A vaccine at what cost.

While some argue that it isn't worth risking human lives for research, other say it's the only way we'll develop a vaccine

A group of human guinea pigs staring down death for a higher good has all the makings of the best drama: altruism overcoming risk and government red tape to arrive at a tremendously happy ending.

So when the International Association of Physicians in AIDS Care announced that hands were going up around the nation in response to its call for volunteers to test a live-virus HIV vaccine, the group captured the imagination of the media. Here were individuals willing to risk their lives in an attempt to end an epidemic. It made for the kind of headlines that stop readers in their tracks: VOLUNTEERS TO GET A DOSE OF HIV.

The media attention "came to my absolute amazement," says Charles Farthing, medical director of the AIDS Healthcare Foundation in Los Angeles and chairman of the Chicago-based IAPAC's vaccine subcommittee. "I was somewhat embarrassed, but it brought the issue to debate."

The risk, however, could be greater than the volunteers imagine. While the vaccine they hope to take is an attenuated, or weakened, version of HIV, some researchers strongly believe it is too dangerous for human use. No matter how well-developed such a vaccine may be, it holds the risk of producing HIV infection, potentially leading to the development of AIDS. "This is just not something I would consider a potential human vaccine, both safe and efficacious," says Ruth Ruprecht, an associate professor at Harvard Medical School and at the DanaFarber Cancer Institute. "The whole thing is a game played with fire."

IAPAC's volunteers--originally a group of 50, although hundreds more have sought to join their ranks since hearing of the vaccine effort--believe the hazards are not as great as critics claim. In any event, they argue, the enormity of the epidemic dwarfs any personal risks. "As an AIDS advocate, I felt we had to step forward and do our part," says Jose Zuniga, deputy director of IAPAC. "Ultimately, what informed my decision was a risk-benefit analysis. If, in fact, we can prove that an attenuated vaccine is safe and effective, that outweighs the minimal risk we're talking about."

Zuniga is no stranger to risk--or to controversy. In 1993, at age 24, he announced at the gay and lesbian march on Washington that he was gay. The public statement was not as unusual as his position at the time: a sergeant who had been chosen the Army's Sixth Division Soldier of the Year and a married man (although he later revealed that his wife was a lesbian). The announcement brought Zuniga an enormous amount of attention from the media as well as from his superiors, who promptly called him in for questioning. Even though he had won several awards as an Army journalist and a Combat Medical Badge for serving as a medic during Operation Desert Storm, he was forced to leave the military.

Zuniga then wrote a book about his experiences, titled Soldier of the Year: The Story of a Gay American Patriot. He returned to journalism, reporting on AIDS, and eventually became communications director for the AIDS Action Council, a national lobbying group based in Washington, D.C. He assumed his job at IAPAC in August. As an openly gay man, Zuniga says, he has come to live under the shadow of HIV. "Not to generalize, but we're conditioned to think that we're always at risk for HIV," he says. "I know that anytime I've gone for an HIV test, I always worry, even if I know I don't engage in unsafe sexual behavior or inject drugs."

Most of the volunteers are medical professionals--and presumably more informed than the average layperson about the risks they're taking, therefore drastically reducing liability concerns. For Helen Miramontes, an associate clinical professor at the school of nursing at the University of California San Francisco, and a member of the Presidential Advisory Council on HIV/AIDS, the reasons for participating are both professional and personal. "I am well aware of the dangers of a live attenuated vaccine, but I felt it was right for me because this is something I've been pushing for a long time." Miramontes has two gay sons, one of whom has AIDS.

"This is a difficult one, because there is a risk involved," says Farthing, who is himself a volunteer in the study. "But I see nothing wrong with it morally, especially when you look at the thousands being infected every day. The 5% or 1% or 0.1% risk to a few trial participants is surely justified if there is the high likelihood that a vaccine comes out of it."

In fact, Farthing says, recent advances in HIV treatment have produced optimal conditions for a trial. "Now is a better time to do a safety trial in human beings because five years ago we were unable to control this disease," he says. "Now we can in the vast majority of people. I don't see it as risking my life. The biggest risk I'm taking is having to take the drugs my patients take."

It will be a long time before Farthing, Zuniga, and other volunteers have a chance to take the vaccine, however. Indeed, they may never have the chance at all. The vaccine has to be cleared by the federal Food and Drug Administration, which must be satisfied that the vaccine is reasonably safe. This process means a trial is at least two years away. If the FDA rejects the vaccine, IAPAC is willing to consider basing the trial in another country as "a last-resort option," Zuniga says.

Miramontes says such a move would do more harm than good: "I know that some people say they will do it if the FDA does not approve the vaccine, but I think that might hurt us. I want people to focus on the vaccine."

IAPAC's initiative has brought attention to the vaccine effort because it finally gives it a human face. Even critics of the project concede that the debate it has engendered has been beneficial. "The need for a safe HIV vaccine has been put back on the agenda, even though the type of vaccine they are advocating is not one I think is fit for human use," says Ruprecht. "That has been a positive outcome."

