Enhancing durability of V3 glycan vaccine responses in rhesus macaques - ABSTRACT Developing an HIV vaccine capable of eliciting a durable broadly neutralizing antibody (bnAb) response is needed for ending the HIV/AIDS epidemic. Inducing bnAbs will likely require a sequential vaccination approach with perhaps 5 to 6 immunizations. High and sustained bnAb titers should be elicited only after preceding immunizations drive affinity maturation of bnAb lineages. Inducing high antibody titers at earlier stages of the vaccine regimen could interfere with the subsequent steps of bnAb affinity maturation. Thus, learning how to induce a durable bnAb response would best be accomplished in the context of a vaccine regimen that is capable of inducing affinity matured bnAb lineages. This proposal leverages a novel 6-shot germline-targeting HIV vaccine regimen that has been validated to elicit a specific genetic-class (BG18) of cross-clade neutralizing antibody in non-human primates. Investigating the last step of the sequential regimen will allow us to probe the durability of the BG18-class long-lived plasma cells that have undergone the necessary affinity maturation. We will systematically investigate four key concepts: (1) assessing the inherent durability of a 6-shot sequential vaccine regimen that induces BG18-class cross-neutralizing antibodies in non-human primates; (2) evaluating the impact of a yearly maintenance shot on durability and whether deflecting competitor antibody responses during these boosts is necessary; (3) evaluating nanoparticle or fractionated escalating dose trimer delivery for the last immunization to improve durability; (4) investigating whether an mRNA sequential regimen with a last boost of adjuvanted protein, generates a durable bnAb response. To address these concepts, we will probe key immunological outputs such as quantification of B cell populations, including memory B cells in PBMCs, germinal center B cells in lymph nodes and long-lived plasma cells (LLPCs) in bone marrow. Additionally, monoclonal antibody and serum responses will be characterized for immunodominance, binding and neutralization capacity. By focusing on the final stage of a multi-step HIV vaccine regimen, that induces cross-neutralizing BG18-class responses, this project will explore durability in the phase of HIV vaccine development that was previously inaccessible to detailed investigation; post-elicitation of matured bnAb lineages. Identifying the immune outputs that most closely correlate with bnAb durability will be a central goal, providing invaluable insights for optimizing the design of an effective HIV vaccine.
