Project 1: Immunogen Design and Delivery

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PROJECT SUMMARY/ABSTRACT The development of an effective HIV vaccine remains a major challenge. Previous strategies for HIV vaccine design aimed to elicit protective T cell responses, non-neutralizing antibodies, broadly neutralizing antibodies (bnAbs), or some combination of the three but have failed to protect against infection. There is a growing consensus that critical elements to a successful bnAb-based vaccine will be its ability to: i) efficiently activate and expand multiple rare naïve bnAb-encoding B cell precursors; ii) immunofocus these B cell responses to canonical, conserved bnAb epitopes on the HIV Env trimer and away from off-target epitopes; and iii) affinity- mature these response to breadth by heterologous vaccinations. The study design proposed in this application addresses each of the critical aspects of bnAb elicitation. The grant aims to elicit bnAbs by a novel strategy that combines priming of HIV bnAb encoding rare B cell precursors by rationally designed germline-targeting trimer immunogens and expand their breadth with diverse heterologous trimer boosts. The project 1 includes three aims: Aim #1 will develop an HIV trimer immunogen that can target rare V2-apex and V3-glycan bnAb-encoding precursor B cells. Using in-vitro directed reverse vaccine engineering platform, we will develop germline-targeting priming immunogen that exhibits enhanced affinity for V2 apex and V3-glycan bnAb UCAs to utilize as a priming immunogen to active rare bnAb B cell precursors to these sites. Aim #2 will investigate the priming efficiency of GT-trimer immunogen delivered through various vaccine platforms, to in vivo activate V2-apex and V3-glycan bnAb B cell precursors in various bnAb precursor expressing animal models. The aim is to generate a robust epitope specific memory B cell response that could be further boosted toward breadth. Aim #3 will investigate various boost strategies using newly designed diverse HIV trimers to expand the neutralization breadth of the V2-apex and V3-glycan specific bnAb B cell responses. If successful, the study will be the first of its kind, would represent a new paradigm for rational vaccine design strategies for HIV.