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With the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here, we developed a panel of neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) that bound the receptor binding domain of the spike protein at distinct epitopes and blocked virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Although several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by ancestral SARS-CoV-2 strains, others induced escape variants in vivo or lost neutralizing activity against emerging strains. One mAb, SARS2-38, potently neutralized all tested SARS-CoV-2 variants of concern and protected mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engaged a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of neutralizing antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants. [Display omitted] • SARS-CoV-2 mAbs recognizing the RBD block viral attachment and/or entry • SARS2-38 mAb efficiently inhibits infection of a broad panel of SARS-CoV-2 variants • Cryo-EM shows SARS2-38 binds a highly conserved region of the spike protein • SARS2-38 controls infection in vivo in K18-hACE2 transgenic mice and hamsters VanBlargan et al. describe a potently neutralizing mAb, SARS2-38, that recognizes a panel of SARS-CoV-2 variants and confers therapeutic protection in vivo. Structure analysis of SARS2-38 bound to the viral spike protein reveals the basis of its broadly neutralizing activity, highlighting an epitope target for antibody therapeutics and vaccine design. [ABSTRACT FROM AUTHOR]

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes. [Display omitted] • Natural SARS-2 infection induces a subset of potent N-terminal domain-specific mAbs • N-terminal domain reactive human monoclonal antibodies can neutralize live virus • COV2-2676 and COV2-2489 offer protection in a hACE2-transgenic mouse model • COV2-2676 and COV2-2489 Fc-effector functions are essential for optimal protection Suryadevara et al. find human neutralizing antibodies to the spike protein N-terminal domain that arise from natural infection with SARS-CoV-2. These antibodies inhibit post-attachment steps of the viral cycle and initiate protective immune responses via the antibody Fc domain. [ABSTRACT FROM AUTHOR]