Project 2: Development of vaccines in preclinical models to induce V2-apex bnAb responses

Previous strategies to develop an effective neutralizing antibody-based HIV-1 vaccine have failed to consistently induce bnAb responses or confer clinical protection in NHPs or humans. We believe this failure has in part been due to the fact that preclinical animal model testing has not been sufficiently rigorous and stringent, allowing many candidate vaccines to advance prematurely to late-stage development. The goal of Project 2 is to develop and use stringent preclinical murine and rhesus models to test candidate immunogens developed in Project 1 to down-select candidates with a high likelihood of inducing bnAbs in NHPs and humans. This IPCAVD grant aims to accomplish this goal by means of a novel strategy that combines – for the first time – germline-targeting, immunofocusing and molecularly-guided affinity maturation of novel candidate immunogens designed from a “molecular blueprint” of successful B cell priming and Env-Ab coevolution leading to V2 apex bNAb induction SHIV-infected RMs and HIV-1 infected humans. The proposed study design evolves from a growing consensus that critical elements to a successful bnAb-based vaccine will be its ability to efficiently bind and activate rare naïve B cell germline precursors of bnAbs; to immunofocus these B cell responses to canonical, conserved bnAb epitopes on the HIV Env trimer and away from off-target strain specific or trimer base epitopes; and to mature or “polish” this bnAb lineage response by a process of molecularly guided Env-Ab coevolution. Project 2 of this IPCAVD will assess each of these three essential requirements for bnAb induction in newly-developed human and rhesus Ig gene knockin (KI) mouse models and in RMs. The lead investigators of Project 2 and of this IPCAVD more generally represent a highly collaborative research team with a strong track record of scientific discovery, bioengineering and molecular tool development, and vertebrate primate modeling of HIV infection. This expertise is evident in the development of novel germline targeted V2 apex immunogens (Andrabi), bioengineering and clinical development of the novel saponin SMNP adjuvant (Irvine), discovery of V2 apex immunofocusing chimpanzee simian immunodeficiency viral Envs (Hahn), creation of CRISPRCas9 knock-in mice (Batista), development of next-generation “designer” SHIVs (Shaw), the discovery and clinical development of the highly successful mRNA-LNP (lipid nanoparticle) immunization platform (Weissman) and successful preclinical-clinical translation (Price). Project 2 consists of two aims: Aim #1 will develop and use novel KI preclinical mouse models with B cells bearing human or rhesus inferred germline (iGL) precursors to V2-apex bnAbs to downselect prime-boost immunogens for NHP trials; Aim #2 will develop and use validated models of rhesus V2 apex bnAb induction to test and further down-select candidate immunogens from Project 1 for advancement to GMP production (Project #3) and it will iteratively test candidate sequential boost immunogens to move toward a complete protective regimen that consistently elicits bNAbs in outbred NHPs and potentially in humans. Project Number: 1U19AI188562-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: GEORGE SHAW | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $2,750,363 | Activity Code: U19 | Study Section: Special Emphasis Panel[ZAI1 SAG-A (S1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1U19AI18856201