Engineering Durable HIV Vaccine Responses (ENDURE) (R01 Clinical Trial Not Allowed)

HIV vaccines will ultimately require broad and durable immunity. Durability of vaccine responses varies widely, with estimated half-lives ranging from months to decades. Yellow fever and smallpox vaccines confer life-long protection, while vaccines for influenza and SARS-CoV-2, mutation-prone viruses, require frequent boosting. Multiple properties of the vaccine and target virus influence the durability of a vaccine response: viral diversity, incubation period, antigen valence, vaccine platform, adjuvant, route of administration, and others. For example, a 60-mer nanoparticle of an engineered outer domain HIV Env immunogen induced larger germinal centers and more sustained antigen-specific antibody responses than a 4-mer nanoparticle in a murine model. To engineer or induce a durable vaccine response, we must clarify factors generating durable immunity, immune responses associated with durable immunity, and methods for measuring durable immunity. This Notice of Funding Opportunity (NOFO) solicits applications addressing these areas through basic or applied research. Vaccines induce a cascade of immune responses, beginning with innate immune signals and ending with varied types and magnitudes of long-lived B and T cell memory. Identifying the connection between immediate, early vaccine responses that induce or predict persistent immune responses will enable design of optimized vaccines and facilitate more rapid vaccine development, including vaccines for HIV. Vaccine-induced protection is commonly assessed by measurement of serum antibody titers. While serum antibodies can be protective, this measure often does not fully or accurately reflect vaccine-induced immunologic memory. Germinal center B cells and T follicular helper cells, thought to be necessary for a long-lived antibody response, reside in lymphoid tissues, including lymph nodes. Long-lived plasma cells, the primary mediator of long-term antibody memory, reside in specialized niches in the bone marrow. Memory T cells may circulate, reside in lymphoid tissue, or become tissue resident memory cells. The specific functions, kinetics, and location of these adaptive immune responses, their interplay with innate immunity, and implications for vaccines remain gaps in the field. Accessing and measuring these cell types is challenging, and there is a need to develop less invasive and more comprehensive methods to assess vaccine-induced memory.