Discovery of SARS-CoV-2 neutralizing Abs for therapy, prophylaxis and vaccine development.

$188,714UM1FY2020AINIH

Scripps Research Institute, The, La Jolla CA

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Abstract

This application is being submitted in response to NOT-AI-20-030 Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses and the subfamily consists of only 2 members, Alpha- and Betacoronavirus which infect mammals and generally result in respiratory illnesses. In 2019, the World Health Organization was notified of a cluster of pneumonia cases possibly originating from a seafood market in Wuhan city, Hubei Province, China. Within three weeks, a total of 198 cases of novel coronavirus-infected pneumonia were confirmed, and an analysis of 138 cases at the Zhongnan Hospital of Wuhan University found a mortality rate of 4.3%. As of February 25, 2020, there were 79,331 confirmed cases of a clinical syndrome now called COVID-19, as the result of infection by a novel virus named SARS-CoV-2. The rapid global spread of COVID-19 is possible in part because there is no clinically approved treatment or vaccine for SARS-CoV-2. This supplement application will leverage our existing expertise in antibody discovery and characterization to rapidly identify pan-CoV neutralizing antibodies. Recovered Abs will function both as lead therapeutics to address the ongoing COVID-19 outbreak and tools for evaluating candidate vaccines, by addressing 3 Specific Aims: Aim 1: Isolation of SARS-CoV-2 neutralizing antibodies. Antibodies will be isolated from plasmablasts (acute infection) and memory B cells (convalescence) of COVID-19 patients. Aim 2: Characterization of pan-CoV neutralizing antibodies. Isolated mAbs will be screened for neutralization using a SARS-CoV-2 pseudovirus assay as well as a panel of Betacoronavirus pseudoviruses to determine the breadth of neutralization across the Coronavirus subfamily. Aim 3: Optimization of potency and developability of neutralizing antibodies. Antibodies in the most promising cocktail will be affinity matured to improve their overall potency and to remove potential manufacturing liabilities.

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