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Antibodies are a principal determinant of immunity for most RNA viruses and have 54 promise to reduce infection or disease during major epidemics. The novel 55 coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections 56 and hundreds of thousands of deaths to date 1,2 . In response, we used a rapid 57 antibody discovery platform to isolate hundreds of human monoclonal antibodies 58 (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five 59 major classes based on their reactivity to subdomains of S protein as well as their 60 cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic 61 SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding 62 domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and 63 demonstrates the speed and robustness of new antibody discovery methodologies. 64 65 Human mAbs to the viral surface spike (S) glycoprotein mediate immunity to other 66 betacoronaviruses including SARS-CoV 3-7 and Middle East respiratory syndrome 67 (MERS) 8-17 . Because of this, we and others have hypothesized that human mAbs may 68 have promise for use in prophylaxis, post-exposure prophylaxis, or treatment of SARS-69 CoV-2 infection 18 . MAbs can neutralize betacoronaviruses by several mechanisms 70 including blocking of attachment of the S protein RBD to a receptor on host cells (which 71 for SARS-CoV and SARS-CoV-2 1 is angiotensin-converting enzyme 2 [ACE2]) 12 . We 72 hypothesized that the SARS-CoV-2 S protein would induce diverse human neutralizing 73 antibodies following natural infection. While antibody discovery usually takes months 74 to years, there is an urgent need to both characterize the human immune response to 75 SARS-CoV-2 infection and to develop potential medical countermeasures. Using Zika 76 virus as a simulated pandemic pathogen and leveraging recent technological advances 77in synthetic genomics and single-cell sequencing, we recently isolated hundreds of 78 was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

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Unrelated individuals can produce genetically similar clones of antibodies, known as public clonotypes, which have been seen in responses to different infectious diseases as well as healthy individuals. Here we identify 37 public clonotypes in memory B cells from convalescent survivors of SARS-CoV-2 infection or in plasmablasts from an individual after vaccination with mRNA-encoded spike protein. We identified 29 public clonotypes, including clones recognizing the receptor-binding domain (RBD) in the spike protein S1 subunit (including a neutralizing, ACE2-blocking clone that protects in vivo ), and others recognizing non-RBD epitopes that bound the S2 domain. Germline-revertant forms of some public clonotypes bound efficiently to spike protein, suggesting these common germline-encoded antibodies are preconfigured for avid recognition. Identification of large numbers of public clonotypes provides insight into the molecular basis of efficacy of SARS-CoV-2 vaccines and sheds light on the immune pressures driving the selection of common viral escape mutants.