Conformational flexibility in neutralization of SARS-CoV-2 by naturally elicited anti-SARS-CoV-2 antibodies

Ruofan Li, Michael Mor, Bingting Ma, Alex E. Clark, Joel Alter, Michal Werbner, Jamie Casey Lee, Sandra L. Leibel, Aaron F. Carlin, Moshe Dessau, Meital Gal-Tanamy, Ben A. Croker*, Ye Xiang*, Natalia T. Freund*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

As new variants of SARS-CoV-2 continue to emerge, it is important to assess the cross-neutralizing capabilities of antibodies naturally elicited during wild type SARS-CoV-2 infection. In the present study, we evaluate the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralization of SARS-CoV-2 VOCs as pseudoviruses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which retain their potency against all VOCs tested. At the second part of our study, we reveal the neutralization mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralizing mAbs by structural characterization. We solve the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å resolutions, respectively, revealing a similar mode of binding to that between the RBD and ACE2. Furthermore, we provide five additional structures (at resolutions of 4.7 Å, 7.3 Å, 6.4 Å, 3.3 Å, and 6.1 Å) of a second antibody, TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralization that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra- and inter-spike RBD subunits. Our study provides additional mechanistic understanding about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insights on the likelihood of reinfections.

Original languageEnglish
Article number789
JournalCommunications Biology
Volume5
Issue number1
DOIs
StatePublished - Dec 2022

Funding

FundersFunder number
BEI Resources
Beijing Frontier Research Center for Biological Structure
KillCorona ISF3711/20
National Institute of Infectious DiseasesNR-55611
National Institutes of Health
National Institute of Allergy and Infectious DiseasesNR-52281, NR-54982, NR-54009, K08AI130381, hCoV-19/Japan/TY7-503/2021
Burroughs Wellcome Fund
University of California, San Diego
BARD401/18, -5270-20R
United States-Israel Binational Science Foundation
National Natural Science Foundation of China31861143027, 31925023, 21827810
Ministry of Science and Technology of the People's Republic of China2021YFA1300200
Israel Science Foundation1422/18
Tsinghua University
Chinese Center for Disease Control and Prevention
Beijing Advanced Innovation Center for Structural Biology, Tsinghua University

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