Antibody evasion by the P.1 strain of SARS-CoV-2

Wanwisa Dejnirattisai; Daming Zhou; Piyada Supasa; Chang Liu; Alexander J. Mentzer; Helen M. Ginn; Yuguang Zhao; Helen M.E. Duyvesteyn; Aekkachai Tuekprakhon; Rungtiwa Nutalai; Beibei Wang; César López-Camacho; Jose Slon-Campos; Thomas S. Walter; Donal Skelly; Sue Ann Costa Clemens; Felipe Gomes Naveca; Valdinete Nascimento; Fernanda Nascimento; Cristiano Fernandes da Costa; Paola Cristina Resende; Alex Pauvolid-Correa; Marilda M. Siqueira; Christina Dold; Robert Levin; Tao Dong; Andrew J. Pollard; Julian C. Knight; Derrick Crook; Teresa Lambe; Elizabeth Clutterbuck; Sagida Bibi; Amy Flaxman; Mustapha Bittaye; Sandra Belij-Rammerstorfer; Sarah C. Gilbert; Miles W. Carroll; Paul Klenerman; Eleanor Barnes; Susanna J. Dunachie; Neil G. Paterson; Mark A. Williams; David R. Hall; Ruben J.G. Hulswit; Thomas A. Bowden; Elizabeth E. Fry; Juthathip Mongkolsapaya; Jingshan Ren; David I. Stuart; Gavin R. Screaton

doi:10.1016/j.cell.2021.03.055

Antibody evasion by the P.1 strain of SARS-CoV-2

Wanwisa Dejnirattisai^*, Daming Zhou, Piyada Supasa, Chang Liu, Alexander J. Mentzer, Helen M. Ginn, Yuguang Zhao, Helen M.E. Duyvesteyn, Aekkachai Tuekprakhon, Rungtiwa Nutalai, Beibei Wang, César López-Camacho, Jose Slon-Campos, Thomas S. Walter, Donal Skelly, Sue Ann Costa Clemens, Felipe Gomes Naveca, Valdinete Nascimento, Fernanda Nascimento, Cristiano Fernandes da CostaPaola Cristina Resende, Alex Pauvolid-Correa, Marilda M. Siqueira, Christina Dold, Robert Levin, Tao Dong, Andrew J. Pollard, Julian C. Knight, Derrick Crook, Teresa Lambe, Elizabeth Clutterbuck, Sagida Bibi, Amy Flaxman, Mustapha Bittaye, Sandra Belij-Rammerstorfer, Sarah C. Gilbert, Miles W. Carroll, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Neil G. Paterson, Mark A. Williams, David R. Hall, Ruben J.G. Hulswit, Thomas A. Bowden, Elizabeth E. Fry, Juthathip Mongkolsapaya^*, Jingshan Ren^*, David I. Stuart^*, Gavin R. Screaton^*

^*Corresponding author for this work

Research & Development Institute Divisional Office

Research output: Contribution to journal › Article › peer-review

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Abstract

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

Original language	English
Pages (from-to)	2939-2954.e9
Number of pages	24
Journal	Cell
Volume	184
Issue number	11
Early online date	30 Mar 2021
DOIs	https://doi.org/10.1016/j.cell.2021.03.055
Publication status	Published - 30 Mar 2021

