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

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