B cell lineage directed rational vaccine strategies based on CAP256SU Env-Ab coevolution

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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. This grant aims to elicit bnAbs by a novel strategy that combines priming of multiple V2 apex bnAb germline precursors, immunofocused boosting, and molecularly-guided affinity-maturation. This study design derives from 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 this response by a process of molecularly-guided Env-Ab co-evolution. The study design proposed in this application addresses each of these three critical aspects of bnAb elicitation. Importantly, we propose to target the V2 apex bnAb supersite because of its unique vulnerabilities, which allow it to be targeted by bnAbs with less somatic hypermutation and affinity maturation, without V-gene insertions or deletions and with less restriction for particular light chain pairings. Our proposal is thus unique among the constellation of other HIV-1 vaccine programs that target relatively more challenging bnAb targets such as the CD4bs, V3-glycan patch, fusion peptide or MPER. The project includes three aims: Aim #1 will isolate HIV envelope V2-apex site bnAbs from CAP256.SU Env SHIV (simian-human immunodeficiency virus)-infected RMs, identify their unmutated common ancestors (UCAs) through lineage-tracing by Next-Gen sequencing, and infer through Env-Ab co-evolution analyses CAP256.SU “Env immunotypes” that select for affinity-maturation and neutralization breadth. Aim #2 will develop CAP256.SU trimer immunogens that exhibit enhanced affinity for V2 apex bnAb UCAs by employing in-vitro directed reverse vaccine engineering that targets multiple rhesus and human V2 apex bnAb UCAs. We will validate this optimized CAP256.SU GT-trimer for native configuration and prepare it as a soluble SOSIP trimer and nanoparticle-displayed trimer for testing as a prime to activate multiple rare V2-apex bnAb B cell precursors in outbred RMs. Aim #3 will investigate a B cell lineage-based prime-boost immunization strategy in RMs to induce V2-apex bnAb responses by rationally engineered Env trimer protein immunizations. Novel aspects of this vaccination regimen will be an HIV-1 Env SOSIP prime that activates multiple germline precursor B cells; a V2 apex immunofocused boost using MT145KdV5 SOSIP Env (a simian immunodeficiency virus Env from chimpanzees that retains selective antigenic cross-reactivity with HIV-1 in V2 apex C-strand epitopes), and “polishing” immunizations with Env SOSIP trimers corresponding to affinity-graded V2 apex antigens from Env- Ab coevolution analyses from SHIV.CAP256.SU infected RMs. This study will be the first of its kind, and if successful in inducing bnAbs in RMs, would represent a new paradigm for lineage-based vaccine design.