Bibliographical note

Funding Information: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant 2018-I2M-2-002 ) to D.I.S. and G.R.S. H.M.E.D. and J.R. are supported by the Wellcome Trust ( 101122/Z/13/Z ), Y.Z. by Cancer Research UK ( C375/A17721 ), T.A.B. and R.J.G.H. by the UKRI MRC ( MR/S007555/1 ), and D.I.S. and E.E.F. by the UKRI MRC ( MR/N00065X/1 ). D.I.S. is a Jenner Investigator . We are also grateful for a Fast Grant from Fast Grants, Mercatus Center to support the isolation of human mAbs to SARS-CoV-2 and Schmidt Futures for support of this work. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z ). This is a contribution from the UK Instruct-ERIC Centre . The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant 090532/Z/09/Z ). F.G.N. is a CNPq fellow and is supported by FAPEAM (PCTI-EmergeSaude/AM call 005/2020 and Rede Genômica de Vigilância em Saúde - REGESAM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant 403276/2020-9), and Inova Fiocruz/Fundação Oswaldo Cruz (Grant VPPCB-007-FIO-18-2-30 - Geração de conhecimento). Virus used for the neutralization assays was isolated by Julian Druce (Doherty Centre, Melbourne, Australia). Chanice Knight, Emily Chiplin, Ross Fothergill, and Liz Penn contributed to assays. We acknowledge Diamond Light Source for time on Beamline I03 under proposal lb27009 for COVID-19 Rapid Access. Huge thanks to the teams, especially at the Diamond Light Source and Department of Structural Biology (Oxford University), that have enabled work to continue during the pandemic. The computational aspects of this research were supported by the Wellcome Trust Core Award (grant 203141/Z/16/Z ) and the NIHR Oxford BRC . The Oxford Vaccine work was supported by UK Research and Innovation , Coalition for Epidemic Preparedness Innovations , National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre , and Thames Valley and South Midland’s NIHR Clinical Research Network . We thank the Oxford Protective T-cell Immunology COVID-19 (OPTIC) clinical team for participant sample collection and the Oxford Immunology Network Covid-19 Response T Cell Consortium for laboratory support. We acknowledge the rapid sharing of Victoria, B.1.1.7 and B.1.351, which was isolated by scientists within the National Infection Service at PHE Porton Down. We thank The Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining P.1 samples. This work was supported by the UK Department of Health and Social Care as part of the PITCH ( Protective Immunity from T cells to Covid-19 in Health workers ) Consortium, the UK Coronavirus Immunology Consortium (UK-CIC), and the Huo Family Foundation . E.B. and P.K. are NIHR Senior Investigators, and P.K. is funded by WT109965MA and the NIH ( U19 I082360 ). J.C.K. is a Wellcome Investigator (WT204969/Z/16/Z) and is supported by NIHR Oxford Biomedical Research Centre and CIFMS. D.S. is an NIHR Academic Clinical Fellow. The views expressed in this article are those of the authors and not necessarily those of the National Health Service (NHS), the Department of Health and Social Care (DHSC), the National Institutes for Health Research (NIHR), the Medical Research Council (MRC), or Public Health, England.
G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is chair of the UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the World Health Organization’s (WHO’s) SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication.

Open Access: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Publisher Copyright:© 2021 The Author(s). Published by Elsevier Inc.

Citation: Wanwisa Dejnirattisai, Daming Zhou, Piyada Supasa, Chang Liu, Alexander J. Mentzer, Helen M. Ginn, Yuguang Zhao, Helen M.E. Duyvesteyn, Aekkachai Tuekprakhon, Rungtiwa Nutalai, Beibei Wang, César López-Camacho, Jose Slon-Campos, Thomas S. Walter, Donal Skelly, Sue Ann Costa Clemens, Felipe Gomes Naveca, Valdinete Nascimento, Fernanda Nascimento, Cristiano Fernandes da Costa, Paola Cristina Resende, Alex Pauvolid-Correa, Marilda M. Siqueira, Christina Dold, Robert Levin, Tao Dong, Andrew J. Pollard, Julian C. Knight, Derrick Crook, Teresa Lambe, Elizabeth Clutterbuck, Sagida Bibi, Amy Flaxman, Mustapha Bittaye, Sandra Belij-Rammerstorfer, Sarah C. Gilbert, Miles W. Carroll, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Neil G. Paterson, Mark A. Williams, David R. Hall, Ruben J.G. Hulswit, Thomas A. Bowden, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, Gavin R. Screaton,
Antibody evasion by the P.1 strain of SARS-CoV-2, Cell, Volume 184, Issue 11, 2021, Pages 2939-2954.e9, ISSN 0092-8674,

DOI: https://doi.org/10.1016/j.cell.2021.03.055.

