Experts agree: an AIDS vaccine is doable.

In the battle against AIDS, protease inhibitors have held center stage since they were first approved over a year ago. Yet for some, there remains an even better solution to the crisis: a preventive vaccine that stops people from getting infected in the first place.

"The weight of enthusiasm over the past year was treatment and idea that you could potentially eradicate infection," says Julie McElrath, an associate professor of medicine at the University of Washington in Seattle. "That certainly put a vaccine on the back burner. Now that the excitement has peaked, it's clear what the long-term solution is. Everyone is back to saying we've got to get a vaccine."

Despite recent advances in AIDS treatments, the number of people becoming infected with HIV continues its unabated rise, leading scientists and health care advocates to conclude that a preventive vaccine is the way to cut the epidemic off at its knees. "The old adage is true: An ounce of prevention is worth a pound of cure," says Robert Belshe, director of the division of infectious diseases at Saint Louis University's medical school. "We need a vaccine."

Unfortunately, say activists, the need has yet to translate into strong action. While important research and testing is being done by universities and pharmaceutical firms, overall the effort has been disappointingly small.

"There is not enough going on in any sector: not in government or industry or groups that represent affected communities," says David Gold a member of the AIDS-Vaccine Advocacy Coalition, a group promoting the development of a safe and effective vaccine. "We really need a reinvigorated effort."

Surprisingly, most scientists agree that a vaccine is indeed feasible, despite the notoriously complex nature of HIV. "There's a belief that it can be done," says Cladd Stevens, head of epidemiology at the New York Blood Center and lead investigator for HIVNET, a network of domestic and international field sites evaluating prevention efforts, including vaccine research. Still, says Bill Snow, a member of AVAC, "the realistic people say it's going to be a long time" before a vaccine is available.

Although the search for a vaccine began soon after HIV was identified as the cause of AIDS, the few experimental vaccines that have been produced have been confined either to animal testing or to small pools of volunteers. No vaccine has proved promising enough to merit the large-scale testing on thousands of volunteers that researchers call a Phase III trial.

Public apathy is partly responsible for the lack of success, says Chris Collins, an AVAC member and a policy specialist at the Center for AIDS Prevention Studies at the University of California, San Francisco. "People haven't focused too much on HIV vaccines," he says. "They're waiting for a big scientific breakthrough. But the speed at which that scientific breakthrough is accomplished is to some degree determined by public attention, because it affects decisions in both industry and government."

The recent advances in AIDS treatment may be helping to make the task seem less daunting. "Somehow or other the psychology has changed," says Snow. "HIV seems beatable now in a way it didn't before. It's no longer the virus you can't do anything about."

Still, according to a study of industry investment in research released by AVAC in December, "the current HIV vaccine effort is a patchwork of efforts, not the aggressive, well-funded and well-coordinated international strategy that is required." Why? "One reason," says Collins, "is that the science is difficult. Another is that other investment opportunities are more promising."

AVAC members say that their interviews with pharmaceutical-industry scientists indicate that private-sector researchers are looking for government leadership. They hope the appointment of David Baltimore, a Nobel prize-winning microbiologist, as chairman of a National Institutes of Health vaccine committee, will bring more attention to the effort. "Baltimore is a major figure," says Gold. "His appointment is an important step, but it's only a step."

Snow points out that vaccine research "gets the least money" of the areas that the Office of AIDS Research funds. Gold, who is also a consultant on vaccine issues for the American Foundation for AIDS Research, estimates that the entire annual budget, counting federal and private-industry moneys, is at most $150 million. "That's not a whole hell of a lot when you consider that many Hollywood movies spend that much producing and marketing one film," he says.

Yet money alone will not solve the problem. "You can't just take money and throw it at something," says Ellen Blackstone, a health educator at the University of Washington site of the AIDS Vaccine Evaluation Group, an organization conducting clinical tests of experimental vaccine antigens at six university sites. "You need the ideas."

So far, most vaccine research has concentrated on using a genetically engineered version of an HIV protein to try to produce an immune response. Gold contends that the research, while valuable, needs to cast a broader,net in order to find an effective vaccine.

Another approach is a vaccine based on a subunit of the HIV protein. In the past the federal government has determined that two trials using the subunit approach did not merit Phase III study. The advantage of the approach, however, is that it is safe. "We're not challenging people with HIV," Blackstone stresses. A vaccine using a live, if modified, version of HIV could result in HIV infection and possibly AIDS, whereas the vaccine being tested at AVEG sites avoids that danger.

AVEG researchers hope to avoid past failures with subunit vaccines by combining them with another vaccine--for the canary pox virus, which is safe in humans. The vaccine is known as ALVAC-HIV.

"The canary pox vaccine would be a delivery system for genetic material for HIV," says Connie Celum, principal investigator for the University of Washington's HIVNET site, "The hope is that the combination will stimulate both arms of the immune system: an antibody response and a cellular response."

AVEG and HIVNET plan to launch a Phase II trial in April. The trial will not, however, determine whether the vaccine produces resistance to HIV, but only whether it produces a good enough immune response to make a wide-scale trial worthwhile. Within a year scientists will have to decide whether the vaccine is promising enough to warrant a Phase III study. "It's both a scientific and political decision-making process," says Celum. "It will probably be a heated discussion."

One issue concerning scientists is whether any trial in the United States could be big enough to produce the results needed. "The rock-bottom issue is, are infection rates high enough to run a trial?" says Snow. "The only way to have an outcome from a trial is to have two arms, where the outcome in one is higher than in the other." Because infection rates in the general U.S. population are, in mathematical terms, low, the vaccine and a placebo would have to be tested on two huge groups of volunteers for any statistically significant differences to show up between the two groups.

Such an effort would, of course, be costly. "These large-scale clinical trials are very expensive to run," notes Belshe. Moreover, the effort is unlikely to end with just one trial. "Chances are the first vaccine would be only partially effective. Then we would have to run another trial comparing the new vaccine to the, old one. It will be an ongoing process."

Yet as important as an effective vaccine would be, it would probably fall short of the kind of overwhelming success people might expect from it. Researchers believe no vaccine will produce immunity in 100% of those injected with it. Still, an HIV vaccine could fall considerably short of that figure and deserve government approval. "The benchmark for success would be a vaccine with a minimum of 60% efficacy," says McElrath, "because that would obviously produce enough cases of immunity to make it worth marketing."

Belshe points out that even a relatively modest rate of efficacy could have outsize dividends, since fewer infected people could produce an exponential reduction in the risk of contracting HIV among uninfected individuals. "Public health authorities say that with 50% efficacy under certain circumstances, you can reduce new cases of infection by 90%," he says. "It multiplies and over time reduces the number of new cases by a much larger proportion."

Ultimately, a vaccine will probably join the arsenal of AIDS prevention weapons, not replace it. "It's part of a broad picture," says Celum. "The key with transmission is that you have to approach it from different angles. You don't let your guard down about safe sex or do away with needle-exchange programs. You have to look at multiple ways to prevent infections rather than looking for the magic bullet."