This project will test the ability of T follicular helper (Tfh) cell-targeting “genetic adjuvants” to improve immunogenicity of an advanced HIV envelope (Env) trimer. Eliciting neutralizing antibodies (nAb) against HIV will likely be required to create effective therapeutic vaccines that attenuate HIV disease progression, reduce HIV infectiousness, or even effect sustained remission in the absence of daily antiretroviral drug therapy. However, eliciting such antibodies is a challenge that can be frustrated at multiple steps in B-cell development, particularly in HIV-infected people. Of greatest relevance to this application, low-affinity germline B cells reactive to neutralizing epitopes may not successfully compete with cells binding non-neutralizing epitopes for antigen, or the amount of antigen acquired may be insufficient to stimulate Tfh cells to provide the required help. Tendel Therapies Inc. developed B-cell adjuvant technology that augments Tfh cells and is designed for use with vectored vaccines. Our preliminary data show that the adjuvant acts on both Tfh and B cells to promote uniquely intense and durable antibody responses. We propose to use these adjuvants in combination with two promising B-cell immunogens to reliably elicit tier-2 neutralizing antibodies in macaques: (i) an advanced BG505 SOSIP-like trimer designed to promote focused responses to nAb targets and minimize reactivity of non-neutralizing Env epitopes such as the V3 loop or non-neutralizing CD4 binding site sub-regions, and (ii) bacteriophage VLPs displaying the HIV fusion peptide (FP) in highly multimeric form. We hypothesize that novel Tfh-targeting adjuvants promote broader nAb responses to an advanced HIV Env immunogen via mechanisms including democratic naïve B-cell recruitment and stimulation of Tfh responses. Aim 1. Assess the intensity and durability of nAb, Tfh, and germinal center B-cell responses to an advanced HIV envelope trimer, delivered with or without Tendel adjuvants, as mRNA in lipid nanoparticles. The goals are (i) to test if Tendel adjuvants have similar potency for augmentation of antibody responses to mRNA-vectored vaccination against native-like HIV Env trimers, as previously shown for augmentation of responses against the SARS-CoV-2 receptor binding domain; and (ii) to select one regimen for evaluation in Aim 2 subsequent to fusion-peptide priming. Aim 2. Evaluate the effect of priming immunization with the HIV Env fusion peptide, FP8, on neutralization breadth achieved by Tendel adjuvants and HIV Env native-like trimers. This priming regimen is intended to provide an additional epitopic focus for nAb responses. Due to the combination of anti- FP nAbs with other nAbs provided by trimer immunization, the FP8-primed regimen should result in nAb responses of increased breadth and perhaps higher titer.