Abstract - Project 1 Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and Middle East Respiratory coronavirus (MERS- CoV) in 2012. In Dec 2019, a third novel coronavirus (CoV) designated SARS-CoV-2 emerged in Wuhan China and in the space of 11 months, has caused over 85 million cases, >1.8 million deaths in >217 countries. Over 1/5 of these total cases have been reported in the US, resulting in over 350,000 deaths. In humans, virus infection results in COVID-19 disease, characterized by pneumonia and severe acute respiratory distress syndrome (ARDS), an often-fatal end-stage lung disease. In addition to SARS-CoV2, multiple other SARS-like and MERS-like CoV strains reside in bats and other species and are poised to emerge at some point in the future. The threat posed by these viruses creates a need for the development of broadly efficacious antivirals and vaccines that will protect against this heterogeneous family of highly pathogenic emerging viruses. In response, our assembled team in this P01 of leading virologists with complementary expertise in viral immunity, CoV pathogenesis, antibody repertoire mapping, vaccinology and structure-based vaccine design have developed an integrated program designed to develop panbetaCoV vaccines that protect against the Merbecoviruses (MERS-like group 2c) and Sarbecoviruses (SARS-like group 2b CoV). Project 1, led by the Baric and Heise laboratories at UNC, will develop and test panels of wildtype and chimeric vaccines developed in the context of a well-established alphavirus replicon particle (VRP) vaccine platform. They will interface with other projects and cores to map the location of broadly neutralizing antibody epitopes that will inform panCoV vaccine design. They will also produce killed and live attenuated viruses as vaccine gold standards and models for vaccine induced immune pathology phenotypes (VARED). Project 1 also provides mouse models of human disease, including the first lethal mouse adapted SARS-CoV-2 MA10 variant that replicates efficiently and produces ARDS like disease phenotypes in standard laboratory mice. They also provide novel mouse models of human disease for other SARS-like and MERS-like CoV. Project 1 also provides reporter viruses expressing nLUC, that span the group 2 and group 1 CoV that provide precise measures of neutralizing antibody titer, breadth and magnitude following natural infection and vaccination. Finally, they provide robust heterologous challenge models for evaluating the breadth and performance of emerging coronavirus vaccines. The overall goal is to develop a panCoV vaccine that will universally protect against group 2b and 2c CoV. Aim 1 deciphers the antigenic structure of the BetaCoV. Aim 2 measures group 2b and 2c vaccine performance after virus challenge. Aim 3 develops and tests panbetaCoV vaccine candidates.