RELATED ITEMS On washingtonpost.com Corporate information on companies seeking an AIDS vaccine: Chiron SmithKline Beecham Merck & Co. On the Web The AIDS Education Global Information System has scientific information about canarypox tests available online. The estimated 1997 budget for the National Institutes of Health is online. The AIDS Vaccine Advocacy Coalition published a December 1996 report on the status of finding a vaccine. A press release from the International Association of Physicians in AIDS Care describes their call for doctors to volunteer as subjects. From the AP Related articles from the Associated Press are available online. Editor's Note: Some of the above links will take you out of The Post's Web site. To return, use the Backbutton on your browser. Go to National Section Go to Home Page

The process has been a study in disappointment, and AIDS vaccine researchers repeatedly have had to lower their expectations. The idea of creating a vaccine that would not only prevent new infections but would also be therapeutic in people already infected with HIV has mostly dropped by the wayside, for example. With the exception of one or two companies banking on the long shot of therapeutic vaccination, everyone trying to develop an AIDS vaccine is now focusing on prevention.

Even the goal of completely preventing HIV infection — what scientists call "sterilizing immunity" — is not considered achievable, at least for now. The current aim is to make a vaccine that can muffle the normally rampant viral multiplication that occurs soon after infection — the "viremia" through which a small platoon of viruses in a few drops of semen or blood blossoms into a florid infection. The hope is that the body will be able to keep the few remaining viruses suppressed, and symptoms at bay, for many years and perhaps indefinitely.

"In the past we maybe inappropriately said we'll judge a vaccine primarily on the basis of being able to prevent infection completely," said NIAID chief Anthony S. Fauci. "Now we're thinking maybe it's enough if you get infection but not disease. Until recently we never considered that."

Increasingly, these more modest goals are coming within reach. Chimpanzees and monkeys inoculated with experimental vaccines and then challenged with big doses of HIV (or SIV, the monkey equivalent of HIV) have in several cases been able to block the initial viremia, with virus levels dropping quickly to near zero — although in some cases infection reappears later, evidence that the virus was simply suppressed for a time.

It would be unethical, of course, to expose human volunteers to HIV deliberately. But in recent tests in volunteers, several different vaccines have elicited responses similar to those seen in animals.

In early human tests of the canarypox vaccine given to Lynch, for example, the bird virus and its Trojan horse cache of HIV genes stimulated a potent blend of both killer T-cells and antibodies. Moreover, researchers found they could boost HIV antibody levels in these volunteers even higher by following up with additional shots of gp120, a laboratory-grown protein identical to one found on the outer envelope of HIV.

In an especially inspiring result reported in May, killer T-cells induced by the canarypox vaccine fought off multiple strains of HIV in test tubes — including strains from Africa and Asia — even though the vaccine is made from genes taken from a single North American strain of HIV. That provided the first solid hope that researchers may not have to develop separate vaccines for each of the eight major known strains of HIV that infect people in different parts of the world.

In June, the NIH gave the nod to try this "prime-boost" approach — modified canarypox followed by gp120 — in a phase II test of 420 people in 14 cities, including St. Louis. If the vaccine still looks safe and stimulates reasonable numbers of antibodies and T-cells in these people, then it may become the first AIDS vaccine ever to be promoted to a full-scale testing to determine its effectiveness.

That trial would be unprecedented in size, scope and significance, involving 5,000 to 10,000 HIV-negative men and women deemed at high risk of getting AIDS, and would go on for several years. Out of such a trial, the world's first marketable AIDS vaccine would emerge.

The canarypox vaccine, made by Pasteur-Merieux/ Connaught, is only the second AIDS vaccine to have made it even to phase II testing in the United States. The other, a genetically engineered version of gp120 given alone, gave mixed results a few years ago that some interpreted as hopeful and others as too equivocal to justify the expense of a phase III study. In June 1994, citing gp120's inability to stimulate T-cells, the failure of gp120 antibodies to neutralize some strains of HIV, and a lack of support from the gay community — where the vaccine would be tested — NIAID director Fauci decided against large-scale testing.

It was a decision that haunts Fauci to this day — not because he thinks it was wrong, but because he will never know whether he was right. Others, like Belshe, are more certain.

"It was the worst decision the NIH ever made in terms of vaccine development," Belshe said. "We knew it was safe. We knew it induced antibodies. I have no idea how well it might have worked, but now we never will know because they pushed a negative decision too fast."

Moreover, Belshe argues, that controversial decision had repercussions beyond gp120 that can still be felt today. "It showed uncertain support from the government. It said to manufacturers, 'We're not going to back this effort.'‚"

Corporate reticence has persisted ever since, according to a December 1996 analysis by the nonprofit AIDS Vaccine Advocacy Coalition (AVAC). "Of the five leading global vaccine manufacturers, only two (Pasteur-Merieux-Connaught and Chiron) have broad-based HIV vaccine programs that are pursuing a number of approaches," the group found.

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.