The Design of AIDSVAX
AIDSVAX is designed to stimulate antibodies that prevent the HIV virus infecting target cells. The antibodies attach to specific sites on gp120 protein on the virus’ surface and prevent them from binding with receptors on the target cell. Unable to bind with and enter the cell, HIV is neutralized.
In 1992, Genentech genetically engineered a version of the gp120 protein. Antibodies to this gp120 protein bound to a neutralizing site found on 65% of subtype B viruses. This virus was labeled B(MN) and was believed to represent the majority of HIV in the United States. Subsequently, synthetic gp120 of HIV (BMN) was incorporated into a monovalent AIDSVAX formulation, designated AIDSVAX B.
Genentech used this AIDSVAX B formulation to vaccinate humans in Phase I and Phase II clinical trials. Phase I trials were used to test for dosage and safety. Phase II trials were used to determine whether the vaccine stimulated the desired immune system response.
Antibodies obtained from 100% of those vaccinated with AIDSVAX B neutralized the B(MN) virus in laboratory tests. Further tests demonstrated that these antibodies bound to the gp120 protein of all HIV subtype B viruses tested. However, in laboratory tests and Phase II clinical trials, antibodies to B(MN) neutralized, to a greater extent, HIV of T-tropic strains compared to HIV of M-tropic strains.
To improve the breadth of the immune response, we identified a second virus, B(GNE8), from the M-tropic strain, and a synthetic version of its gp120 protein was added to the vaccine. The resulting bivalent vaccine, AIDSVAX B/B, which is designed to address two HIV strains, considerably expanded the vaccine’s breadth of neutralization. While the monovalent vaccine could stimulate the production of four different types of antibodies that reacted with binding-sites to cell receptors, the bivalent vaccine could stimulate the production of seven. We believe that these seven antibodies cover virtually all known strains of HIV in North America.
As a general strategy, we plan to develop AIDSVAX formulations that will stimulate antibodies against multiple binding sites on gp120. Our goal is to expand the range of antibodies that are stimulated by a vaccine to neutralize a broader group of HIV. A practical application of this strategy has been the conversion of AIDSVAX from a monovalent to a bivalent formulation.
Formulations of AIDSVAX
AIDSVAX consists of two biologically active ingredients: antigens and an adjuvant. An antigen is the ingredient in vaccines that activates the human immune system response. The antigen in AIDSVAX is synthetic gp120 protein. An adjuvant is an active ingredient in vaccines that improves the human immune system response by attracting immune cells into the region where the vaccine is injected. The adjuvant in AIDSVAX is alum, or aluminum hydroxide. Since the vaccine contains only a synthetic fragment of the virus and no genetic material, it is incapable of causing HIV infection.
Three different formulations of the AIDSVAX vaccine have been developed and clinically tested in Phase I/II trials. These include: monovalent AIDSVAX B for HIV infections in North America and Europe, bivalent AIDSVAX B/B for HIV infections in North America and Europe, and bivalent AIDSVAX B/E for HIV infections in Southeast Asia. All three formulations use alum as an adjuvant.
INITIAL TESTING OF AIDSVAX IN CHIMPANZEES
The chimpanzee is the only laboratory animal susceptible to HIV infection. In the initial protection trials conducted by Genentech, chimpanzees were vaccinated with three doses of monovalent AIDSVAX B. The vaccinated animals, along with unvaccinated control animals, were then injected intravenously with high doses of infectious HIV of the same strain that was used for the preparation of the vaccine. None of the AIDSVAX vaccinated animals became infected with HIV. All of the unvaccinated control chimpanzees became infected with HIV. HIV in chimpanzees rarely causes AIDS.