Potently neutralizing and protective human antibodies against SARS-CoV-2

The COVID-19 pandemic is a major threat to global health(1) for which there are limited medical countermeasures(2,3). Moreover, we currently lack a thorough understanding of mechanisms of humoral immunity(4). From a larger panel of human monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein(5), we identified several that exhibited potent neutralizing activity and fully blocked the receptor-binding domain of S (S(RBD)) from interacting with human ACE2 (hACE2). Competition-binding, structural, and functional studies allowed clustering of the mAbs into classes recognizing distinct epitopes on the S(RBD) as well as distinct conformational states of the S trimer. Potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two mouse models of SARS-CoV-2 infection, passive transfer of either COV2-2196 or COV2-2130 alone or a combination of both mAbs protected mice from weight loss and reduced viral burden and inflammation in the lung. In addition, passive transfer of each of two of the most potently ACE2 blocking mAbs (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on S(RBD) and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutics.