Title: Immunologic evaluation of HIV-1 HVTN experimental medicine trials HVTN 307, HVTN 309 and HVTN312 as a supplemental application for the Duke CHAVD year 6 Barton F. Haynes, MD, CHAVD, PI The overall hypothesis for this proposal is that deep interrogation of HVTN experimental medicine clinical trials will provide the information needed to successfully and quickly iterate immunogen design to be able to select for mature bnAbs in at least 1 or more bnAb B cell lineages by June 2026. The scientific premise is that studying the frequency of bnAb precursors in blood or leukapheresis cells (naïve or memory B cells) and LNs both after immunization with germline-targeting and then boosting immunogens will be an optimal strategy to determine the efficacy of vaccination. We now know that Nojima cultures followed by antigen-specific paired VH + VL sequencing with 10X genomics is a powerful and rapid way to determine the effect of vaccination with Env immunogens on HIV bnAb precursor populations in Discovery Medicine Phase I trials. Here we propose to bring these and other technologies to the study of the HVTN 307, HVTN 309 and HVTN 312 HIV vaccine clinical trials and in doing so answer critical questions needed to make progress on the design of a practical HIV vaccine.