Rationally designed targeted immunogens to elicit HIV envelope V2-apex broadly neutralizing antibodies - overall: project summary our primary goal in this ipcavd program is to develop a…

Rationally designed targeted immunogens to elicit HIV envelope V2-apex broadly neutralizing antibodies - overall: project summary our primary goal in this ipcavd program is to develop a germline-targeting priming immunogen for the HIV envelope V2-apex broadly neutralizing antibody (BNAB) site. We aim to test its ability to activate V2-apex BNAB precursors in preclinical animal models and manufacture IT under GMP standards for human clinical testing. To address this comprehensively, in this ipcavd grant proposal we have assembled a highly skilled team of investigators with expertise in rational protein design, bioengineering, B and T cell immunology, vaccine evaluation models, antibody discovery, and viral immunology and pathogenesis. We hypothesize that BNAB B cell germline-targeting, immunofocusing and molecularly guided affinity maturation are the essential components of an effective vaccine strategy for eliciting protective HIV ENV V2-apex targeted BNAB responses. Leveraging our strong preliminary work in targeted immunogen development, novel vaccine delivery platforms, adjuvants, and immune monitoring tools, this ipcavd proposal integrates these elements for testing rationally designed prime-boost vaccination strategies in relevant pre-clinical animal models. The overall specific aims of this ipcavd program are: aim #1. Rationally design HIV ENV V2-apex BNAB-site-targeting vaccines through reverse vaccine engineering. Aim #2. Develop vaccination strategies for inducing epitope-targeted HIV BNAB responses using novel preclinical animal models and vaccine delivery platforms. Aim #3. GMP-manufacture the lead germline-targeting vaccine immunogen with the goal for human clinical testing to induce BNAB B cell responses. This ipcavd application builds on a foundation of success in eliciting V2 apex bnabs in multiple rhesus macaques (RMS) by novel simian-human immunodeficiency virus (SHIV) infections and then deconvoluting ENV- AB coevolution pathways to identify novel candidate prime and boost immunogens. From 150 SHIV-infected RMS, we identified the Q23 ENV as our lead platform. Our ipcavd comprises three projects: project 1, through reverse vaccine engineering approaches, will further develop a Q23 ENV-based germline-targeting immunogen to most efficiently engage multiple rhesus and human V2-apex BNAB B cell precursors in vivo and by EX vivo analyses. This is the crux of successful BNAB induction. Project 1 will also design mrna-launched trimer boost immunogens for expanding the breadth of NAB responses. Project 2 will assess the in vivo priming efficiency of the germline-targeted immunogen, and neutralization breadth expansion ability of the mrna-launched trimer boost strategies, first in the V2-apex BNAB UCA expressing KI mice, and subsequently in the NHP model. We will down-select the Q23 germline-targeting priming immunogen and this will be GMP-manufactured in collaboration with project 3, with the goal of human clinical evaluation. If successful, our immunogen regimen could swiftly transition into human clinical testing to induce protective bnabs against HIV.