AIDS is a preventable disease, nevertheless millions of new infections occur every year according to UNAIDS. A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 would be the best way to prevent the spreading of the AIDS pandemic, however, no efficacious vaccine has been developed to date. Previous efforts to design an antibody-based vaccine have been unsuccessful, in part due to the limited information available at the time on the HIV-1 particle, its mechanism of infection and the anti HIV-1 antibody responses elicited in infected individuals. Recent advances in the field have opened new avenues for vaccine design that we will investigate as part of the research of this proposal. Our work recently showed that common vaccination strategies using singular Envelope (Env)-based immunogens were not suitable to elicit anti HIV-1 bNAbs; instead, novel sequential immunization strategies elicited neutralizing antibodies of remarkable potency and breadth in knock-in mouse models with a restricted antibody repertoire. In this proposal, we aim to design and evaluate new immunogens and sequential immunization strategies to elicit bNAbs in animal models that have a complete immunoglobulin (Ig) repertoire. In particular we plan to: 1) test new immunogens and sequential immunization regimens to elicit bNAbs against the V3-N332 epitope of Env in a) wild type mice, b) AlivaMAb mice carrying human Ig loci and c) mice expressing the human terminal deoxynucleotidyl transferase (Tdt) enzyme as models that more closely resemble the human Ig repertoire; and 2) document the requirement of glycans on the V3-N332 epitope at the early stages of V3-N332 bNAb development. The results of the proposed research will provide valuable information for the design of a vaccine against HIV-1. This work will also inform about general rules governing the antibody maturation process upon sequential immunization that could facilitate the design of vaccines against other unrelated pathogens. The K99 phase of this proposal will take place in the Nussenzweig laboratory at The Rockefeller University in collaboration with the Bjorkman laboratory in Caltech. Both groups and institutions will offer an outstanding environment and all necessary resources to carry out the research of this proposal. The Nussenzweig laboratory has a long and consolidated trajectory studying B cells and HIV-1. The Bjorkman laboratory specializes in structural biology and is particularly interested in the immune recognition of viral pathogens such as HIV-1. The work of the Bjorkman group perfectly complements the areas of expertise of the Nussenzweig laboratory and provides an optimal scenario for the research of this proposal. The training received during the K99 phase in this terrific environment will undoubtedly propel and facilitate my transition to independence.
According to UNAIDS, 36.7 million (M) people were living with HIV-1 at the end of 2015, 2.1 M were newly infected and 1.1 M died due to AIDS-related diseases. No efficacious vaccine has been designed to date. A vaccination regimen that protects against HIV-1 infection is therefore of general public interest. !