Keywords

P.1
RBD
SARS-CoV-2
VH3-53
antibody
escape
neutralization
spike
structure
variant

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Dejnirattisai2021AntibodyEvasionByTheP.1StrainOfSARS-CoV-2CellFinal published version, 7.55 MBLicence: CC BY

Cite this

Dejnirattisai, W., Zhou, D., Supasa, P., Liu, C., Mentzer, A. J., Ginn, H. M., Zhao, Y., Duyvesteyn, H. M. E., Tuekprakhon, A., Nutalai, R., Wang, B., López-Camacho, C., Slon-Campos, J., Walter, T. S., Skelly, D., Costa Clemens, S. A., Naveca, F. G., Nascimento, V., Nascimento, F., ... Screaton, G. R. (2021). Antibody evasion by the P.1 strain of SARS-CoV-2. Cell, 184(11), 2939-2954.e9. https://doi.org/10.1016/j.cell.2021.03.055

@article{a54cd61f86614c948812cae16366467e,

title = "Antibody evasion by the P.1 strain of SARS-CoV-2",

abstract = "Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.",

keywords = "P.1, RBD, SARS-CoV-2, VH3-53, antibody, escape, neutralization, spike, structure, variant",

author = "Wanwisa Dejnirattisai and Daming Zhou and Piyada Supasa and Chang Liu and Mentzer, {Alexander J.} and Ginn, {Helen M.} and Yuguang Zhao and Duyvesteyn, {Helen M.E.} and Aekkachai Tuekprakhon and Rungtiwa Nutalai and Beibei Wang and C{\'e}sar L{\'o}pez-Camacho and Jose Slon-Campos and Walter, {Thomas S.} and Donal Skelly and {Costa Clemens}, {Sue Ann} and Naveca, {Felipe Gomes} and Valdinete Nascimento and Fernanda Nascimento and {Fernandes da Costa}, Cristiano and Resende, {Paola Cristina} and Alex Pauvolid-Correa and Siqueira, {Marilda M.} and Christina Dold and Robert Levin and Tao Dong and Pollard, {Andrew J.} and Knight, {Julian C.} and Derrick Crook and Teresa Lambe and Elizabeth Clutterbuck and Sagida Bibi and Amy Flaxman and Mustapha Bittaye and Sandra Belij-Rammerstorfer and Gilbert, {Sarah C.} and Carroll, {Miles W.} and Paul Klenerman and Eleanor Barnes and Dunachie, {Susanna J.} and Paterson, {Neil G.} and Williams, {Mark A.} and Hall, {David R.} and Hulswit, {Ruben J.G.} and Bowden, {Thomas A.} and Fry, {Elizabeth E.} and Juthathip Mongkolsapaya and Jingshan Ren and Stuart, {David I.} and Screaton, {Gavin R.}",

