The first expanded Phase II clinical trial of experimental vaccines to prevent HIV disease has begun in Seattle, Baltimore, St. Louis, Nashville and Rochester through the network of AIDS vaccine evaluation units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).
The vaccine trial will employ two genetically engineered products based on gp120, one of HIV's envelope proteins. The goal is to gather extensive information about the safety and immune-stimulating ability of each preparation by testing both in a large and diverse population of uninfected people. An important aspect of the investigation will be to determine if host factors specific to different populations influence how the volunteers respond to each experimental vaccine.
We are pleased that progress in HIV vaccine research allows us to move these products into the first Phase II trial of prophylactic candidate HIV vaccines," says NIAID director Anthony S. Fauci, M.D. "Because the trial seeks participation from a broad spectrum of uninfected people, we need the full support of all segments of the community affected by AIDS. We anticipate that this trial will generate valuable data for planning large-scale efficacy trials for those populations that will derive the greatest benefit from effective vaccines to prevent HIV infection."
NIAID will continue to work with the manufacturers of these and other products to identify the best candidate vaccines for such large-scale efficacy trials as modified formulations and other vaccine preparations become available.
Ideally, a preventive vaccine will stimulate binding antibodies, neutralizing antibodies and/or cellular immune responses of sufficient intensity, duration and breadth to prevent the virus from causing disease," explains Daniel Hoth, M.D., director of NIAID's Division of AIDS (DAIDS).
The breadth of the immune response is believed to be particularly important to ensure that the vaccine will effectively counter a variety of HIV strains," comments Dr. Hoth. Many HIV strains exist, individuals can become infected by more than one strain and any strain that infects an individual usually mutates over time. Both candidate vaccines have caused no serious adverse effects in small phase I clinical trials in humans and have shown promising evidence that they induce antibodies that can neutralize several different HIV strains.
The gp120 proteins in the trial vaccines were genetically engineered from two of the most common HIV strains circulating in the United States today. Recombinant gp120 (rgp120), made by Genentech of South San Francisco, uses the HIV-1 MN strain; rgp120 made by Biocene of Emeryville, CA, uses the closely related HIV-1 sf-2 strain. Biocene is a joint venture of Chiron and CIBA-GEIGY.
Both candidate vaccines are made in mammalian cells, ensuring that their three-dimensional structures closely resemble that of native gp120, an attribute thought to be important for stimulating better immunity. Because they are made from a subunit of the virus and are not produced from live HIV or an infected human cell line, neither preparation can cause HIV infection in any trial volunteer.
The two candidate vaccines also are formulated with adjuvants, substances that boost specific immune responses to the vaccine. The Genentech product is made with alum, the only adjuvant currently used in human vaccines licensed by the Food and Drug Administration. The Biocene product uses an experimental adjuvant, MF59, that has proved safe and promising in Phase I human trials.
The Phase II study has as its goal to recruit 330 men and women ages 18 to 60 years old who test negative for HIV infection by the standard HIV ELISA antibody test. Because initial trials showed both candidate vaccines to be safe, the criteria for enrollment will be less restrictive than for the earlier trials in order to recruit a diverse group of uninfected volunteers. Minorities and people representing several different populations hardest hit by the epidemic will especially be encouraged to enroll. The more extensive information collected from this and other Phase II trials of preventive HIV vaccines will help NIAID and others design Phase III trials of vaccine efficacy.
All participants will be counseled to avoid behavior that puts them at high risk for acquiring HIV. Anyone who becomes infected naturally during the trial will be carefully examined and will be given the option of switching to a separate study where the course of their disease will be monitored closely.
Trial volunteers will be randomly assigned to receive one of the candidate vaccines or one of the adjuvants, the latter to serve as placebos. Neither the investigators nor the patients will know what preparation is used. All participants will receive an initial inoculation into the muscle and booster injections one and six months later.
Patricia Fast, M.D., and Nzeera Ketter, M.D., both of DAIDS vaccine research and development branch, are coordinating the trial with the study co-chairs, Lawrence Corey, M.D., and Julie McElrath, M.D., both of the University of Washington.
For more information on the trial or how to enroll, call the AIDS clinical trials hotline, 1-800-TRIALS-A, or contact the individual units at the telephone numbers below.