Development of pan-betacoronavirus vaccines

PROJECT SUMMARY/ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus identified at the end of 2019, has led to the current global pandemic. The SARS-CoV-2 virus belongs to the subgenus sarbecovirus of the genus betacoronavirus, the genus from which two SARS-CoV-2 closely related viruses (SARS-CoV-1 and MERS-CoV) have crossed the species barrier to humans in the past 17 years. These coronaviruses have crossed into humans through zoonotic transmissions from animal reservoirs highlighting a potential threat for future spillovers. Therefore, development of intervention strategies that can mitigate outbreaks of future coronaviruses is critical. To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting neutralizing antibody (nAb) responses against diverse CoVs. Currently there are two major challenges to develop prophylactic vaccine-based strategies against coronaviruses; 1) identification of CoV spike broadly neutralizing antibody (bnAb) sites for vaccine targeting; and 2) the development of vaccine strategies that can reproducibly induce durable and protective bnAb responses against a broad range of coronaviruses. In this R01 grant application, we will squarely address these knowledge gaps by employing a bnAb epitope based rational vaccine design approach to develop immunogens and immunization strategies that can induce coronavirus protective bnAb responses by vaccination. The project consists of 3 aims: Aim #1 will design novel spike S2 stem bnAb site targeting vaccine immunogens using a rational reverse vaccine engineering approach. Using CoV spike S2 stem helix bnAbs and their UCAs we will design, CoV S2 stem peptide-based nanoparticles, rationally engineered S2 bnAb germline-targeting S-protein trimer immunogens and their multimerized nanoparticle versions that can efficiently in vivo activate B cell precursors targeting the S2 stem region conserved across β-CoV spikes. Aim #2 will iteratively evaluate and optimize prime boost immunization strategies in appropriate pre-clinical animal models to develop vaccine protocols that can reproducibly induce durable and protective bnAb responses against diverse β-CoVs. We will assess the in vivo protective efficacy of the vaccine- induced bnAb responses in appropriate virus challenge models. Aim #3 will generate spike S2 stem helix bnAb based "super antibodies" against β-coronaviruses by utilizing rational antibody engineering approaches. The overall goal of this R01 grant proposal is to rationally design novel vaccine immunogen candidates, develop robust vaccination strategies that can induce durable protective bnAb responses against a broad range of β- coronaviruses and develop "super antibody" molecules promising for broad coronaviruses intervention strategies to mitigate SARS-CoV-2 variants of concern and emerging coronaviruses as part of pandemic preparedness.