AIDS vaccines: the problems of human testing.

AIDS Vaccines: The Problems of Human Testing

When researchers met at the NationalInstitutes of Health (NIH) in March to discuss the progress and problems of developing an AIDS vaccine, they had a walking experiment in their midst. One of the workshop participants, the University of Paris researcher Daniel Zagury, had been the first human to inject himself with a candidate AIDS vaccine, along with several other volunteers in Zaire (SN: 3/18/87, p. 198).

It's unlikely that Zagury and his fellowvolunteers will remain the world's only human test subjects of AIDS vaccines for very long. In the United States, for example, the Food and Drug Administration expects to approve the initial phase of human trials for some test vaccines this year (SN: 4/4/87, p.213). If all goes smoothly, thousands of people may eventually be involved in AIDS vaccine testing.

But while vaccine research is movinginto the human arena, there are still serious scientific challenges in the way of developing a safe and effective vaccine against the human immunodeficiency virus (HIV), which causes the disease (SN: 5/9/87, p.297). And even if these challenges are met, it could be at least eight to 20 years before a vaccine is available to the public, according to Assistant Secretary for Health Robert E. Windom, who addressed the NIH workshop in Bethesda, Md.

Until then--and for that matter, longafter--scientists and society will be faced with some equally serious ethical, legal and logistical questions, including:

Who should be the first U.S. testsubjects? How many people will be required and how long will the studies take?

Should vaccine developers have toshow that an inoculated animal is protected against AIDS infection before the vaccine is tried in humans?

Will false hopes be raised by theprospect of a vaccine, leading people to be less careful about avoiding exposure to the AIDS virus?

How will scientists balance theirresponsibility to teach test subjects how to avoid becoming infected by the virus with their desire to do rigorous efficacy tests, which, on scientific grounds, would require that subjects be exposed to the virus?

If and when an AIDS vaccine isdeveloped, will U.S. manufacturers be able to wrestle with the long-standing liability problem of distributing vaccines to a litigious public?

"We must develop ethical and legalanswers that are as sophisticated as the science that develops the vaccine itself,' stressed NIH's Charles McCarthy at the recent workshop, which was convened in part to anticipate and address these concerns.

Participants at the workshop did notcome to a consensus on the detailed logistical design of the three phases of human trials that are required in the United States. But the general feeling was that each Phase I trial--in which a candidate vaccine's safety and ability to invoke an immune response is tested-- would involve fewer than 20 volunteers who are not homosexual men, intravenous drug users or other people thought to be at high risk of encountering the virus. In Phase II, anywhere from 40 to 200 people from both high- and low-risk groups might be studied to determine dosage and timing between doses. And in the final stage, Phase III, the efficacy of a vaccine would be evaluated.

AIDS "brings us to a new era of testingvaccine efficacy,' David T. Karzon of Vanderbilt University in Nashville told the workshop. He and others predict that clinical trials of AIDS vaccines will be very costly and lengthy. They also anticipate that Phase III studies would need to involve an extraordinarily large number of subjects in order to yield meaningful statistics, because it can take more than five years for a person infected with HIV to develop clinical signs of the disease.

In contrast, "essentially all the vaccinesthat have been developed before have dealt with diseases that were acute and had some way of expressing themselves as a disease in a reasonably short period of time,' says June Osborn, dean of the School of Public Health at the University of Michigan in Ann Arbor.

HIV's long incubation period is onereason why some researchers think it's essential to develop a vaccine that blocks infection by the virus, rather than arresting the virus at a later stage. But because HIV can enter the body in a latent form hidden inside cells, some researchers question whether this will be possible. If it is not, scientists may try to develop a vaccine that prevents postinfection disease, or at the very least, blocks the transmission of the disease from one person to another. But no one yet knows if even these are realistic goals.

Almost all researchers think it is crucialthat vaccine trials be carefully controlled with the use of placebos. Many also believe the trials for some types of AIDS vaccines may have to be controlled with the use of other vaccines against other diseases. This is important because scientists will need to know which immune responses are due to an AIDS vaccine, which are part of the immune system's natural variability and which might result from vaccination in general.

Osborn and others also argue thatthere is a need for long-term follow-up studies to ensure that there are no unexpected adverse side effects. Many workshop participants noted, however, that it would probably be impossible to continue long-term studies with placebos: If a vaccine were shown to be at all beneficial, every study participant would want to ensure that he or she received a vaccine and not a placebo, and scientists could not ethically withhold a vaccine from anyone in the study.

McCarthy warns that the demand for avaccine in that case would be many times greater than that for azidothymidine (AZT), a drug that appears to prolong the lives of some AIDS victims. When some benefit had been shown for AZT, placebo-controlled trials of the drug were halted just seven months after they had begun (SN: 9/27/86, p.196.)

AIDS vaccine researchers are concernedabout many other issues, including how and when testing in children might be conducted, how vaccines developed in the United States would be tested or distributed in other countries and the need to give trial participants a certificate assuring insurance companies and employers that their HIV antibodies are due to a vaccine and not to exposure to the virus. They also worry about how they could anticipate what kinds of tests should be performed on trial participants before they fully understand the workings of the AIDS virus and the immune responses necessary to defeat HIV. And they debate what should be expected from animal studies and at what point in human studies the results from animal work should be required (see box).

One ethical dilemma voiced by many atthe workshop is the problem of wanting to balance the welfare of the test volunteers against the need for scientifically sound trials. "What will make this the hardest vaccine trial in history,' says Osborn, ". . . is that as soon as you've established an investigator-investigatee relationship, you're honor bound to use that relationship to maximize the safety of the participant, and that means teaching them how not to come into any contact with the virus.' But if trial participants avoid exposure to HIV, the vaccine will not be given a good run for the money.

