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Highlights d Natural SARS-2 infection induces a subset of potent N-terminal domain-specific mAbs d N-terminal domain reactive human monoclonal antibodies can neutralize live virus d COV2-2676 and COV2-2489 offer protection in a hACE2transgenic mouse model d COV2-2676 and COV2-2489 Fc-effector functions are essential for optimal protection Authors

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technological advances 77in synthetic genomics and single-cell sequencing, we recently isolated hundreds of 78 was not certified by peer review) is the author/funder.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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Understanding the molecular basis for immune recognition of SARS-CoV-2 spike (S) glycoprotein antigenic sites will inform development of improved therapeutics. We determined the structures of two human monoclonal antibodies AZD8895 and AZD1061, which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor binding domain (RBD) of SARS-CoV-2, in order to define the genetic and structural basis of neutralization. AZD8895 forms an “aromatic cage” at the heavy/light chain interface using germline-encoded residues in complementarity determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1, and HCDR3 make interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germline-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.