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HIVRAD P01 2024 MISSION:
A central goal in HIV/AIDS vaccine research is the elicitation of broadly neutralizing antibodies (bNAbs). During the previous funding period, the Bjorkman lab used novel design strategies to develop HIV-1 envelope (Env) trimer-based immunogens to elicit bNAbs against single and multiple epitopes, including the V3 glycan patch, CD4 binding site (CD4bs), and triple V3/CD4bs/V1V2 targets. In publications among the 32 supported by the previous HIVRAD P01 award AI100148, the Bjorkman and Nussenzweig labs were the first to show that sequential immunizations with multimerized immunogens on protein nanoparticles elicited heterologous neutralizing antibodies (Abs) in inferred germline (iGL) mice, and more impressively, in wildtype (wt) animals with polyclonal Ab repertoires [mice, rabbits, and rhesus macaques (RMs)]. However, the elicited cross-neutralizing Abs did not confer protection from heterologous viral challenge, due at least in part to increasing off-target responses following multiple boosts and the failure of the cross-neutralizing Abs to affinity mature to achieve high potency, breadth, and durability. This led to the discovery by Nussenzweig of Ab feedback and epitope masking, which attenuate focused B cell responses, a concept now becoming entrenched in the HIV-1 vaccine field. The goal of this renewal application is to build on these fundamental discoveries and design more strategic and effective priming and boosting immunogens. To accomplish this, we added a third collaborating research team (Hahn/Shaw/Weissman) that brings expertise in the SHIV model of bNAb induction and mRNA immunogen design. We will gain unique synergies from these highly collaborative research teams as follows:
Project 1 (Bjorkman) will design next-generation prime and boost immunogens based on structural and biophysical analyses of GL-targeted and lineage-based Env-Ab recognition from Project 2; Project 2 (Hahn/Shaw/Weissman) will decipher molecular pathways of Env-Ab coevolution shared among different SHIV-infected RMs that develop neutralization breadth as a “molecular guide” for novel lineage-based immunogen design in Project 1 and will test these new protein nanoparticle and mRNA vaccine platforms for immunogenicity and protection in RMs; and Project 3 (Nussenzweig) will delineate the impacts of Ab feedback, epitope masking, and T follicular helper (Tfh) cell repertoire on enhancing or attenuating on-target B cell responses.
These projects will be enabled by a Protein Expression and Automated Assays Core A (Vielmetter) and an Administrative Core B (Bjorkman). Our hypothesis is that by incorporating lineage-based Env “immunotypes” that elicited bNAbs in SHIV infected RMs in novel nanoparticle and mRNA-LNP vaccine designs (Projects 1 and 2) and by modulating epitope masking and Tfh responses in germinal centers (Projects 1 and 3), we can develop new prime and boost immunogens that lead to neutralization breadth, potency, and durability in wt animals. Achieving this goal would represent a major scientific advance directly translatable to vaccine efforts in humans.