The volunteer effort is the most recent and perhaps most successful attempt to rekindle interest in an HIV vaccine. Last May, President Clinton urged scientists to produce a vaccine within the next decade (although he provided no additional federal funding for vaccine research). The month before, the president's advisory council on HIV/AIDS announced that a vaccine "is clearly feasible and should be considered the highest priority of our government."

As much as everyone involved in HIV vaccine research seems to welcome the attention, it only underscores how neglected the topic has been. "Why does it take this kind of human-interest hook to get people interested in what they should have been talking about for a while?" says Seth Berkley, president of the International AIDS Vaccine Initiative, a New York City-based group advocating vaccine development.

Some scientists complain privately that IAPAC's initiative is more public relations grandstanding than scientific effort. For the initiative's supporters, however, each day that passes without a vaccine means that thousands more people around the world become infected.

"If AIDS has shown us anything, it has shown us that the orthodox way of doing research has gone out the window when you consider that delays in research or putting out drugs translates into lost lives," says Zuniga. "When you look at the way activists both in the streets and behind the scenes pushed for accelerated drug approval, there is no feeling that that was grandstanding or a publicity stunt." If anything, Zuniga argues, the lack of progress toward a vaccine shows a fresh approach is necessary: "This disease requires bold steps. It requires new ways of trying to work within and outside the system."

While the IAPAC initiative has focused attention on a live-virus vaccine--that is, a vaccine that uses a version of HIV with some genetic elements of the virus deleted so as to weaken it--research using other types of vaccines has been going on for years. On October 16, St. Jude Children's Research Hospital in Memphis, Tenn., announced that it had received permission to begin trials on human volunteers of a vaccine that uses the genetic "envelope" that surrounds HIV. Although most scientists believe the research to date has been worthwhile, they also believe the vaccine effort in general has been somewhat desultory and unfocused.

"When you look at the vaccine effort, it's fragmented," says Miramontes. "There isn't a comprehensive plan. We haven't put the kind of energy and resources, including human resources, that we need to put into it."

Indeed, other countries seem to be pushing harder. At an international AIDS congress held October 27 in the Philippines, medical experts announced that the first large-scale vaccine trial will likely occur in Thailand, perhaps as early as 2000. "We could not wait for the Western countries to do this for us," Thai virologist Prasert Thongcharoen told Reuters. "The problem in the West is less and less, but not in our country, not in Asia."

"There's not a push," agrees Berkley. "There's no one screaming for it. The big story is, we're 17 years into the epidemic, and we have not yet tested a single vaccine for efficacy. "

Most researchers have used a genetically altered version of an HIV protein--or a subunit of the HIV protein combined with the canary pox virus--to produce an immune response. Those vaccines have been tested on a small pool of volunteers, although no vaccine has been deemed worthy of wide-scale testing. Because these vaccines use only portions of an HIV protein and not a version of the virus itself, they are incapable of infecting a volunteer with HIV. Such is not the case with a live-virus vaccine.

The vaccine IAPAC wants to use is the result of work done on monkeys by Ronald Desrosiers, chairman of the microbiology division at the New England Regional Primate Research Center in Southborough, Mass. His research has led him to argue that a weakened form of simian immunodeficiency virus, a cousin of HIV that infects monkeys and other apes, can protect the animals from subsequent exposure to the virus. Desrosiers declined to be interviewed for this story. In a statement provided to the media, he praised the "high sense of altruism" motivating the volunteers.

Other scientists have had worrisome results with similar experiments on monkeys. According to Science magazine, at least four separate researchers have seen results ranging from immunesystem damage to deem in some of the monkeys inoculated with weakened versions of SIV. (Also, Desrosiers has had two of 45 monkeys to whom he has given some form of weakened SIV develop high levels of the virus in their blood.) The experiments did not show whether SIV caused disease in its weakened form or mutated to become virulent. Still, the fact that some of me monkeys became ill raises concerns about a human trial, many scientists argue.

"The trials are causing AIDS in adult animals and killing newborns," says Ruprecht. "When you see a 50% incidence of AIDS, that's certainly cause for worry." Among the prominent AIDS scientists who deem the live-virus vaccine too risky for humans are Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and Robert Gallo, codiscoverer of HIV.

Some scientists believe the initiative is simply moving too fast. "I'm not 100% opposed to it, but I am scared that everyone will jump on the bandwagon," says Bijan Etemad-Moghadam, an openly gay postdoctoral fellow at the Dana-Farber Cancer Institute who is studying vaccines in monkeys.

Arthur Ammann, president of the American Foundation for AIDS Research, says the IAPAC initiative has "called attention to the epidemic more, and I think it's had a good impact. But I still think it's premature. I know the animal studies very well. Many of the animals have gotten progressive disease and have been infected. We have to learn a lot more about attenuation before we go on to human volunteers."