note = "Funding Information: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant 2018-I2M-2-002 ) to D.I.S. and G.R.S. H.M.E.D. and J.R. are supported by the Wellcome Trust ( 101122/Z/13/Z ), Y.Z. by Cancer Research UK ( C375/A17721 ), T.A.B. and R.J.G.H. by the UKRI MRC ( MR/S007555/1 ), and D.I.S. and E.E.F. by the UKRI MRC ( MR/N00065X/1 ). D.I.S. is a Jenner Investigator . We are also grateful for a Fast Grant from Fast Grants, Mercatus Center to support the isolation of human mAbs to SARS-CoV-2 and Schmidt Futures for support of this work. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z ). This is a contribution from the UK Instruct-ERIC Centre . The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant 090532/Z/09/Z ). F.G.N. is a CNPq fellow and is supported by FAPEAM (PCTI-EmergeSaude/AM call 005/2020 and Rede Gen{\^o}mica de Vigil{\^a}ncia em Sa{\'u}de - REGESAM), Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (grant 403276/2020-9), and Inova Fiocruz/Funda{\c c}{\~a}o Oswaldo Cruz (Grant VPPCB-007-FIO-18-2-30 - Gera{\c c}{\~a}o de conhecimento). Virus used for the neutralization assays was isolated by Julian Druce (Doherty Centre, Melbourne, Australia). Chanice Knight, Emily Chiplin, Ross Fothergill, and Liz Penn contributed to assays. We acknowledge Diamond Light Source for time on Beamline I03 under proposal lb27009 for COVID-19 Rapid Access. Huge thanks to the teams, especially at the Diamond Light Source and Department of Structural Biology (Oxford University), that have enabled work to continue during the pandemic. The computational aspects of this research were supported by the Wellcome Trust Core Award (grant 203141/Z/16/Z ) and the NIHR Oxford BRC . The Oxford Vaccine work was supported by UK Research and Innovation , Coalition for Epidemic Preparedness Innovations , National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre , and Thames Valley and South Midland{\textquoteright}s NIHR Clinical Research Network . We thank the Oxford Protective T-cell Immunology COVID-19 (OPTIC) clinical team for participant sample collection and the Oxford Immunology Network Covid-19 Response T Cell Consortium for laboratory support. We acknowledge the rapid sharing of Victoria, B.1.1.7 and B.1.351, which was isolated by scientists within the National Infection Service at PHE Porton Down. We thank The Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining P.1 samples. This work was supported by the UK Department of Health and Social Care as part of the PITCH ( Protective Immunity from T cells to Covid-19 in Health workers ) Consortium, the UK Coronavirus Immunology Consortium (UK-CIC), and the Huo Family Foundation . E.B. and P.K. are NIHR Senior Investigators, and P.K. is funded by WT109965MA and the NIH ( U19 I082360 ). J.C.K. is a Wellcome Investigator (WT204969/Z/16/Z) and is supported by NIHR Oxford Biomedical Research Centre and CIFMS. D.S. is an NIHR Academic Clinical Fellow. The views expressed in this article are those of the authors and not necessarily those of the National Health Service (NHS), the Department of Health and Social Care (DHSC), the National Institutes for Health Research (NIHR), the Medical Research Council (MRC), or Public Health, England. G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is chair of the UK Department Health and Social Care{\textquoteright}s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the World Health Organization{\textquoteright}s (WHO{\textquoteright}s) SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication. Open Access: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Publisher Copyright:{\textcopyright} 2021 The Author(s). Published by Elsevier Inc. Citation: Wanwisa Dejnirattisai, Daming Zhou, Piyada Supasa, Chang Liu, Alexander J. Mentzer, Helen M. Ginn, Yuguang Zhao, Helen M.E. Duyvesteyn, Aekkachai Tuekprakhon, Rungtiwa Nutalai, Beibei Wang, C{\'e}sar L{\'o}pez-Camacho, Jose Slon-Campos, Thomas S. Walter, Donal Skelly, Sue Ann Costa Clemens, Felipe Gomes Naveca, Valdinete Nascimento, Fernanda Nascimento, Cristiano Fernandes da Costa, Paola Cristina Resende, Alex Pauvolid-Correa, Marilda M. Siqueira, Christina Dold, Robert Levin, Tao Dong, Andrew J. Pollard, Julian C. Knight, Derrick Crook, Teresa Lambe, Elizabeth Clutterbuck, Sagida Bibi, Amy Flaxman, Mustapha Bittaye, Sandra Belij-Rammerstorfer, Sarah C. Gilbert, Miles W. Carroll, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Neil G. Paterson, Mark A. Williams, David R. Hall, Ruben J.G. Hulswit, Thomas A. Bowden, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, Gavin R. Screaton, Antibody evasion by the P.1 strain of SARS-CoV-2, Cell, Volume 184, Issue 11, 2021, Pages 2939-2954.e9, ISSN 0092-8674, DOI: https://doi.org/10.1016/j.cell.2021.03.055.",

