Uncovering a conserved vulnerability site in SARS-CoV-2 by a human antibody.

Li, Tingting; Cai, Hongmin; Zhao, Yapei; Li, Yanfang; Lai, Yanling; Yao, Hebang; Liu, Liu Daisy; Sun, Zhou; van Vlissingen, Martje Fentener; Kuiken, Thijs; GeurtsvanKessel, Corine H; Zhang, Ning; Zhou, Bingjie; Lu, Lu; Gong, Yuhuan; Qin, Wenming; Mondal, Moumita; Duan, Bowen; Xu, Shiqi; Richard, Audrey S; Raoul, Hervé; Chen, JianFeng; Xu, Chenqi; Wu, Ligang; Zhou, Haisheng; Huang, Zhong; Zhang, Xuechao; Li, Jun; Wang, Yanyan; Bi, Yuhai; Rockx, Barry; Chen, Junfang; Meng, Fei-Long; Lavillette, Dimitri; Li, Dianfan

An essential step for SARS-CoV-2 infection is the attachment to the host cell receptor by its Spike receptor-binding domain (RBD). Most of the existing RBD-targeting neutralizing antibodies block the receptor-binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non-RBM-targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a KD of 5.6 nM, neutralizes SARS-CoV-2 including the current Variants of Concern such as B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta), displays modest cross-reactivity against SARS-CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted 'ideal' vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20-binding but confers little or no resistance to neutralization. Finally, in vitro mode-of-action characterization and negative-stain electron microscopy suggests a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS-CoV-2 Spike for the development of potential antiviral drugs.