Multivalent mRNA HIV vaccine using Envelopes from recently circulating viruses.

ABSTRACT Despite the advent of highly active anti-retroviral therapy, there are ~1 million new HIV infections and hundreds of thousands of deaths annually. Thus, HIV is still a global health concern, and there remains an unmet critical need for an effective vaccine to prevent HIV-1 acquisition. One strategy for an effective HIV vaccine is to elicit broadly neutralizing antibodies (bnAbs) that target conserved epitopes on Envelope (Env) of diverse HIV strains of different subtypes. Recent studies have shown that subtype C HIV-1 Env diversification over time has resulted in greater resistance to nAbs and Fc-mediated antiviral activities, thus highlighting the need for bnAb-inducing vaccine strategies to target recent subtype C viruses. However, there remains a gap in our knowledge regarding the induction of bnAbs, including those that can target subtype C HIV Envs. A common vaccination strategy for the development of bnAbs is the initial priming and subsequent boosting or maturation of B cells that have the capacity to develop bnAb status with heterologous HIV neutralization breadth. In this proposal, I will use a single priming Env immunogen followed by multivalent Env boosts to mature V2-apex nAbs to bnAb status in a NHP model. My central hypothesis is that a V2-apex precursor B cell engaging prime and multivalent boosting with computationally selected immunogens that captures the diversity in the V2 region of recently circulating subtype C HIV, will engage and mature B cell lineages capable of generating robust polyfunctional Env V2-targeting Abs that can neutralize heterologous HIV, including subtype C Envs. The scientific premise for this project is that identifying vaccine immunogens capable of inducing V2- targeting polyfunctional Abs that can recognize recently circulating viruses, including subtype C will provide a much-needed component of a successful vaccine that can prevent HIV-1 acquisition. At the completion of the proposed research, my expected outcomes are two-fold and related to: 1) scientific achievements: development of an HIV-1 vaccine that elicits robust polyfunctional anti-V2 Ab responses against subtype C Envs in an NHP model; and 2) career development: to gain knowledge and skills for leading a preclinical and translational research program using NHP models to develop and test vaccines and immunoprophylaxis strategies for HIV and other emerging/established pathogens.