Farthing argues that a live attenuated vaccine is me only one that can succeed against HIV. "Everything else in animal models has been dismal," he says, adding that the differences between HIV and SIV are significant enough to make the live attenuated HIV vaccine fairly safe.

Ruprecht, however, argues that scientists have yet to strike the balance necessary for a successful live-virus vaccine. "The rationale is to weaken the ability of the virus to replicate just enough so that it won't cause AIDS but sufficient enough to provide protection," she says. But Ruprecht says scientists have yet to find the "command I center,' in the virus that leads to the development of the disease and therefore are uncertain whether the virus is being weakened where it needs to be. Her own research, she says, has made her "very pessimistic that this approach will ever work."

No vaccine is completely risk-free. Farthing notes that the polio vaccine, one of the triumphs of 20th-century medicine, causes polio in about one out of every million people who take it. Ammann says that, as an immunologist, he has cared for some people who developed paralytic polio from the vaccine. "It's not inconsequential," he says. Among the other questions a live-virus vaccine raises are whether the weakened strain may change to a disease causing one over time and whether even the weakened strain could trigger illness as the strength of the immune system diminishes with age.

Etemad-Moghadam is concerned that the fatalism about HIV that marks the lives of many gay men may lead them to discount the risks from the vaccine. "I know a lot of people close to me who say that maybe it's not a bad idea," he says. "If a certain percentage get infected from the vaccine, a certain percentage will get infected anyway, because it's just a matter of time." He is also worried that gay men may become less careful about practicing safer sex if they believe a vaccine is close to reality.

"Fear should not be the ultimate factor in whether to move forward on a clinical trial," Zuniga says. Fear could affect vaccine production, however. Without a change in liability law, a pharmaceutical company producing a vaccine with even a very low risk of side effects could face multimillion-dollar lawsuits. Money is also the reason most companies have shied away from vaccine research to begin with. "You could as a company put in $100 million and come out with zero," Berkley says. "If I were a company, I wouldn't do it."

In an interview in IAVI's newsletter "IAVI Report," David Baltimore, head of AIDS vaccine research at the National Institutes of Health, said, "I cannot say that I am satisfied with the level of investment in the private sector. We may need to provide some incentives for companies to insure that multiple approaches are being pursued."

What is important, says Berkley, is that vaccine research get moving. "Could we have had a vaccine five years ago?" he asks. "Probably. But we're never going to get it by sitting around." The problem, he says, is "the shortage in political will and the willingness to take risks." While the live attenuated vaccine may not be the answer, another vaccine could be.

Unless the status quo changes, however, we will never know. "At the end of the day, the only bad vaccine is the one from which you don't get information," says Berkley. "You test it, and based on what you find, you go back to the lab, take what you ream, develop a new candidate, and test it again. If we don't test it in humans, we're never going to get there."

Zuniga hopes that perhaps at last people will begin to consider an AIDS vaccine a moral imperative. "What I find surprising is having to convince people who thought outside the box earlier in the epidemic about the need to fight aggressively for a vaccine," he says. "I honestly feel that if we killed off the concept of a live attenuated vaccine and it turns out to succeed, how could we live with the idea that our failure may have resulted in so many lost lives?"

Zuniga is gambling that the vaccine will succeed. Otherwise the lost lives could include his own.

RELATED ARTICLE: Rolling up their sleeves

For these vaccine volunteers, the risk of contracting HIV is eclipsed by the potential for a breakthrough

Helen Miramontes Age: 66 Family: six children, ten grandchildren Residence: Daly City, Calif. Occupation: associate clinical professor, school of nursing, University of California, San Francisco Reason for volunteering: "I decided to do it because I have been doing AIDS work for 14 years, mostly training providers and doing prevention work. Two of my six children are gay, and I have a son who has AIDS."

Charles Farthing Age: 44 Family: partner, mother, brother Residence: Los Angeles Occupation: physician; medical director, AIDS Healthcare Foundation Reason for volunteering: "I started working on AIDS in the United Kingdom at the beginning of the epidemic. When the gay community was not taking AIDS seriously at all, I was on television saying, `This is how this disease got transmitted.' To me, if something should be done, all hurdles can be overcome. It's the morally right thing to do."

Sara Unruh Age: 54 Family: three daughters, one grandson Residence: Casper, Wyo. Occupation: AIDS educator, Wyoming AIDS Education and Training Center Reason for volunteering: "I've lost a huge number of people I have really loved. The first time it hit me between the eyes was in 1983 at a conference. My best friend in Nebraska was the mother of three sons with hemophilia and realized she was going to lose her kids. All three kids are dead now."

Jose Zuniga Age: 28 Family: partner, father, sister Residence: Chicago Occupation: deputy director, International Association of Physicians in AIDS Care Reason for volunteering: "As gay men we're conditioned to think we're always at risk for HIV. I know that anytime I've gone for an HIV test, I always worry, even if I know I didn't engage in unsafe sexual behavior or inject drugs."