American Foundation for AIDS Research, May 2003
David Gilden, with research by Gretchen Schmelz

AIDS fighters' fondest hope has been that an HIV vaccine will simply and neatly do away with the epidemic, rendering moot all the political and personal barriers to traditional AIDS prevention. They have awaited the results of the first large-scale vaccine efficacy trial with increasing anticipation since the International AIDS Conference last July. At the conference, VaxGen, the vaccine's developer, announced that its vaccine could be on the market within three years.

The hopes for VaxGen's AIDSVAX vaccine became more desperate this winter after an early version of the promising Merck HIV vaccine was the subject of a negative report at the 10th Retrovirus Conference. Monkeys who received the Merck vaccine were unable to withstand a challenge infection with an HIV-like virus. They first contracted low-level, sub-acute infections but later sickened and died.

The Merck vaccine triggers immune cells to kill HIV-infected cells, but AIDSVAX provokes the production of antibodies to block free-floating HIV. These antibodies may be critical in protecting against initial infection.

Finding a successful antibody-based vaccine faces sizable obstacles because HIV rapidly mutates to protect itself from antibody attack. AIDSVAX is based on only two strains of HIV. More could be added to protect against escape variants, but chasing HIV in this manner threatens to be a Sisyphean task.

Twisting the Data their Way
VaxGen announced its results at a press conference on Monday, February 24. But the twist that the company gave the data left vaccine development as muddled as ever.

Overall, the vaccine seemed to have no protective effect on 5,000 volunteers recruited because of their high risk for acquiring HIV. About 5.7% of the enrollees in both the vaccine and placebo cohorts became infected with HIV in the course of three years follow-up. "Everyone is very disappointed that we did not see any overall efficacy of the vaccine," said Susan Buchbinder, an AIDSVAX investigator who enrolled 150 volunteers at the San Francisco Department of Public Health.

Some 95% of the study volunteers were gay men, most of them white. But a breakdown by race found a surprising difference: Of the 203 blacks who received the vaccine, four (2.0%) became infected compared with 9 of 111 (8.1%) in the placebo group. VaxGen hailed the calculated 78% protection. "This is the first time we have specific numbers to suggest that a vaccine has prevented HIV infection in humans," said Phillip Berman, VaxGen's Senior Vice President of Research and Development.

But the more analyses you do, the greater your probability of finding a positive response somewhere. Buchbinder noted, "If indeed the vaccine is efficacious in African-Americans, that would be fantastic. But the study was not designed specifically to get an efficacy answer in different racial groups, and it is possible that the result, while statistically significant, is not ‘real.' So it is possible that other factors, like trial site, behavior, age, or gender could explain differences between African-Americans receiving vaccine versus placebo."

Most of the apparent benefit occurred because four black Chicago women in the placebo arm acquired HIV. Another odd aspect is that the placebo and vaccine arms were quite close together until the final months of the trial, when several placebo recipients became infected. Chance variations in safe sex or HIV strain could explain these results.

What a Wonderful Study It Would Be
VaxGen is promising further analyses to prove that some difference in immune response – such as level and type of anti-HIV antibodies – underlies the observed differences in vaccine efficacy. There are no established standards for correlating vaccine protection with antibodies. Persons who produce higher or more potent antibodies after the vaccine might well have been more immune to HIV even before the vaccine. One obvious fact is that African-Americans are not less susceptible to HIV than Americans of European origin. Why then should they respond better to an HIV vaccine?

The company's emphasis on its very limited dataset from a small nonwhite subgroup is meant to keep its hopes alive (as well as its stock price, which nevertheless fell by over 50% after the trial announcement). VaxGen is playing on the desperate hopes of African-Americans and Africans, too.

A solid demonstration that AIDSVAX works only in persons of African or African-American descent – or in women –would have required enrolling thousands of such persons. At best, the current trial demonstrates how the lack of HIV research in disadvantaged groups leads to confusion. The worst is that over 5,000 high-risk volunteers are now ineligible for vaccine studies with more hope for success.

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