Structural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2

Kuan-Ying A. Huang (), Xiaorui Chen, Arpita Mohapatra, Hong Thuy Vy Nguyen, Lisa Schimanski, Tiong Kit Tan, Pramila Rijal, Susan K. Vester, Rory A. Hills, Mark Howarth, Jennifer R. Keeffe, Alexander A. Cohen, Leesa M. Kakutani, Yi-Min Wu, Md Shahed-Al-Mahmud, Yu-Chi Chou, Pamela J. Bjorkman, Alain R. Townsend and Che Ma ()
Additional contact information
Kuan-Ying A. Huang: National Taiwan University Hospital, College of Medicine, National Taiwan University
Xiaorui Chen: Academia Sinica
Arpita Mohapatra: Academia Sinica
Hong Thuy Vy Nguyen: Academia Sinica
Lisa Schimanski: University of Oxford, John Radcliffe Hospital
Tiong Kit Tan: University of Oxford, John Radcliffe Hospital
Pramila Rijal: University of Oxford, John Radcliffe Hospital
Susan K. Vester: University of Oxford
Rory A. Hills: University of Oxford
Mark Howarth: University of Oxford
Jennifer R. Keeffe: California Institute of Technology
Alexander A. Cohen: California Institute of Technology
Leesa M. Kakutani: California Institute of Technology
Yi-Min Wu: Academia Sinica
Md Shahed-Al-Mahmud: Academia Sinica
Yu-Chi Chou: Academia Sinica
Pamela J. Bjorkman: California Institute of Technology
Alain R. Townsend: University of Oxford, John Radcliffe Hospital
Che Ma: Academia Sinica

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Antibody-mediated immunity plays a crucial role in protection against SARS-CoV-2 infection. We isolated a panel of neutralizing anti-receptor-binding domain (RBD) antibodies elicited upon natural infection and vaccination and showed that they recognize an immunogenic patch on the internal surface of the core RBD, which faces inwards and is hidden in the “down” state. These antibodies broadly neutralize wild type (Wuhan-Hu-1) SARS-CoV-2, Beta and Delta variants and some are effective against other sarbecoviruses. We observed a continuum of partially overlapping antibody epitopes from lower to upper part of the inner face of the RBD and some antibodies extend towards the receptor-binding motif. The majority of antibodies are substantially compromised by three mutational hotspots (S371L/F, S373P and S375F) in the lower part of the Omicron BA.1, BA.2 and BA.4/5 RBD. By contrast, antibody IY-2A induces a partial unfolding of this variable region and interacts with a conserved conformational epitope to tolerate all antigenic variations and neutralize diverse sarbecoviruses as well. This finding establishes that antibody recognition is not limited to the normal surface structures on the RBD. In conclusion, the delineation of functionally and structurally conserved RBD epitopes highlights potential vaccine and therapeutic candidates for COVID-19.

Date: 2023
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DOI: 10.1038/s41467-023-35949-8

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