Advances Inject Hope Into Quest for Vaccine

Two other global companies (SmithKline Beecham and Wyeth Lederle) have no significant AIDS vaccine effort, while the remaining large company (Merck & Co.), and several smaller biotech companies, are focused on a single approach each -- meaning that if a company's particular idea fails, then that company's participation in AIDS vaccine research will abruptly end.

Why aren't companies battling to dominate the potentially huge AIDS vaccine market? AVAC found that corporate officers were intimidated by the scientific difficulty of the task and were concerned about potential liability. A recent analysis by the Washington-based International AIDS Vaccine Initiative confirmed a "low level of commitment from private industry," and blamed it in part on corporate fears that the vaccine would not prove profitable since it would be marketed mostly in developing countries.

A lack of coordination in the government's own basic research program has also slowed progress, according to a March 1996 report commissioned by the NIH. In response to that report, NIH chief Harold E. Varmus set up an AIDS Vaccine Research Committee, headed by Nobel laureate David Baltimore, to help coordinate the government's support of basic AIDS vaccine research.

NIH's budget for HIV vaccine research is scheduled to increase next year to about $ 117 million, or 17 percent of the total NIAID budget. That's up from 11 percent this year but still lags significantly behind the proportions going to basic AIDS research (23 percent) and AIDS therapies (45 percent).

Most of this attention will be focused on three types of vaccines: genetically engineered proteins and peptides such as gp120, live virus vaccines such as the canarypox formulation, and "naked DNA" vaccines made from raw pieces of HIV genetic material that mimic a real HIV infection. A fourth approach -- more radical and controversial than any other -- could also start to get renewed attention: vaccination with a strain of weakened but living HIV itself.

The prospect of injecting healthy HIV-negative people with live AIDS viruses is seen by many people as irrational and unethical, since even weakened viruses can turn deadly. In two recent experiments, monkeys inoculated with a weakened version of SIV quickly came down with an AIDS-like disease, apparently as a result of the vaccine itself.

Moreover, HIV belongs to a family of viruses known for their ability to cause cancer many years or even decades after infection. "How long are you going to wait before you determine that a live HIV vaccine is safe?" asked Robert C. Gallo, chief of the Institute of Human Virology in Baltimore and co-discoverer of HIV. "What if you wait 10 years, and then after 20 or 30 years you find out it causes leukemia?"

Yet proponents of a "live attenuated" HIV vaccine note that the most effective viral vaccines today -- including those directed at smallpox, yellow fever, measles, mumps and rubella -- are made from weakened viruses. And despite some failures, animal studies of live attenuated AIDS vaccines have mostly been extremely encouraging.

Human trials have also been done, through accidents of nature. In Australia, scientists have been studying about a dozen men who became infected with a strain of HIV that naturally lacks a gene called nef, which normally helps the virus replicate. These men have remained healthy since becoming infected many years ago, even though at least one of them has apparently had multiple exposures to virulent strains of HIV since then.

Recently, Ronald DesRosiers of the New England Regional Primate Research Center in Southborough, Mass., created a version of HIV that lacks not only the nef gene but also three other chunks of HIV DNA, as an added safety margin. Now scientists are starting to ask whether the time is right to test this vaccine in people -- and if so, who should be the first to accept such a potentially dangerous mission?

Last month, in a bold move, the Chicago-based International Association of Physicians in AIDS Care called for doctors to volunteer as test subjects for a proposed trial of the DesRosiers vaccine to start by the year 2000. "It is time to follow in the tradition of Louis Pasteur, Walter Reed, and hundreds of our other colleagues who made the commitment to be the first human subjects in critical clinical trials," wrote Charles F. Farthing, a member of the 5,500-member organization. More than 25 volunteers signed up in the first two weeks.

But even if testing of a live HIV vaccine someday passes muster with regulators, it will be well into the next millennium before it progresses to efficacy testing, experts said. By contrast, a decision to conduct wide-scale testing of the canarypox vaccine could come as early as a year from now, when data from the current studies come together.

Then, as in 1994, Fauci will face the unenviable task of weighing the many risks and potential benefits of injecting thousands of people with the experimental product. He and his advisers will have far more information about AIDS and immunology than they had three years ago and will face a much more receptive audience of potential volunteers. They will also feel the heat of Clinton's call for progress, and the weight of the world's growing need for a vaccine.

At the same time, Fauci will be burdened by many of the same unknowns that plagued him in 1994 -- questions about safety and efficacy that can never be fully answered without going forward, and uncertainties about whether it is wiser to wait for the next best product or to move ahead with what is in hand.

For Fauci, who has devoted so much of his professional life to battling AIDS, and for the millions of people in the world who today walk the precipice between health and infection with HIV, it may be the most important decision he ever makes.

"You hope the data will be so strong that it becomes a no-brainer," Fauci said. But he's been in the trenches long enough to know that nothing about HIV is that simple. "You hope it will be a slam dunk, but it's unlikely that will be the case."