Human antibody-based countermeasures against the Wuhan Coronavirus SARS-CoV-2

Project Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virusthat was first isolated in Wuhan China in December, 2019. SARS-CoV-2 is the cause of coronavirus disease2019 (COVID-19), which is now a pandemic and has caused more than 1.3 million confirmed cases and 72,000deaths, with an estimated case fatality rate of 4%, with substantially higher death rates (~15%) in the elderly orimmunocompromised. 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, mostlikely 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, nocountermeasures are licensed for human use. The development, characterization, and ultimately deployment ofan antibody-based treatment against SARS-CoV-2 could prevent substantial morbidity and mortality, andpossibly mitigate its epidemic spread. This interactive multi-PI proposal leverages complementary expertise inthe Diamond, Crowe, and Baric laboratories to rapidly develop highly neutralizing and therapeutic humanmonoclonal antibodies (mAbs) against SARS-CoV-2 for immediate use in humans. To achieve this goal, we willgenerate and interrogate human mAbs against SARS-CoV-2 that are obtained from multiple convalescentsubjects. We will identify potently neutralizing mAbs and optimize them for affinity by selecting naturally occurringsomatic variants identified by repertoire sequencing and sibling analysis and Fc effector functions. Protectiveactivity of top candidate coronavirus mAbs will be tested in newly-generated and optimized mouse models ofSARS-CoV-2 infection, including those expressing human ACE2 receptors (hACE2). To define correlates ofprotection, we will use chimeric viruses, shotgun mutagenesis, and neutralization escape to identify the epitopesof our most protective mAbs. Our team has extensive experience in the generation, characterization andoptimization of antibodies, CoV biology, and animal models of disease and protection. A therapy composed ofone to three highly neutralizing mAbs may provide an immediate countermeasure against the pandemic spreadof SARS-CoV-2 and help establish correlates of structural and functional humoral protection that ultimatelyinform vaccine efforts.