Immunogen and Antibody Core

SUMMARY The use of stabilized envelope trimers as immunogens has greatly advanced the HIV vaccine field, reliably triggering neutralizing antibodies against tier 2 viruses that represent circulating strains. However, thus far these antibodies have been strain-specific, and the field needs novel approaches to drive these responses towards breadth. The role of T cell help in the development of neutralizing Abs has been highlighted in clinical studies of HIV infected individuals who develop broadly neutralizing antibodies (bNAbs). We hypothesize that vaccine strategies that recruit T cell help for envelope-based immunogenicity studies (including the fusion peptide) will enhance B cell responses, and that such help may be augmented by Tfc cells. In the Immunogen and Antibody Core, we will use well-developed SOSIP platforms to synthesize, purify and characterize advanced HIV envelope (Env) immunogens engineered to drive Tfh induction and bNAb maturation. These immunogens, including novel fusion proteins to be used in Projects 2 and 3, will be based on a clade-C 327C derived envelope (MD37), and will be combined with VLPs expressing the fusion peptide for vaccine studies. SOSIP trimers will be assessed for structural and antigenic integrity and provided as immunogens and tools for downstream analyses to Projects 2 and 3. The core will also provide the tools and technologies to assess binding and neutralizing antibodies as well as Fc effector function in human samples from broad neutralizers in infection cohorts and clinical trial participants, as well as human B cells derived from co-culture and organoid studies (Project 1). In Projects 2 and 3, Core 1 will assess humoral responses in non-human primate (NHP) plasma from immunogenicity studies comparing multiple vaccine platforms (Projects 2 and 3). Supporting Projects 1, 2 and 3, we will also perform detailed bioinformatic analyses of vaccine-induced or organoid-derived B cells, to assess the maturation of humoral responses. Finally, these data will be provided to the Data Monitoring and Analysis Core (DMAC) to integrate datasets and define correlates of immunity. Overall, our highly experienced core is well placed to use an array of serological, structural and genetic approaches to provide a comprehensive profile of binding and neutralization activity in sera from infection, vaccination and B cell cultures.