The antigenic anatomy of SARS-CoV-2 receptor binding domain

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 mu g/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

Automated summary

Antibodies play a crucial role in immune protection against SARS-CoV-2, with some being used as therapeutics. A study identified 377 human monoclonal antibodies, focusing on 80 that bind the virus spike, and found that most highly inhibitory antibodies can block the virus-receptor interaction. Novel binding modes of potent inhibitory antibodies were discovered, showing potential for prophylactic or therapeutic use in animal models.