Project Abstract Project Title: B-Cell Bioinformatics and Analytics for the HVTN Discovery Medicine Program This proposal outlines the scientific agenda for the HIV Vaccine Trials Network (HVTN) Statistical and Data Management Center (SDMC) to expand our capacity in carrying out B-cell bioinformatics and analytics work. This effort is aimed at supporting the increasing demands of the rapidly growing HVTN Discovery Medicine Program which is poised to evaluate more than 15 protocols in the current HVTN grant cycle. Given the promising outcome of several broadly neutralizing antibody (bnAb)-inducing vaccine immunogens which have demonstrated initial success in eliciting tier 2 heterologous neutralization antibodies and expanding HIV-1 bnAb precursors, we recognize that it is strategically crucial to evaluate additional vaccine candidates. These candidates should pair prime and boosting immunogens carefully selected to optimally mature B-cell responses towards broad neutralization against HIV. To accomplish this, it is imperative to evaluate and down-select immunogens using assays that provide both cellular- and molecular-level information about evolution of vaccine-induced B-cell repertoires. Addressing these needs necessitates the establishment of robust and standardized computational and analytical pipelines adapted to interrogate B-cell phenotyping (BCP) and B-cell receptor (BCR) sequencing data. The HVTN SDMC has made significant progress since 2020 in developing various aspects of the computational and analytical pipeline that supports its Discovery Medicine Program. However, the SDMC’s funding has become insufficient to meet the critical strategic requirements of the program, particularly those needed to expedite the generation of reports and datasets summarizing BCP and BCR sequencing data to vaccine developers. These reports are critical to accelerate the design and down- selection of boost immunogens required to continue guiding affinity maturation of vaccine-induced B- cells toward neutralization against HIV. These reports are also central to quickly guiding programmatic decisions from the HVTN and NIAID leaderships. This funding shortfall is primarily attributed to the escalating complexity of research studies, the iterative nature of immunogen designs, the increased number of studies in the pipeline, and the expectation that summaries and interpretation of these complex laboratory data should be distributed quickly. Consequently, the HVTN SDMC is seeking supplemental funding for Fiscal Years (FY) 2024 through 2027 to bolster the success of the HVTN Discovery Medicine Program.

Project Narrative This supplement aims to advance preventive HIV vaccine development by enhancing the analytical capacity of the HVTN SDMC to evaluate vaccine candidates that seek to induce broadly neutralizing antibody responses. Through improving bioinformatics and analytics tools for B-cell responses and expanded capacity in carrying out such analyses, this supplement supports the essential mission of the HVTN and accelerates vaccine research that could lead to significant reductions in the rates of HIV transmission and acquisition, ultimately improving public health outcomes globally.