Our vaccine design program is based on the concept of using “transition state” HIV envelope structures, which occur after attachment of HIV gp120 to its cellular CD4 receptor, as a vaccine immunogens to raise antiviral antibody responses. Unlike the envelope spike on free virions, these post-attachment structures are highly conserved even among diverse HIV strains. Furthermore, epitopes that exhibit enhanced exposure after attachment of HIV-1 gp120 to CD4 (including ones located in and around the coreceptor binding site) comprise some of the most conserved and functionally important residues on the viral envelope. Consequently, antibody responses to these epitopes (designated CD4-induced or CD4i) should be highly cross reactive and potentially useful for HIV vaccine development. This concept is embodied by an antigen designed to contain both gp120 and CD4 in such a manner that it forms a transition state structure within a single protein (termed a single chain complex) that can be used as a vaccine.
Three separate studies have addressed this concept by vaccination of rhesus macaques with single chain complexes designed to raise humoral responses against CD4i epitopes followed by rectal challenge with SHIV162P3, which encodes a heterologous HIV envelope versus the immunogen. In two studies, we found that animals vaccinated with a single chain gp120-rhesus macaque CD4 complex (rhFLSC) and then challenged with a very high dose of SHIV, exhibited significantly accelerated clearance of plasma viremia and an absence or reduction of long term tissue viremia compared to unvaccinated control animals. Such control of infection correlated with stronger responses to CD4-induced epitopes and other conserved epitopes have recently identified that mediate antibody-mediated antiviral effects. In a third set of experiments, vaccinated animals given a low dose SHIV challenge (approaching natural human exposure) exhibited signs of complete protection form infection for a limited period of time. Our current efforts are focused on clinical testing of these vaccines for safety and immunogenicity and on devising ways to combine the proteins with other vaccine components that are based on similar HIV envelope structures.