HUMAN CLINICAL TRIALS
Human clinical trials for vaccines involve three steps:
- Phase I — tests for dosage and safety;
- Phase II — larger-scale tests for safety, as well as a determination of whether the vaccine stimulates antibodies and immune memory; and
- Phase III — multi-center, placebo-controlled, double-blind tests to assess protection conferred by vaccination (“efficacy”). These efficacy tests are performed in volunteers who have a high risk of HIV infection.
PHASE I TRIALS — DOSAGE AND SAFETY, MONOVALENT AIDSVAX B
Phase I trials with monovalent AIDSVAX B vaccine were conducted by Genentech. AIDSVAX B was clinically evaluated in 671 HIV-negative volunteers and 662 HIV-positive volunteers. None of the vaccinees reported serious side effects. Some vaccinees occasionally experienced pain at the injection site, as is common with many vaccines.
AIDSVAX B was tested at three doses: 100 mg, 300 mg and 600 mg of gp120. The 300 mg dose was consistently found to be most effective, stimulating a higher antibody response without serious side effects.
The clinical trial results also indicated that monovalent AIDSVAX B, at all three doses tested, did not alter the progression of ongoing HIV infection. Thus should efficacy be demonstrated in Phase III trials, we intend to apply to the FDA for broad use of the vaccine in high-risk groups without prescreening for HIV infection.
PHASE II TRIALS — ANTIBODY STIMULATION, MONOVALENT AIDSVAX B
One hundred forty HIV-negative volunteers were vaccinated and boosted three times with monovalent AIDSVAX B vaccine. Vaccinations were given at time 0, 1 month and 6 months with an additional booster at 12 or 18 months. Antibodies stimulated by vaccination with AIDSVAX B were measured for their ability to neutralize HIV in culture tests. All of the vaccinated volunteers produced antibodies in their blood that neutralized infectivity of HIV B(MN), the strain that was used for preparation of AIDSVAX B. These neutralization tests were considered of key importance since they measured the actual biological activity of the vaccine-stimulated antibodies.
Memory of the immune response to HIV in the same volunteers was measured by examination of neutralizing antibody levels stimulated by sequential booster shots. All vaccine recipients produced high levels of neutralizing antibody with boosting. These antibody levels gradually declined with time. Each booster shot, however, resulted in a rapid antibody response of even higher concentration, demonstrating a memory recall of the antibody response. This is strong evidence of immune memory being stimulated by the vaccine. We believe that such memory will be key for protection, enabling the educated immune system to ward off HIV infection before it establishes itself.
PHASE I/II TRIALS — BIVALENT AIDSVAX
We believe that, since an antibody to a single receptor-binding site can cause neutralization, antibodies to multiple receptor-binding sites will result in yet broader neutralization. On this basis we developed and tested two formulations of bivalent AIDSVAX.
We conducted two Phase I/II trials in the United States and Thailand in 214 HIV-negative volunteers. The trials used two bivalent formulations of AIDSVAX. The volunteers were vaccinated and then given one booster one month later. The vaccine tested in the United States was AIDSVAX B/B. The vaccine tested in Thailand was AIDSVAX B/E. Each of the vaccines was selected for the known prevalence of these virus subtypes in the particular countries tested. The trials were also designed to compare the results of bivalent AIDSVAX to those of monovalent AIDSVAX. Four factors were monitored:
- safety;
- dosage;
- antibody stimulation; and
production of antibodies that would neutralize strains used in bivalent AIDSVAX.
The vaccine did not cause any serious side effects. Vaccinees occasionally experienced pain at the injection site, as is common with many vaccines. In a dose response study, the bivalent AIDSVAX demonstrated the same results as those observed with the monovalent vaccine.
The Phase I/II studies also demonstrated the stimulation of antibodies to receptor-binding sites on gp120 proteins that were contained in the respective vaccines. AIDSVAX B/B stimulated antibodies to M-tropic and T-tropic HIV found in the United States. AIDSVAX B/E stimulated antibodies to M-tropic and T-tropic HIV found in Thailand. In contrast, the monovalent vaccine stimulated a narrower range of antibodies, primarily to T-tropic strains.
We believe these findings support our hypothesis that a combination of gp120 proteins in the bivalent vaccine would stimulate antibodies to a broader range of HIV strains.
PHASE III CLINICAL TRIALS FOR AIDSVAX
In June 1996, we met with the FDA and its Vaccine and Related Biological Products Advisory Committee to review the statistical protocol and conduct of our North American Phase III clinical trial. At this meeting, a discussion and vote was conducted on the issue of whether the interim analysis could be used to determine vaccine efficacy. By a vote of 12 – 0 in favor, it was agreed “. . . that the data safety monitoring board will . . . recommend that the study be terminated if the trial detects an efficacy of greater than 30%.” In such a case, the halt of the trial would be followed by vaccination of the placebos and we will begin the application process for licensure of the vaccine.
In May 1998, the FDA informed us that the data from our Phase I/II studies were acceptable and that we could proceed to Phase III clinical trials principally in North America. The first volunteers in the Phase III clinical trial were vaccinated in June 1998.
The Thai FDA is the governmental body involved in final approval to manufacture and market medical products. As part of the Thai FDA review, the Thai Ministry of Public Health has several subcommittees involved in making key decisions. In the area of HIV/AIDS, this includes the Technical Subcommittee on AIDS Vaccine, the Ethical Review Committee of the Research Committee, Ministry of Public Health, and the Institutional Review Boards from the participating institutions in the clinical trial.
In May 1998, we outlined our plans for Phase III clinical trials in Thailand and in February 1999, we received an import license from the Thai FDA with approval to begin Phase III clinical trials. In March 1999, the first volunteers in Bangkok were vaccinated, initiating the Phase III clinical trial.