Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1276-1289.e6 |
| Journal | Immunity |
| Volume | 54 |
| Issue number | 6 |
| Early online date | 2021 |
| DOIs | |
| Publication status | Published - 8 Jun 2021 |
Keywords
- B.1.1.7
- SARS-CoV-2
- antibody
- immune escape
- neutralization
- neutralizing epitope
- variant of concern
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In: Immunity, Vol. 54, No. 6, 08.06.2021, p. 1276-1289.e6.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant
AU - Graham, Carl
AU - Seow, Jeffrey
AU - Huettner, Isabella
AU - Khan, Hataf
AU - Kouphou, Neophytos
AU - Acors, Sam
AU - Winstone, Helena
AU - Pickering, Suzanne
AU - Galao, Rui Pedro
AU - Dupont, Liane
AU - Lista, Maria Jose
AU - Jimenez-Guardeño, Jose M.
AU - Laing, Adam G.
AU - Wu, Yin
AU - Joseph, Magdalene
AU - Muir, Luke
AU - van Gils, Marit J.
AU - Ng, Weng M.
AU - Duyvesteyn, Helen M. E.
AU - Zhao, Yuguang
AU - Bowden, Thomas A.
AU - Shankar-Hari, Manu
AU - Rosa, Annachiara
AU - Cherepanov, Peter
AU - McCoy, Laura E.
AU - Hayday, Adrian C.
AU - Neil, Stuart J. D.
AU - Malim, Michael H.
AU - Doores, Katie J.
N1 - Funding Information: This work was funded by; King's Together Rapid COVID-19 Call award to M.H.M. K.J.D. and S.J.D.N. UK Medical Research Council (MRC) Discovery award MC/PC/15068 to S.J.D.N. K.J.D. and M.H.M. Fondation Dormeur, Vaduz for funding equipment to K.J.D. a Huo Family Foundation award to M.H.M. K.J.D. M.S.H. and S.J.D.N. MRC Programme Grant (MR/S023747/1 to M.H.M.), Wellcome Trust Multi-User Equipment Grant 208354/Z/17/Z to M.H.M. S.J.D.N. K.D. and A.C.H. Wellcome Trust Investigator Award 106223/Z/14/Z to M.H.M. NIAID Awards U54 AI150472 and AI076119 to M.H.M. The UK CIC (Covid-Immunology-Consortium) to A.C.H. the Rosetrees Trust to A.C.H. and UCL Coronavirus Response Fund to L.E.M. (made possible through generous donations from UCL's supporters, alumni, and friends). M.S.H. is funded by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. This study is part of the EDCTP2 program supported by the European Union (grant number RIA2020EF-3008 COVAB). The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. C.G. and H.W. were supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). S.A. was supported by an MRC-KCL Doctoral Training Partnership in Biomedical Sciences industrial Collaborative Award in Science & Engineering (iCASE) in partnership with Orchard Therapeutics (MR/R015643/1). Work in P.C. laboratory is funded by the Francis Crick Institute (FC001061), which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. T.A.B. is supported by the Medical Research Council (MR/S007555/1). The Wellcome Centre for Human Genetics is supported by Wellcome Centre grant 203141/Z/16/Z. L.E.M. was supported by a Medical Research Council Career Development Award MR/R008698/1. This work was supported by the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St. Thomas? NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. Thank you to Philip Brouwer and Rogier Sanders (University of Amsterdam) for the Spike protein construct, and James Voss and Deli Huang for providing the HeLa-ACE2 cells. Conceptualization, K.J.D. M.H.M. C.G. J.S.; Methodology, C.G. J.S. I.H. H.K. N.K. S.A. H.W. S.P. R.P.G, L.D. M.J.L. J.M.J.-G. L.M. W.M.N. H.M.E.D. Y.Z. T.A.B.; Formal analysis, K.J.D. C.G. J.S. I.H. H.K. W.N.G. T.A.B.; Resources, A.G.L. Y.W. M.J. M.S.-H. A.R. P.C. L.E.M. A.C.H. M.J.v.G.; Supervision, K.J.D. M.H.M. S.J.D. A.C.H. L.E.M. P.C.; Writing ? original draft, K.J.D. C.G. J.S. I.H. H.K. M.H.M.; All authors reviewed and edited the manuscript. The authors declare no competing interests. Funding Information: This work was funded by; King’s Together Rapid COVID-19 Call award to M.H.M., K.J.D., and S.J.D.N., UK Medical Research Council (MRC) Discovery award MC/PC/15068 to S.J.D.N., K.J.D., and M.H.M., Fondation Dormeur, Vaduz for funding equipment to K.J.D., a Huo Family Foundation award to M.H.M., K.J.D., M.S.H., and S.J.D.N., MRC Programme Grant ( MR/S023747/1 to M.H.M.), Wellcome Trust Multi-User Equipment Grant 208354/Z/17/Z to M.H.M., S.J.D.N., K.D., and A.C.H., Wellcome Trust Investigator Award 106223/Z/14/Z to M.H.M., NIAID Awards U54 AI150472 and AI076119 to M.H.M., The UK CIC (Covid-Immunology-Consortium) to A.C.H., the Rosetrees Trust to A.C.H., and UCL Coronavirus Response Fund to L.E.M. (made possible through generous donations from UCL’s supporters, alumni, and friends). M.S.H. is funded by the National Institute for Health Research Clinician Scientist Award ( CS-2016-16-011 ). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. This study is part of the EDCTP2 program supported by the European Union (grant number RIA2020EF-3008 COVAB ). The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. C.G. and H.W. were supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences ( MR/N013700/1 ). S.A. was supported by an MRC-KCL Doctoral Training Partnership in Biomedical Sciences industrial Collaborative Award in Science & Engineering (iCASE) in partnership with Orchard Therapeutics ( MR/R015643/1 ). Work in P.C. laboratory is funded by the Francis Crick Institute ( FC001061 ), which receives its core funding from Cancer Research UK , the UK Medical Research Council , and the Wellcome Trust . T.A.B. is supported by the Medical Research Council ( MR/S007555/1 ). The Wellcome Centre for Human Genetics is supported by Wellcome Centre grant 203141/Z/16/Z . L.E.M. was supported by a Medical Research Council Career Development Award MR/R008698/1 . This work was supported by the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King's College Hospital NHS Foundation Trust . Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6/8
Y1 - 2021/6/8
N2 - Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.
AB - Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.
KW - B.1.1.7
KW - SARS-CoV-2
KW - antibody
KW - immune escape
KW - neutralization
KW - neutralizing epitope
KW - variant of concern
UR - http://www.scopus.com/inward/record.url?scp=85103980605&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.immuni.2021.03.023
DO - https://doi.org/10.1016/j.immuni.2021.03.023
M3 - Article
C2 - 33836142
SN - 1074-7613
VL - 54
SP - 1276-1289.e6
JO - Immunity
JF - Immunity
IS - 6
ER -