ABSTRACT - Project 3 Coronaviruses havethe potential to cause significant morbidity andmortality as demonstrated by the ongoing SARS-CoV-2 pandemic. The purpose of this program project is to develop safe and broadly-protective group 2b and 2c betacoronavirus (panbetaCoV) vaccines capable of inducing protective immune responses and evaluate them in animal challenge models. The fact that there has been 3 major CoV outbreaks (SARS-CoV-1, MERS and SARS-CoV-2) in less than 20 years strongly supports the idea of generation of broadly protective panbetaCoV vaccines that can significantly contribute to global pandemic preparedness against future CoV epidemics and pandemics. Coronaviruses (CoVs) have significant pandemic potential, as illustrated by the outbreaks of SARS-CoV-1, MERS and SARS-CoV-2 in less than 20 years. The outbreak of a novel CoV, SARS- CoV-2, has resulted in at over 85 million infections and 1.8 million deaths. Thus, development of panbetaCoV vaccines is essential to preventing a future outbreaks due to an emerging new zoonotic CoV. Messenger RNA/LNP-based vaccines have proved to be highly effective against cancer and infectious diseases and one of the most effective platforms comprises nucleoside-modified mRNA (mod mRNA) encapsulated in LNPs. Two of the leading COVID-19 vaccines in phase 3 clinical trials by Moderna and Pfizer/BioNTech use our nucleoside-modified mRNA-LNP vaccine platform and are 95% protective in Phase 3 trials. Besides potency, mRNA/LNPs can undergo rapid, scalable production and induced durable immune responses. In Project 3, we propose to develop cross-protective and safe mod mRNA-LNP vaccines against animal and human betaCoVs and evaluate their immunogenicity and protective efficacy in preclinical studies. We hypothesize that mod mRNA-LNP vaccines encoding CoV immunogens capable of inducing broadly protective and broadly cross-protective B and T cell responses will effectively provide protection against future outbreaks of zoonotic CoVs.. We propose the following Specific Aims: Aim 1) Development of neutralizing antibody panbetaCoV vaccines using mod mRNA-LNP. Aim 2) Development of T cell vaccines using mod mRNA-LNP. In summary, this proposal aims to develop panbetaCoV vaccines that are safe, easy-to-produce and can induce protective immune responses in animal challenge models. The data generated will be capable of moving this panbetaCoV vaccine approach to clinical development.