Contributions of durable, high-avidity T-cell responses to protection achieved using the Opti-FliP vaccine regimen

University Of California At Davis, Davis CA

Investigators

Abstract

The goals of Project 2 are to test innovative approaches to elicitation of uniquely durable, high-avidity T cells; test if such responses have any independent protective efficacy against SHIV infection; and learn how best to combine the T-cell regimens with B-cell vaccines to maintain the advantages of each. The lack of efficacy in HVTN 702, 705, and 706 has crystallized the truth that transformative advances in vaccine technology and immunology will be required before we can hope to generate protective immunity against HIV. Through the approaches below we aim to create unique T-cell responses, qualitatively different from those tested for protective efficacy before, and which can support FP-inclusive vaccine regimens via multiple pathways. One approach uses IL-10 partial-agonist cytokines to support more intense and durable T-cell responses including both conventional cytotoxic responses and CXCR5+ follicular T cells with B-cell helper function. We predict that this constellation of responses will support FP vaccination both directly, via support for B-cell development in germinal centers and resulting production of neutralizing antibody, and indirectly, via provision of cytotoxic T cells that have been shown in some circumstances to cooperate with antibodies for protective efficacy. The second approach seeks to preferentially expand high-avidity cytotoxic and helper T cells that are believed to be more functional due to superior sensitivity to peptide:MHC complexes on the surface of infected cells. Such high-avidity cells may exhibit superior cytotoxicity and/or could differentiate into the T cell subsets most valuable for driving the maturation of B-cell immunity. We hypothesize that unique adjuvant approaches can expand T cells that are durable and of uniformly high avidity, that span cytotoxic and follicular-helper functions, and that support bnAb development in combined vaccine regimens. 1. Optimize T-cell response durability using IL-10 inhibition and mRNA vaccination. 2. Selectively boost high-avidity cytotoxic T cells by targeting CD8 independence. 3. Test the mutual effects of protein+VLP and optimized T-cell vaccines either given synchronously, or when initial T-cell vaccination precedes the first B-cell vaccination. If successful, this work will provide new tools for accelerating and broadening neutralizing antibody development in primates, reveal new information about potential of CD8+ T cells to support antibody responses, and suggest new approaches to vaccines that rely simultaneously on antibodies and T cells for protective efficacy.