Human monoclonal antibodies for prophylaxis and therapy against the new coronavirus

The WHO and US authorities have declared a public health emergency over the recent outbreak of a newcoronavirus (CoV) originating from Wuhan, China (nCoV-2019, recently renamed SARS-CoV-2 andresponsible for causing the coronavirus disease termed COVID-2019). The discovery of human monoclonalantibodies to this new CoV and obtaining a molecular understanding of its target epitopes will advance thedevelopment of diagnostics, therapeutics and vaccines to limit virus spread. The overall goal of this proposal is to discover and characterize potent broadly neutralizing antibodiesto nCoV-2019 that also neutralize closely related strains of CoV such as SARS and other variants currentlyfound in bats but likely to be able to produce human infections in the future. The Nussenzweig laboratoryhas developed robust methods to isolate, recombinantly produce and characterize human antibodies fromthe memory B cells of individuals infected by a series of different pathogens including HIV-1, Flavivirusesincluding Zika, and Hepatitis B virus (1, 2). These methods have also been used by other laboratories toisolate neutralizing antibodies to malaria, Ebola, influenza and other human infections (reviewed in (3)). TheBjorkman laboratory has performed structural studies using these antibodies to obtain information that directsvaccine design and therapies (2, 4-23). In Aim 1, we obtain samples from nCoV-2019 convalescing individuals (see letter from Dr. WesleyVan Voorhis). Serum samples will be tested for binding to the trimeric nCoV-2019 spike protein (S) and to theisolated receptor binding domain (RBD) of the S protein (see letter of collaboration from Dr. John Pak at Chan-Zuckerberg Biohub). Individuals with high titers against S and RBD will be recruited for large blood donations.Antibodies will be identified from the memory B cells of these individuals. In Aim 2 we will clone and expressthe antibodies obtained in Aim 1. The anti-nCoV-2019 antibodies will be tested for binding to the S proteinfrom Severe Acute Respiratory Syndrome (SARS) and other closely related bat-derived CoV to test for cross-reactivity. Any promising antibodies will be evaluated for neutralizing activity (see letter by Dr. TimothySheahan at the University of North Carolina). In Aim 3 Dr. Bjorkman will solve crystal structures of antibodyFabs, and cryo-EM structures of coronavirus spike trimers complexed with Fabs from antibodies identifiedfrom Aims 1 and 2. In addition to helping guide vaccine development through the identification of neutralizing targets, theproposed discovery of human monoclonal antibodies to nCoV-2019 and related viruses bears a significanttranslational potential, such as the treatment and prophylaxis of severe medical conditions associated withnCoV-2019 infection by passive antibody transfer.