(19g) Development of a Virus-like Particle Based HIV Vaccine Candidate

Worldwide, 35 million people are infected with HIV. Antiretroviral therapies have helped to decrease the mortality rate, but their expensive nature makes them inaccessible to many millions of clinically eligible individuals. Despite over 30 years of intense efforts, an HIV vaccine is still not in sight. A prophylactic HIV vaccine would prevent the infection and do so at a much lowered cost, thus increasing access, particularly in the developing world. Whole-killed vaccines, in which the virus is physically destroyed by chemicals, heat or radiation, are used for many other diseases, but do not lead to a relevant immune response against HIV. The mutation rate of HIV is very high, so variant strains that are resistant to vaccines prepared against individual strains emerge rapidly.

Our approach aims to create an HIV vaccine candidate targeting the process by which the virus infects cells. In order to infect a new cell, the HIV membrane must fuse with the cell membrane. This membrane-fusion event is mediated by a specific protein on the surface of the virus, called gp41, which is highly conserved at both the nucleotide and amino acid levels. Earlier work in the field has elucidated the overall features of this membrane-fusion event, including an intermediate state of gp41 called the pre-hairpin intermediate (PHI). An FDA-approved drug, Fuzeon, binds to the PHI, preventing membrane fusion and blocking HIV infection. Additionally, a monoclonal antibody targeting this PHI (called D5) has been shown to prevent infection of cells by various strains of HIV. Together, these results validate our approach to use the PHI as a vaccine target.

Our proposed vaccine candidate consists of an engineered virus-like particle scaffold displaying both a PHI mimetic and stimulators of the innate immune system. Using the engineered virus-like particle scaffold results in a vaccine candidate with the correct size for efficient trafficking to the lymph nodes. We have produced a PHI mimetic in a scalable cell-free protein synthesis system and have optimized the attachment of the PHI mimetic to the virus-like particle in an ordered, repetitive fashion similar to that of the natural virus. Co-attached innate immune stimulators will act as a non-denaturing adjuvant to further ensure a strong protective response. Consequently, our PHI mimetic will provide a broadly protective immune response to many subtypes of HIV. Promising vaccine candidates will be evaluated in guinea pigs for serum responses which provide viral neutralization in an in vitro assay.