Trials and tribulations: disappointing results from the first-ever human AIDS vaccine trial leave researchers asking what's next. (AIDS Research).

Three years ago Mark Moreau, a young gay New York actor, saw an ad seeking volunteers for the first full-scale trial of an AIDS vaccine. Two of his close friends had recently tested HIV-positive, and "I just wanted to do something," he says. "I had no idea whether or not this vaccine would work. I needed to take an action."

So Moreau enrolled. The 5,417 volunteers--consisting of more than 5,100 gay men and about 300 women in the United States, Canada, and the Netherlands--were divided into a vaccine group and a placebo group; like other participants, Moreau was never told which group he was in. He was urged regularly not to engage in riskier sexual behavior just because he might have gotten the vaccine. Over three years he received seven injections. At one point, after he had unprotected sex with someone who later acknowledged being HIV-positive, he called the vaccine trial counselors in a panic. "The staff couldn't have been better," he says. "It turned out that I still tested negative."

After the trial ended last year, VaxGen, the company that was testing its vaccine, AIDSVAX, began tabulating and analyzing blood and other tests given volunteers. On February 24 the company announced its main finding: Overall, the vaccine had failed to offer protection against HIV. The percentage of those who received the placebo and became infected was 5.8%, virtually the same as the 5.7% who received the vaccine and became infected.

Moreau, now 30, is convinced the trial was worth doing: Even finding out that something doesn't work, he says, is "one more piece of information." And despite the overall failure, the results of the landmark VaxGen trial spotlighted the accelerating search for an AIDS vaccine. Seth Berkley, president of the International AIDS Vaccine Initiative, a nonprofit group, called the VaxGen news disappointing but added, "We are not discouraged.... Scientists remain confident that an AIDS vaccine is possible. Alternative AIDS vaccines, employing different design strategies, are now in development."

Wayne Koff, IAVI's senior vice president for research and development, echoes other researchers in saying the VaxGen results hadn't altered the vaccine outlook. On the positive side, Koff says government funding of AIDS vaccine research has increased substantially in the United States, even if not as much as he would like. He says some large drug companies, such as Merck, are investing substantial resources in finding a vaccine, and IAVI itself is collaborating on developing one. The stock price of VaxGen, a small Brisbane, Calif.-based biotechnology firm, plummeted after the results were released, which likely will make it harder for that firm to raise private capital, but there was no indication that the results affected efforts at any other drug company.

Still, the obstacles to rapid vaccine development remain substantial. Koff says that after VaxGen releases findings, due by year's end, on a separate trial of its vaccine in Thailand, it will be four to five years before data from another full-scale trial come in. When asked when a proven vaccine might be available, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, replies, "It's impossible to predict. It could be as much as seven to 10 years.... We could be lucky and it could be a little bit shorter, but you just don't know."

VaxGen's experience could influence the vaccine search because of two additional findings, one extremely controversial and the other less publicized but applauded by researchers:

First, in analyzing results among volunteer subgroups, VaxGen reported that AIDSVAX seemed to produce a significant reduction in HIV infection among blacks, Asians, and other non-Hispanic minorities. Some statisticians criticized VaxGen's methods of analysis in reaching that conclusion, and some researchers and activists said the company was making too much of the findings. The AIDS Vaccine Advocacy Coalition, Treatment Action Group, Project Inform, and Gay Men's Health Crisis joined in accusing the company of failing to emphasize that the minority results were based on very small numbers of infections in its limited sample of minority participants. The groups urged that the minority findings "be treated with extreme skepticism until subjected to a detailed, independent scientific evaluation."

VaxGen defended its findings as statistically significant but pledged to continue its analysis and submit results for scrutiny by AIDS experts. Michael Para, an AIDS researcher and a principal investigator in the study, says the greater protection the vaccine offered minorities also appeared to correlate with a higher level of vaccine-induced protective antibodies found in black and Asian volunteers.

Phill Wilson, founding director of the Black AIDS Institute, says that while he also was skeptical about the apparent greater benefit to blacks, "to just dismiss the VaxGen data is a mistake.... Given the disproportionate impact of HIV and AIDS among black people, we should not be cavalier about a study that showed the vaccine might [be effective] among blacks and Asians." Wilson urges increasing recruitment efforts to enroll more blacks in future trials.

Second, and almost overlooked because of the debate, were three encouraging findings. Before the VaxGen trial began, there were fears that not enough volunteers could be recruited, that many would drop out of the three-year test, and that some would engage in riskier sexual behavior than before, thinking they might have vaccine protection. Instead, not only were more than 5,400 volunteers enrolled, but, as Fauci notes, the proportion of people staying in the study was extremely high--90%--and participants did not report changing their sexual behavior in a negative way. VaxGen officials say preliminary analysis indicates that risk behavior was reduced in both the placebo and vaccine groups; spokesman Jim Key says this probably happened because counseling and prevention messages that were provided after every injection were effective.

Chris Collins, executive director of the AIDS Vaccine Advocacy Coalition, does not believe the VaxGen experience changes vaccine economics. Historically, he says, vaccines have not been as good an investment as many other drugs, which is why he maintains that government has such "an extremely important role to play" in supporting AIDS vaccine research in federal labs, university medical centers, and sometimes the private sector. Total federal funding for AIDS vaccine research nearly doubled in the last five years, totaling $371.5 million in 2002, most of it through the National Institutes of Health, according to the coalition. The increased funding, Collins says, has contributed to researchers' progress in learning what may make a vaccine effective. But he worries that "in the face of federal budget deficits ... the NIH won't be able to increase its efforts in this area and for AIDS in general."

The VaxGen vaccine is composed of a form of a protein--gp120--that is on the surface of HIV and helps the virus invade cells; the vaccine aims to stimulate production of antibodies that attach themselves to the protein and block it from infecting cells.

But IAVI's Koff says many researchers are coming to believe that to successfully block HIV, a vaccine may have to do more than what the VaxGen product attempts to do--produce neutralizing antibodies, as vaccines for measles and other diseases do. It also will have to induce a cellular immune response to destroy any cells already infected by HIV, thereby preventing the virus from replicating and infecting other cells. "Common sense tells you it would be advantageous to have both," Koff says. "We just won't know until we begin to get vaccines that are protective in people."

There are at least 24 ongoing AIDS vaccine trials involving 19 different vaccines, according to IAVI. But most trials are in the earliest phase of testing; only VaxGen's AIDSVAX has reached the final level. IAVI says that with more than 14,000 new HIV infections occurring daily worldwide, only an effective vaccine can end the epidemic.

And yet that end remains elusive. "The whole field of vaccinology is characterized by stops and starts, successes and failures," Fauci says. "It's just that we're not at the goal line yet, and that's going to take some time."

Freiberg has also written for the Washington Blade.