Therapeutic vaccination to boost autologous neutralizing antibodies for ART free HIV Control - Summary Antibody-based approaches to HIV cure or ART-free remission hold promise. Several antibody-based therapeutic HIV vaccine trials are currently underway, leveraging germline-targeting approaches originally developed for HIV prevention, which ignore the existing autologous neutralizing antibody (anAb) responses already present in people with HIV (PWH). Here, we propose an alternative strategy of personalized therapeutic immunization to expand and enhance PWH's own anAb responses with the goal of eliciting antibody-mediated viral control and ART-free remission. We hypothesize that a personalized anAb-boosting vaccine administered after early ART initiation can boost anAb breadth and potency sufficiently to neutralize the replication-competent viral reservoir and elicit ART-free virus control. Recent findings from our group and others support this rationale: 1) Early ART limits reservoir diversity while enabling ongoing anAb evolution; 2) AnAb responses restrict viral rebound after treatment interruption, and correlate with delayed time to rebound; 3) Our TF SHIV-infected nonhuman primate model recapitulates HIV immunopathogenesis, persistence, and the kinetics and potency of anAb responses; 4) New insights into antibody development via vaccination and SHIV infection enables rational immunogen design; 5) Novel mRNA-lipid nanoparticle delivery and Env engineering technologies allow rapid production of personalized stabilized Env immunogens. We propose a coordinated 3- arm rhesus macaque experiment to test whether individualized mRNA-LNP delivered Env immunogens can enhance baseline anAb responses and elicit durable ART-free virus control compared to off-the-shelf germline targeting immunogens or ART alone. We will test a personalized two Env immunogen strategy, based on the unique Env sequence diversity present at early ART initiation in each animal, aiming to engage baseline responses and then broaden them to cover the diversity of viruses in each animal. We will test these vaccination regimens in macaques infected with a validated, barcoded SHIV and early ART treatment. Nine animals in each arm will be (A) immunized with two doses of mRNA-LNP delivered stabilized Env representing the most frequent natural month 4 Env variant in each animal (Env.con), then two doses of a distinct Env designed to more fully cover the diversity of sampled month 4 virus (Env.div), (B) immunized with two mRNA-LNP-delivered doses of an off-the-shelf germline targeting immunogen (BG505.GT1.1), then two doses of the native BG505 Env, or (C) ART alone. Primary study outcomes will be impact of vaccination on post-ART virus control and enhancement of anAb responses. We will also conduct mechanistic studies to characterize virus rebound and identify blood and tissue correlates of post-ART virus control. Results will advance the HIV cure field by defining the potential of HIV-specific humoral responses and the capacity of novel immunogens to grow them. If successful, this approach could be central to a combination cure strategy by pairing it with cellular vaccines or other immunotherapies, then iteratively extending it to PWH on chronic ART, and rapidly translating it into human trials.
