Harnessing CD4 T follicular helper 1 cells for HIV vaccine efficacy

Project Summary This proposal aims to enhance HIV prevention with a vaccine approach that promotes durable immunity. The studies center on CD4 T helper cells within lymph nodes, crucial for humoral and cytolytic memory. Our objective is to induce robust CD4 T follicular helper (Tfh) cells as they are essential for vigorous B cell activity within

germinal centers (GC). We aim to promote Tfh cells that facilitate differentiation of GC B cells to plasma cells, essential for persistent antibodies, by fine-tuning the innate inflammatory response with adjuvanted vector/protein immunization in rhesus macaques. Our published studies in macaques have shown that stimulating specific Tfh1 cell subset promotes HIV Envelope

(Env) antibodies with enhanced persistence and avidity (JVI, 2020; eLife, 2023). In this proposal, we will examine whether a vaccine platform tailored to promote Tfh1 cell differentiation during both the prime and boost, in combination with trimeric Env antigens, enhances Env antibody durability leading to increased protective efficacy

20 weeks after final immunization. Our approach uses adjuvanted Clade A Env DNA (weeks 0, 4, and 8) to prime Tfh1 cells. To intensify the Tfh1 response, a second group will receive an adjuvanted mRNA prime. Groups primed with unadjuvanted DNA and mRNA will assess significance of Tfh1 priming in sustaining humoral immunity. All

four groups will receive Clade A Env protein boosts formulated in ALFQ (weeks 16 and 24) to reinforce Tfh1 cell memory and drive sustained GC responses. In Aim 1, we will perform detailed immune analyses across DNA and mRNA platforms to uncover mechanisms of effective Tfh help in humoral immunity against HIV. In Aim 2, we will evaluate the long-term effectiveness by

measuring protection at week 44, 20 weeks post final boost. In addition to comprehensive cellular immunology analysis of blood and lymph nodes and serological assessments in blood and mucosal sites, animals will be monitored for potential vaccine-related adverse events. Our comprehensive and multifaceted approach, pairing

adjuvanted nucleic acid priming with a protein boost and directly comparing mRNA and DNA priming modalities for immunogenicity and protection, aims to enhance longevity and affinity of HIV-Env antibodies. This innovative strategy targets Tfh cells in a way not previously attempted, offering the potential for insights in HIV vaccine

development. These collaborative studies are supported by teams from the University of Pittsburgh, Emory University, and Louisiana State University. These teams bring a wealth of expertise in adjuvanted vector design, Tfh biology, humoral immunity, as well as bioinformatics and biostatistics. In summary, our studies, centered

around leveraging molecular adjuvants to enhance the Tfh1 cell response, have the potential to innovate HIV vaccine design. Our long-term objectives are to integrate strategies to induce Tfh cells, optimized for B cell helper function, into potent broadly neutralizing antibody-inducing platforms to improve HIV vaccine efficacy.