AIDS Treatment News #164, December 4, 1992
Dave Gilden

Therapeutic vaccines seek to stimulate immune defenses in persons already infected with HIV, by periodically injecting synthetic HIV proteins. Preliminary trials have found that presenting these molecules in a format that differs from natural HIV infection prompts the immune system to increase the number of antibodies it produces against HIV. Other immune system responses may broaden as well.

Therapeutic vaccines' clinical benefits remain a mystery at this point, however, and the best methods for properly evaluating these treatments are unknown. To settle the question, the panel is proposing a "large simple trial" that will test the vaccines efficiently and relatively rapidly by measuring clinical outcome in tens of thousands of persons.

The NIH panel's original mission was to examine a unique $20 million appropriation in the US Army's AIDS research budget. Congress directed that the money be used specifically for a large phase III trial of gp 160, a therapeutic vaccine which is made by MicroGeneSys of Meriden, Connecticut. Researchers at the Walter Reed Army Institute of Research have been testing the vaccine since 1989.

The MicroGeneSys product is the most extensively investigated of the current crop of 14 candidate therapeutic vaccines. It may not be the most effective, however.

NIH director Healy reportedly was infuriated at the way MicroGeneSys used a high-pressure lobbying campaign to avoid the normal scientific review process. She was able to step in with her panel because the appropriation's language provided that the trial would not go forward should the director of the NIH, the commissioner of the FDA and Secretary of Defense jointly oppose it. The money would then go to other Defense Department AIDS research (which is centered on vaccines and diagnostic tests).

Healy's panel opted for a choice that will require wide- scale community participation. The large simple trial will need up to 30,000 volunteers for a two to four year placebo- controlled comparison of three or more different vaccines.

The proposed trial design has many features that make it attractive. People in all T-helper cell ranges would be included, although the majority would be in the above-500 group. Any interested physician or clinic would be able to enroll clients. Data reporting would be minimal: semiannual reports on adverse reactions and current health status are all that would be required for most volunteers. Finally, there would be no limitation on other medications taken along with the periodic vaccine.

The large simple trial concept parallels most of the points raised in a consensus statement on the congressional appropriation signed by 15 AIDS groups around the country. Many researchers, in contrast, wanted the money to go to series of small preliminary trials.

Despite the placebo received by some in the trial, those with minor to moderate immune impairment may have nothing to lose. There have been some concerns that added free HIV envelope protein is in one way or another immunosuppressive, but the experience at Walter Reed and elsewhere has consistently found no evidence of deleterious effects.

For those with lower T-helper cell counts, the trial becomes more problematic. The one small test of a therapeutic vaccine in people below 400 helper T-cells (which used MicroGeneSys's product) found, not unexpectedly, that immune stimulation decreased as T-helper count went down. This one trial does not prove that people with advanced disease cannot benefit, and their inclusion is being justified on humanitarian grounds. Possibly, though, enrolling in the vaccine trial might make them ineligible for other trials of experimental HIV treatments should they arise.

Another issue is how to incorporate future improved vaccine therapies into the large simple trial. Such additions will extend and complicate the study.

An immediate question is whether the Army will agree to put the original $20 million into a community-based trial. Nothing in the legislation requires the Army to follow the NIH lead, and the kind of trial proposed by the expert panel is quite outside the Army's usual practice.

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