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Dejnirattisai, W, Zhou, D, Supasa, P, Liu, C, Mentzer, AJ, Ginn, HM, Zhao, Y, Duyvesteyn, HME, Tuekprakhon, A, Nutalai, R, Wang, B, López-Camacho, C, Slon-Campos, J, Walter, TS, Skelly, D, Costa Clemens, SA, Naveca, FG, Nascimento, V, Nascimento, F, Fernandes da Costa, C, Resende, PC, Pauvolid-Correa, A, Siqueira, MM, Dold, C, Levin, R, Dong, T, Pollard, AJ, Knight, JC, Crook, D, Lambe, T, Clutterbuck, E, Bibi, S, Flaxman, A, Bittaye, M, Belij-Rammerstorfer, S, Gilbert, SC, Carroll, MW, Klenerman, P, Barnes, E, Dunachie, SJ, Paterson, NG, Williams, MA, Hall, DR, Hulswit, RJG, Bowden, TA, Fry, EE, Mongkolsapaya, J, Ren, J, Stuart, DI & Screaton, GR 2021, 'Antibody evasion by the P.1 strain of SARS-CoV-2', Cell, vol. 184, no. 11, pp. 2939-2954.e9. https://doi.org/10.1016/j.cell.2021.03.055

TY - JOUR

T1 - Antibody evasion by the P.1 strain of SARS-CoV-2

AU - Dejnirattisai, Wanwisa

AU - Zhou, Daming

AU - Supasa, Piyada

AU - Liu, Chang

AU - Mentzer, Alexander J.

AU - Ginn, Helen M.

AU - Zhao, Yuguang

AU - Duyvesteyn, Helen M.E.

AU - Tuekprakhon, Aekkachai

AU - Nutalai, Rungtiwa

AU - Wang, Beibei

AU - López-Camacho, César

AU - Slon-Campos, Jose

AU - Walter, Thomas S.

AU - Skelly, Donal

AU - Costa Clemens, Sue Ann

AU - Naveca, Felipe Gomes

AU - Nascimento, Valdinete

AU - Nascimento, Fernanda

AU - Fernandes da Costa, Cristiano

AU - Resende, Paola Cristina

AU - Pauvolid-Correa, Alex

AU - Siqueira, Marilda M.

AU - Dold, Christina

AU - Levin, Robert

AU - Dong, Tao

AU - Pollard, Andrew J.

AU - Knight, Julian C.

AU - Crook, Derrick

AU - Lambe, Teresa

AU - Clutterbuck, Elizabeth

AU - Bibi, Sagida

AU - Flaxman, Amy

AU - Bittaye, Mustapha

AU - Belij-Rammerstorfer, Sandra

AU - Gilbert, Sarah C.

AU - Carroll, Miles W.

AU - Klenerman, Paul

AU - Barnes, Eleanor

AU - Dunachie, Susanna J.

AU - Paterson, Neil G.

AU - Williams, Mark A.

AU - Hall, David R.

AU - Hulswit, Ruben J.G.

AU - Bowden, Thomas A.

AU - Fry, Elizabeth E.

AU - Mongkolsapaya, Juthathip

AU - Ren, Jingshan

AU - Stuart, David I.

AU - Screaton, Gavin R.

