Résumé de l'article

SARS-CoV-2 neutralizing antibodies elicited upon vaccination or viral infection mostly target the ACE2 binding region on the receptor binding domain (RBD) of the spike protein. This region is the most variable on the spike RBD, consistent with the fact that emerging variants fixed mutations in this part possibly reducing the efficiency of current vaccines and therapeutics. Therefore there is an urgent need for broadly neutralizing antibodies targeting less variable epitopes on the spike RBD. We previously identified a potent human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV without competing with ACE2  for spike binding, and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of trimeric SARS-CoV and SARS-CoV-2 spike ectodomains in complex with the 47D11 Fab. 47D11 binds specifically to the closed conformation of the receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a conserved and mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies that target epitopes only exposed in the RBD up conformation. Altogether, these results reveal a mutationally constrained epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or post-exposure therapy for COVID-19 emerging variants.