This is a much greater problem forAIDS trials than for the past development of vaccines against other pathogens, for two reasons. First, AIDS is much deadlier than most other viral diseases, and exposure to HIV carries greater risk. Second, most pathogens for which vaccines exist are transmitted through casual contact, so preventive education played a lesser role.

"This is a nightmare for vaccine trials,'Osborn says, "because you have a strong ethical obligation to take the very best test subjects and turn them into the very worst.'

Assume, however, that an AIDS vaccineis developed, its trials go well and there is still a market for it when it is finally developed. Would manufacturers be able to obtain liability insurance so that they could produce and distribute an AIDS vaccine without great financial risk?

Because of the unusually complicatednature of the AIDS virus, the urgency to develop a vaccine against it and the potential for a vaccine's unforeseen side effects, it's likely that the development of an AIDS vaccine will bring to a head long-standing legal problems associated with distributing vaccines in this country-- especially since plaintiffs injured by vaccines have been increasingly successful in suing companies for damages. As Richard M. Cooper, an attorney at Williams & Connolly in Washington, D.C., noted at the NIH workshop, "there is no vaccine that confers legal immunity.'

A poignant example is the swine fluvaccine. In 1976, an increasing litigious judicial atmosphere, compounded by a trend in the courts holding manufacturers responsible for warning patients of all foreseeable risks, caused the insurance industry to refuse coverage of the swine flu vaccine. Without insurance, the manufacturers would not release their vaccine. Following an outbreak of swine flu, Congress then stepped in with $135 million to purchase the vaccine, and after considerable haggling with insurers, the U.S. government ended up assuming all liability. According to NIH's McCarthy, $4 billion in liability claims have been brought against the government for injuries and deaths caused by the vaccine.

"Although congressional leaders saidat the time that the swine flu case would not be a precedent for future mass immunization programs,' Cooper told the audience, "it may nevertheless be a relevant precedent for an AIDS vaccine.'

Osborn warns that AIDS, with its longincubation period, "will make the swine flu look like a picnic.' Scientists don't know the cause of most neurological diseases, she says, so if anything goes wrong neurologically during that time in people who have been vaccinated, it will be blamed on the vaccine. "I'm not speculating,' she says. "Manufacturers will be sued to the teeth by the time they've had two years' worth of trials. . . . Whether [neurological diseases] are causally related or not, it won't matter because when the smoke has cleared, there'll be so much wreckage, it will be a trivial question.'

What Osborn, who has been avaccine adviser to the Food and Drug Administration for the last 15 years, and others would like to see established is a national vaccine liability program. "We're the only country in the industrialized world that does not have a national solution to the vaccine liability problem,' she says. This is the reason why each vaccine now in use in the United States is made by only one manufacturer, she adds.

"Even with the AIDS monster staringstraight at them,' Osborn says, the Reagan administration has opposed national vaccine liability legislation. So far, the only vaccine legislation approved by Congress is the National Childhood Vaccine Injury Act, which passed last November as part of the Omnibus Health Legislation. This act creates a no-fault compensation scheme for children who suffer injuries from mandatory childhood vaccines, as an alternative to conventional litigation. Cooper says that Congress must enact a special tax on vaccines for this scheme to become operational. The administration opposes both the program and the tax.

According to Mona Sarfaty, associatehealth staff director for Sen. Edward M. Kennedy (D-Mass.), the potential liability problems of an AIDS vaccine were discussed at a recent hearing on AIDS and senate staff members are now "exploring' the possibility of proposing liability legislation for AIDS.

Perhaps the most progressive governmentaction taken so far to reduce the liability risks involved in developing and distributing an AIDS vaccine is legislation enacted in California last year. According to Cooper, this legislation protects the manufacturer of an FDA-approved AIDS vaccine from some, but not all, kinds of liability and establishes a compensation fund for AIDS vaccine victims (financed by a surcharge on the sale of these vaccines in California) to cover those cases in which a manufacturer is not held liable. "The statute also creates a program to provide grants for research on an AIDS vaccine, and a guarantee by the State of California to purchase 500,000 units of an FDA-approved AIDS vaccine,' Cooper told the workshop.

Beyond the liability problems andother concerns, Osborn worries about the impact the well-publicized AIDS-vaccine efforts themselves may have on the behavior of the public. "I can't for a minute argue that this research shouldn't go forward as fast as possible,' she says. "And I think there are situations in other countries where straightforward preventive activities [are less viable and a vaccine would be even more urgently needed].' But in the United States, she says, we have an important opportunity to educate people to avoid becoming infected with the virus.

Echoes Maurice Hilleman of MerckSharp & Dohme Research Laboratories in West Point, Pa., "I think it will be a couple of years before we have much of a fix on whether a vaccine is feasible or not.' But the spread of AIDS could be stopped tomorrow, he says, if certain sexual practices and intravenous drug use were halted.

Osborn argues that when some peoplehear there is a vaccine on the horizon, they become more careless in their behavior. "I get very frustrated because we can get thousands of people to pay lots of attenion to discussions of vaccines, but we can't get anybody at the federal level to talk about direct preventive education,' she says.

"We must not work under the assumptionthat our responsibility is to develop a vaccine at all costs, whether it's a good idea or not,' she told her colleagues at the close of the NIH workshop. "Our [foremost] public health responsibility is to bring the epidemic under control.'