N1 - Funding Information: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant 2018-I2M-2-002 ) to D.I.S. and G.R.S. H.M.E.D. and J.R. are supported by the Wellcome Trust ( 101122/Z/13/Z ), Y.Z. by Cancer Research UK ( C375/A17721 ), T.A.B. and R.J.G.H. by the UKRI MRC ( MR/S007555/1 ), and D.I.S. and E.E.F. by the UKRI MRC ( MR/N00065X/1 ). D.I.S. is a Jenner Investigator . We are also grateful for a Fast Grant from Fast Grants, Mercatus Center to support the isolation of human mAbs to SARS-CoV-2 and Schmidt Futures for support of this work. G.R.S. is also supported as a Wellcome Trust Senior Investigator (grant 095541/A/11/Z ). This is a contribution from the UK Instruct-ERIC Centre . The Wellcome Centre for Human Genetics is supported by the Wellcome Trust (grant 090532/Z/09/Z ). F.G.N. is a CNPq fellow and is supported by FAPEAM (PCTI-EmergeSaude/AM call 005/2020 and Rede Genômica de Vigilância em Saúde - REGESAM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant 403276/2020-9), and Inova Fiocruz/Fundação Oswaldo Cruz (Grant VPPCB-007-FIO-18-2-30 - Geração de conhecimento). Virus used for the neutralization assays was isolated by Julian Druce (Doherty Centre, Melbourne, Australia). Chanice Knight, Emily Chiplin, Ross Fothergill, and Liz Penn contributed to assays. We acknowledge Diamond Light Source for time on Beamline I03 under proposal lb27009 for COVID-19 Rapid Access. Huge thanks to the teams, especially at the Diamond Light Source and Department of Structural Biology (Oxford University), that have enabled work to continue during the pandemic. The computational aspects of this research were supported by the Wellcome Trust Core Award (grant 203141/Z/16/Z ) and the NIHR Oxford BRC . The Oxford Vaccine work was supported by UK Research and Innovation , Coalition for Epidemic Preparedness Innovations , National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre , and Thames Valley and South Midland’s NIHR Clinical Research Network . We thank the Oxford Protective T-cell Immunology COVID-19 (OPTIC) clinical team for participant sample collection and the Oxford Immunology Network Covid-19 Response T Cell Consortium for laboratory support. We acknowledge the rapid sharing of Victoria, B.1.1.7 and B.1.351, which was isolated by scientists within the National Infection Service at PHE Porton Down. We thank The Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining P.1 samples. This work was supported by the UK Department of Health and Social Care as part of the PITCH ( Protective Immunity from T cells to Covid-19 in Health workers ) Consortium, the UK Coronavirus Immunology Consortium (UK-CIC), and the Huo Family Foundation . E.B. and P.K. are NIHR Senior Investigators, and P.K. is funded by WT109965MA and the NIH ( U19 I082360 ). J.C.K. is a Wellcome Investigator (WT204969/Z/16/Z) and is supported by NIHR Oxford Biomedical Research Centre and CIFMS. D.S. is an NIHR Academic Clinical Fellow. The views expressed in this article are those of the authors and not necessarily those of the National Health Service (NHS), the Department of Health and Social Care (DHSC), the National Institutes for Health Research (NIHR), the Medical Research Council (MRC), or Public Health, England. G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is chair of the UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the World Health Organization’s (WHO’s) SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication. Open Access: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Publisher Copyright:© 2021 The Author(s). Published by Elsevier Inc. Citation: Wanwisa Dejnirattisai, Daming Zhou, Piyada Supasa, Chang Liu, Alexander J. Mentzer, Helen M. Ginn, Yuguang Zhao, Helen M.E. Duyvesteyn, Aekkachai Tuekprakhon, Rungtiwa Nutalai, Beibei Wang, César López-Camacho, Jose Slon-Campos, Thomas S. Walter, Donal Skelly, Sue Ann Costa Clemens, Felipe Gomes Naveca, Valdinete Nascimento, Fernanda Nascimento, Cristiano Fernandes da Costa, Paola Cristina Resende, Alex Pauvolid-Correa, Marilda M. Siqueira, Christina Dold, Robert Levin, Tao Dong, Andrew J. Pollard, Julian C. Knight, Derrick Crook, Teresa Lambe, Elizabeth Clutterbuck, Sagida Bibi, Amy Flaxman, Mustapha Bittaye, Sandra Belij-Rammerstorfer, Sarah C. Gilbert, Miles W. Carroll, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Neil G. Paterson, Mark A. Williams, David R. Hall, Ruben J.G. Hulswit, Thomas A. Bowden, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, Gavin R. Screaton, Antibody evasion by the P.1 strain of SARS-CoV-2, Cell, Volume 184, Issue 11, 2021, Pages 2939-2954.e9, ISSN 0092-8674, DOI: https://doi.org/10.1016/j.cell.2021.03.055.

PY - 2021/3/30

Y1 - 2021/3/30

N2 - Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

AB - Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

KW - P.1

KW - RBD

KW - SARS-CoV-2

KW - VH3-53

KW - antibody

KW - escape

KW - neutralization

KW - spike

KW - structure

KW - variant

UR - http://www.scopus.com/inward/record.url?scp=85104114261&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.03.055

DO - 10.1016/j.cell.2021.03.055

M3 - Article

AN - SCOPUS:85104114261

SN - 0092-8674

VL - 184

SP - 2939-2954.e9

JO - Cell

JF - Cell

IS - 11

ER -

Antibody evasion by the P.1 strain of SARS-CoV-2

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