HIV-1 vaccine efficacy trials and multiple animal studies, including those related to HIV-cure strategies, have shown that antibody interactions with cells - mediated by the antibody constant (Fc) region - can harness multiple aspects of the immune system to provide protection through mechanisms other than by neutralization. However, it is unknown whether candidate HIV-1 vaccine regimens that include induction of Fc-mediated antibody functions can be tested in the rhesus macaque (RM) nonhuman primate (NHP) in a way that can be translated to humans. In order to more effectively translate insights gained from RM studies to the clinic, there is a need to fully define the protective signatures of Fc-mediated antibody functions across rhesus macaques and humans. The work we propose will map antibody (Ab) and Fc-receptor (FcR) biology across humans and RMs with the goal of making observed protective responses in RMs more predictive of human responses, thus accelerating the most promising vaccine concepts to be advanced to the clinic with success. Our central hypothesis is that the RM model can be substantially improved for testing antibody-based interventions and vaccines through elucidation of key variables that impact species-specific Fc?R-dependent effector functions (i.e. antibody epitope specificity, immune complex formation, isotype/subclass, glycosylation, and FcR genotype/phenotype). To test this, we propose three synergistic, inter-related scientific Projects supported by three Cores to achieve the following Overall Aims: Overall AIM 1. Characterize effective anti-HIV-1 Fc-FcR biology across RM to humans. Overall AIM 2. Define HIV-1 virion and infected cell epitopes for antibody recognition. Overall AIM 3. Determine the Fv and Fc features of antibodies yielding maximal anti-HIV-1 activity.
This Program will enable refined design and testing of antibodies and vaccines in RM and enable optimization of the RM model to accelerate translation of potential prevention strategies to clinical trials. Successfully completed, this program will have high scientific impact by achieving the following outcomes: 1) Learn to use the RM model to test Fc-mediated antibody functions as correlates of HIV-1 risk/protection and enable translation to humans for testing of HIV-1 immunoprophylaxis, cure strategies and vaccine designs. 2) Identification of the critical regions of virions and infected cells most vulnerable to forming effective immune complexes for mediating antibody Fc-mediated antiviral function(s). 3) Determination of ways to harness antibody cooperativity for maximal antibody Fc-mediated antiviral function(s). Admin-Core 1: Administrative Core Core Leader (CL): Tomaras, G. DESCRIPTION (provided by applicant): The Administrative Core will serve as a resource to the entire Bridging Antibody Fc-mediated Antiviral Functions Across Humans and Non-human Primates PO1, providing overall management, coordination and supervision of the program. The P01 director, Georgia Tomaras will serve as the leader of the Administrative Core, and experienced staff will be responsible for managing and coordinating the entire range of the PO1 activities, monitoring progress and ensuring that the overall goals of the program are implemented effectively and efficiently. Specific Aims will include the following: AIM 1. Provide Scientific Oversight. AIM 2. Facilitate Communication across the Program. AIM 3. Ensure Regulatory Compliance AIM 4. Provide Financial Oversight Through central management of all scientific, regulatory and financial activities of the program, the Administrative Core directly interacts with each of the Projects and Cores. Similarly, each of the Projects and Cores provide direct input to the Administrative Core through the participation of the Project and Core Leads and key investigators as part of the Program's Executive Committee. Collectively, the administrative group at the Duke Human Vaccine Institute has substantial expertise in the management of multi-institution grants and will ensure success in the management of the Bridging Antibody Fc-mediated Antiviral Functions Across Humans and Non-human Primates P01.
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