and public health. This is not a plea for AIDS as a special case; no special dispensation is required. What is needed is to develop AIDS vaccine candidates according to procedures and mile-stone driven strategies which have produced highly successful vaccines which save millions of lives from diseases like polio, whooping cough and measles. It is unethical and violative of human rights to hold AIDS vaccine development hostage to a requirement for scientific exactitude which is unreasonable and may well be unattainable.

"Science is an instrument of public health. The larger responsibility, central to the moral authority and legitimacy of our government, is protection of the public health. The program for AIDS vaccine must be lifted above institutional defensiveness and parochial interests. The health of America and the world needs leadership - 'can do' American leadership - to develop AIDS vaccines. Failing to proceed is unethical and violates basic human rights."

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