@article{cbd6a2b587b44b66a850f9f671f2c79c,
title = "Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity",
abstract = "Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.",
author = "Hejun Liu and Wu, {Nicholas C.} and Meng Yuan and Sandhya Bangaru and Torres, {Jonathan L.} and Caniels, {Tom G.} and {van Schooten}, Jelle and Xueyong Zhu and Lee, {Chang Chun D.} and Brouwer, {Philip J.M.} and {van Gils}, {Marit J.} and Sanders, {Rogier W.} and Ward, {Andrew B.} and Wilson, {Ian A.}",
note = "We thank Henry Tien for technical support with the crystallization robot, Jeanne Matteson and Yuanzi Hua for contributions to mammalian cell culture, Wenli Yu for insect cell culture, Robyn Stanfield for assistance with data collection, and Paul Bieniasz for cells and plasmids for the pseudovirus neutralization assays. We are grateful to the staff of Stanford Synchrotron Radiation Laboratory (SSRL) Beamline 12-1 for assistance. This work was supported by NIH K99 AI139445 (to N.C.W.), the Bill and Melinda Gates Foundation ( OPP1170236 to A.B.W. and I.A.W. and OPP1132237 and INV-002022 to R.W.S.), NIH HIVRAD ( P01 AI110657 to R.W.S., A.B.W., and I.A.W.), NIH CHAVD ( UM1 AI44462 to A.B.W. and I.A.W.), a Netherlands Organisation for Scientific Research (NWO) Vici grant (to R.W.S.), the Fondation Dormeur , Vaduz (to M.J.v.G.), and a Health-Holland PPS allowance ( LSHM20040 to M.J.v.G.). M.J.v.G. is a recipient of an AMC fellowship and a COVID-19 grant from the Amsterdam Institute of Infection and Immunity . J.v.S. is a recipient of a 2017 AMC PhD scholarship. Use of the SSRL, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract DE-AC02–76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and the National Institutes of Health , National Institute of General Medical Sciences (including P41GM103393 ). We thank Henry Tien for technical support with the crystallization robot, Jeanne Matteson and Yuanzi Hua for contributions to mammalian cell culture, Wenli Yu for insect cell culture, Robyn Stanfield for assistance with data collection, and Paul Bieniasz for cells and plasmids for the pseudovirus neutralization assays. We are grateful to the staff of Stanford Synchrotron Radiation Laboratory (SSRL) Beamline 12-1 for assistance. This work was supported by NIH K99 AI139445 (to N.C.W.), the Bill and Melinda Gates Foundation (OPP1170236 to A.B.W. and I.A.W. and OPP1132237 and INV-002022 to R.W.S.), NIH HIVRAD (P01 AI110657 to R.W.S. A.B.W. and I.A.W.), NIH CHAVD (UM1 AI44462 to A.B.W. and I.A.W.), a Netherlands Organisation for Scientific Research (NWO) Vici grant (to R.W.S.), the Fondation Dormeur, Vaduz (to M.J.v.G.), and a Health-Holland PPS allowance (LSHM20040 to M.J.v.G.). M.J.v.G. is a recipient of an AMC fellowship and a COVID-19 grant from the Amsterdam Institute of Infection and Immunity. J.v.S. is a recipient of a 2017 AMC PhD scholarship. Use of the SSRL, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract DE-AC02–76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). H.L. N.C.W. M.Y. and I.A.W. conceived and designed the study. H.L. N.C.W. M.Y. and C.-C.D.L. expressed and purified the proteins for crystallization. T.G.C. P.J.M.B. M.J.v.G. and R.W.S. provided antibody clones and sequences. T.G.C. performed binding analyses, and J.v.S. provided neutralization data. H.L. N.C.W. M.Y. and X.Z. crystallized and determined the X-ray structures. S.B. J.L.T. and A.B.W. provided nsEM data and reconstruction. H.L. N.C.W. M.Y. and I.A.W. wrote the paper, and all authors reviewed and/or edited the paper. A patent application for the SARS-CoV-2 antibody COVA1-16 and other antibodies first disclosed by Brouwer et al. (2020) has been filed by Amsterdam UMC under application number 2020-039EP-PR. I.A.W. is a member of the Immunity Editorial Board.",
year = "2020",
month = dec,
day = "15",
doi = "10.1016/j.immuni.2020.10.023",
language = "English (US)",
volume = "53",
pages = "1272--1280.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}