Strategies for targeting T follicular helper cells to improve HIV Env vaccine immunogenicity and efficacy

Project 3 will optimize a strategy for targeting CD4+ T follicular helper (Tfh) and CD8+ T follicular (Tfc) cells, systemically and mucosally, to improve immunogenicity and efficacy of the Opti-FliP vaccine regimen. We will use innovative approaches including an advanced clade-C HIV-1 Env immunogen, unique adjuvant strategies to boost fusion peptide (FP)-directed neutralizing antibody (nAb) responses elicited by “cocktail” priming with virus like particles (VLPs) and native-like Env trimers, and mucosal delivery of Env immunogens either in adenovectors or in mRNA polyplexes. Eliciting and maturing nAb against HIV can be impeded at multiple steps in B-cell development. Low-affinity germline B cells reactive to neutralizing epitopes may not successfully compete with cells binding non-neutralizing epitopes for antigen, or amount of antigen such B cells acquire may not provision enough MHC class II or class I molecules to stimulate Tfh/Tfc cells to provide adequate help. Differentiation of high-frequency, Env-specific follicular T cells (Tf cells) could help to overcome these roadblocks. We will test innovative vaccines delivered as mRNA lipid nanoparticles (LNP) or polyplexes expressing advanced HIV-1 Env immunogens designed to specifically drive Tf responses (Aim 1) and delivered by systemic and mucosal routes (Aim 2). Approaches that prove advantageous will then be tested in combination with an optimal T cell vaccine based on strategies tested in Project 2, as an integrated vaccine regimen (Aim 3; see Fig. 1 of Overall component). The hypothesis is that vaccines optimized for Tfh/Tfc induction and mucosal delivery will promote B-cell recruitment and development, leading to more intense, broader, and higher-affinity systemic and mucosal nAb responses to HIV-1 Env, leading to improved vaccine efficacy. Aim 1. Test the capacity of physical Tfh targeting to improve neutralizing antibody responses to native- like Env mRNA vaccine after priming with FP-VLPs. Aim 2. Assess the impact of mucosal boosting on Tf responses and antibody titers. Aim 3. Evaluate vaccine efficacy and determine immune correlates of protection for clade-C-based vaccines that generate FP-targeted neutralizing antibodies with high-avidity T cells.