Project 1: Rational design of targeted vaccines to induce HIV V2-apex bnAb responses

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

SUMMARY/ABSTRACT: (Project 1) Developing an effective HIV vaccine remains a formidable challenge. Previous approaches focused on stimulating protective T cell responses, non-neutralizing antibodies or broadly neutralizing antibodies (bnAbs). Unfortunately, all these strategies have fallen short in providing consistent protection against infection in both nonhuman primates (NHPs) and humans. This IPCAVD grant proposal seeks to induce bnAbs through an innovative strategy that integrates germline-targeting, immunofocusing, and molecularly guided affinity maturation. This strategy is rooted in the emerging consensus that a successful bnAb-based vaccine must fulfill three critical requirements: i) efficiently engaging and activating rare naive B cell germline precursors of bnAbs; ii) immunofocusing B cell responses toward canonical, conserved bnAb epitopes on the HIV Env trimer, away from off-target strain-specific or trimer base epitopes; and maturing or "polishing" the bnAb lineage response through molecularly guided Env-Ab coevolution. The proposed study design addresses each of these requirements by aiming to elicit bnAbs targeting the highly conserved HIV-1 V2-apex site. What distinguishes out approach from others, is that we have done extensive preliminary work infecting 150 monkeys with 16 different SHIVs, each expressing a different primary HIV-1 Env. This provided us with reagents and insights essential to the current application: First, it showed that the HIV Q23 Env most often elicited V2-apex bnAbs, albeit still with an overall low frequency. Second, it provided us with 10 unambiguous rhesus V2-apex bnAb UCAs to use as templates in our reverse immunogen engineering strategies. In preliminary findings, we have shown that we can engineer the Q23 Env to enhance UCA binding but further optimization is needed, which we propose to do in this Project. Aim #1 focuses on optimizing this germline-targeting trimer or its nanoparticle version through reverse vaccine engineering, utilizing in-vitro directed evolution approaches to enhance affinity toward rhesus and human V2-apex bnAb UCAs. Our goal is an immunogen that binds all three structural classes of HIV V2-apex bnAbs: needle-like, hammerhead and composite. In collaboration with Project 2, we will evaluate the in vivo priming efficiency of optimized germline-targeting immunogens in V2-apex bnAb UCA expressing KI mice and NHPs. A down-selected priming immunogen will undergo GMP manufacturing in Project 3, with the plans for human clinical evaluation. Aim #2 of Project 1 involves devising mRNA-launched HIV trimer boost strategies in V2-apex bnAb UCA KI mice to broaden bnAb breadth and selecting a boosting regimen for testing in NHPs. Overall, the goal of Aim #2 is to iteratively evaluate mRNA-launched trimer boost strategies to develop vaccine protocols capable of consistently inducing V2-apex bnAb responses in preclinical animal models. Success would mark a significant advancement in HIV-1 vaccine science, potentially paving the way for rapid transition into human testing.