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

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Abstract
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 K D 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 suggest 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.
Funding Information
  • National Natural Science Foundation of China (31870726)
  • National Natural Science Foundation of China (31970880)
  • National Natural Science Foundation of China (31870153)
  • Strategic Priority Research Program of CAS (XDB37020204)
  • Strategic Priority Research Program of CAS (XDB29010102)
  • Key Program of CAS Frontier Science (QYZDB‐SSW‐SMC037)
  • Ministry of Science and Technology of China (2020YFC0845900)
  • Ministry of Science and Technology of China (2017YFA0506700)
  • CAS President's International Fellowship Initiative (2020VBA0023)
  • The Key R&D Program of Jiangsu Province (Social Development) Project (BE2019625)
  • Science and Technology Commission of Shanghai Municipality (20ZR1466700)
  • Science and Technology Commission of Shanghai Municipality (20490760200)
  • Shanghai Municipal Science and Technology Major Project (20431900402)
  • Innovation Capacity Building Project of Jiangsu province Nanjing Unicorn Academy of innovation (BM2020019)
  • European Union's Horizon 2020 Research & Innovation Program (824061)
  • Science and Technology Commission of Hangzhou Municipality (202013A02)
  • RECOVER European Union's Horizon 2020 research and innovation program (101003589)
  • NSFC Outstanding Young Scholars (31822055)
  • Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017122)
  • CAS Grant (JCTD‐2020‐17)
  • CAS Facility‐based Open Research Program

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