Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that was first isolated in Wuhan China in December, 2019. SARS-CoV-2 is the cause of coronavirus disease 2019 (COVID-19), which is now a pandemic and has caused more than 1.3 million confirmed cases and 72,000 deaths, with an estimated case fatality rate of 4%, with substantially higher death rates (~15%) in the elderly or immunocompromised. Virtually all countries and territories have reported cases, with major epidemics in China, Italy, Spain, France, Germany, Iran, and the United States. SARS-CoV-2 is thought to be of zoonotic origin, most likely bats, and is about 75% identical to the original SARS-CoV. Most cases are spread by direct human-to- human transmission, with community transmission in asymptomatic individuals described. Currently, no countermeasures are licensed for human use. The development, characterization, and ultimately deployment of an antibody-based treatment against SARS-CoV-2 could prevent substantial morbidity and mortality, and possibly mitigate its epidemic spread. This interactive multi-PI proposal leverages complementary expertise in the Diamond, Crowe, and Baric laboratories to rapidly develop highly neutralizing and therapeutic human monoclonal antibodies (mAbs) against SARS-CoV-2 for immediate use in humans. To achieve this goal, we will generate and interrogate human mAbs against SARS-CoV-2 that are obtained from multiple convalescent subjects. We will identify potently neutralizing mAbs and optimize them for affinity by selecting naturally occurring somatic variants identified by repertoire sequencing and sibling analysis and Fc effector functions. Protective activity of top candidate coronavirus mAbs will be tested in newly-generated and optimized mouse models of SARS-CoV-2 infection, including those expressing human ACE2 receptors (hACE2). To define correlates of protection, we will use chimeric viruses, shotgun mutagenesis, and neutralization escape to identify the epitopes of our most protective mAbs. Our team has extensive experience in the generation, characterization and optimization of antibodies, CoV biology, and animal models of disease and protection. A therapy composed of one to three highly neutralizing mAbs may provide an immediate countermeasure against the pandemic spread of SARS-CoV-2 and help establish correlates of structural and functional humoral protection that ultimately inform vaccine efforts.