ABSTRACT – Nonhuman Primate Core (Core B) The end of the HIV/AIDS epidemic will be achievable only when an effective vaccine regimen can achieve long- term protective immunity, similar to that of vaccines that have nearly eliminated other global pathogens. The induction of broadly neutralizing antibodies (bnAbs) against the HIV envelope (Env) is considered vital for an effective HIV vaccine. Yet, despite the delineation of the coevolution of Env-specific antibodies and their cognate Env intermediates from the germline BCR to bnAbs, few HIV vaccine strategies have been successful in eliciting HIV Env Abs with broad heterologous neutralization capacity. Our knowledge about critical factors influencing B cell differentiation and lineage commitment remains limited. The proposed research is built on a foundation of prior research observations on the development of bnAbs in ~ 50-60% of infant and adult rhesus macaques and humans immunized with germline-targeting (gt) BG505 GT1.1 SOSIP with adjuvant, and the opportunities provided by the infant RM model to define the specific biological factors that determine B cell lineage commitment by comparing vaccinees with or without bnAb development. Systems biology approaches can be useful to define early immune and molecular gene signatures after the vaccine prime immunization and the role of the intestinal microbiome in vaccine-induced bnAb development. Applying systems biology approaches, the objective of the overall studies is to determine how the modulation of the vaccine prime by different adjuvants and vaccine delivery platforms (Project 1) and changes in the infant microbiome (Project 2) alter the developmental pathways that lead to the induction of bnAbs. We hypothesize that the dynamic nature of the infant immune system and microbiome can be exploited to optimize the induction of bnAbs by HIV vaccines. These questions will be addressed via studies in the infant macaque model. The Nonhuman Primate (NHP) Core is an integral component of the overall HIVRAD Program and provides direct support to the Projects by coordinating and implementing all the NHP experiments (including regulatory approvals, and all procedures related to immunizations and sample collections). This Core has a longstanding track-record of collaboration with the 2 Project Leads/Overall P.I’s, and will communicate frequently with both Projects and other Cores to assure all the experimental needs are met with due diligence. The NHP Core uses the unique resources and infrastructure of the California National Primate Research Center (CNPRC), out of which it operates, and the expertise of the Core Lead and staff. The CNPRC is built on a service-oriented and interdisciplinary mission of advancing non-human primate models of human diseases and translational research. Resources at CNPRC include a large rhesus macaque breeding colony, experience with time-mated pregnancies and rearing of infant macaques, and all other procedures of monitoring and...