Abstract - Overall Compared to SARS-CoV-1 and MERS, the current SARS-CoV-2 virus is highly transmissible and to date has caused over 85,000,000cases worldwidewith over 1,800,000 deaths. With an endemic population of multipleother strains of CoVs in bats, rodents with intermediate hosts, civets and pangolins, and because of the ability of CoVs to recombine, it is a certainty that new CoVs with infectious potential for humans will cause future human pandemics. To address this problem in a focused and integrated way, this P01 team of virologists, immunologists, computational biologists, structural biologists, biophysicists, evolutionary biologists, and traditional vacci nologists will develop panbetacoronavirus (panbetaCoV) vaccines, including Merbecoviruses (group 2c), which gave rise to MERS, and Sarbecoviruses (group 2b), which gave rise to SARS CoV-1 and SARS CoV-2, the three most deadly betaCoV human outbreaks. The Significance of this grant is that it will provide for panbetaCoV vaccines for future epidemics that can be immediately available at the onset of a betaCoV pandemic, avoiding much of the human tragedy and social disruption caused by a pandemic. The Overall Specific Aims of the P01 are: Aim 1. Develop and characterize immunogenicity of PanbetaCoV Sarbecovirus (Group 2b) vaccine candidates. Aim 2. Determine Group 2b vaccine candidate protection capacity against group 2b panel of viruses. Aim 3. Develop PanbetaCoVMerbecovirus (group2c) vaccine candidates, determinetheir immunogenicity, cross- reactivity with other betaCoVs and protection capacity against group 2c panel of viruses. This program project grant includes four projects. Project 1 will design vaccines in alphavirus replicon particle (VRP) vaccine system, develop and test P01 vaccines in their unique mouse CoV challenge models. Project 2 will use structure-based molecular modeling and monomer and multimer nanoparticle spike protein designs and test in wild-type mouse models. Project 3 will both design CoV vaccines and test vaccine designs expressed as mRNAs in liquid nanoparticles (LNPs). Project 4 will computationally design B and T cell panbetaCoV vaccines. This P01 proposes three Cores: an Administrative Core, a Biocontainment and Immune Monitoring Core, and a Non-human Primate Core. Work in this P01 will provide panbetaCoV vaccines to protect against escape mutants of SARS-CoV-2 in the current epidemic, and will be available to protect society against new betaCoVs that might emerge to infect humans in the future.

Narrative Coronaviruses pose a current and future pandemic threat and the development of pan-betacoronavirus vaccines are a global priority. The purpose of this program is to design and develop new panbetacoronavirus vaccines for groups 2b and 2c in the event a novel animal coronavirus spills over into humans resulting in a new severe coronavirus outbreak.