Annual and Interim Progress Report Summaries
Principal Investigator: Barton Haynes
Project: Broadly Reactive Neutralizing Antibodies: Novel Strategies for Vaccine Design
Submitted April 2, 2012 (Final Report)
The CAVD team has been successful and demonstrated that central and peripheral tolerance mechanisms control the expression of gp41 membrane proximal external region (MPER) neutralizing antibodies in knock-in mice, that non-neutralizing MPER antibodies bind to the post-fusion six helix bundle of gp41, and that germline antibodies bind to a host protein in both mouse and human with sequences homologous to the HIV gp41 MPER. Most importantly, this team originated the concept of B Cell Lineage Vaccine Design wherein precursors of desired antibodies are targeted by vaccine design. We have found that tolerance deletion is not complete and B cells making broad neutralizing antibodies (bnAbs) survive in the peripheral immune organs for activation by vaccines. From this work, what is required for induction of bnAbs is directed affinity maturation of a gp41 neutralizing antibody response, as well as breaking peripheral anergy of otherwise unresponsive B cells. MPER peptides in membrane liposomes have been designed to mimic virions, and potent adjuvants have been incorporated into MPER-liposomes. Thus, one lead candidate as an MPER immunogen is liposomes with viral lipids (“virosomes”) containing the gp41 intermediate form of the MPER that may be primed with an endogenous MPER homologous host antigen. Our work focused on immunization studies in rhesus macaques to focus the antibody response on the MPER neutralizing epitopes, and on MPER second generation immunogen design. For gp120 epitopes, this CAVD has identified 3 transmitted founder Envs as candidate vaccines that are both superior as antigenic and immunogenic Envs compared to 28 others tested. Finally, the CAVD team worked to define the correlates of protective immunity to HIV in the RV144 trial samples.