The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

Chang Liu; Daming Zhou; Rungtiwa Nutalai; Helen M.E. Duyvesteyn; Aekkachai Tuekprakhon; Helen M. Ginn; Wanwisa Dejnirattisai; Piyada Supasa; Alexander J. Mentzer; Beibei Wang; James Brett Case; Yuguang Zhao; Donal T. Skelly; Rita E. Chen; Sile Ann Johnson; Thomas G. Ritter; Chris Mason; Tariq Malik; Nigel Temperton; Neil G. Paterson; Mark A. Williams; David R. Hall; Daniel K. Clare; Andrew Howe; Philip J.R. Goulder; Elizabeth E. Fry; Michael S. Diamond; Juthathip Mongkolsapaya; Jingshan Ren; David I. Stuart; Gavin R. Screaton

doi:10.1016/j.chom.2021.11.013

The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

Chang Liu, Daming Zhou, Rungtiwa Nutalai, Helen M.E. Duyvesteyn, Aekkachai Tuekprakhon, Helen M. Ginn, Wanwisa Dejnirattisai, Piyada Supasa, Alexander J. Mentzer, Beibei Wang, James Brett Case, Yuguang Zhao, Donal T. Skelly, Rita E. Chen, Sile Ann Johnson, Thomas G. Ritter, Chris Mason, Tariq Malik, Nigel Temperton, Neil G. PatersonMark A. Williams, David R. Hall, Daniel K. Clare, Andrew Howe, Philip J.R. Goulder, Elizabeth E. Fry, Michael S. Diamond, Juthathip Mongkolsapaya, Jingshan Ren, David I. Stuart, Gavin R. Screaton

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

26 Scopus citations

Abstract

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.

Original language	English
Pages (from-to)	53-68.e12
Journal	Cell Host and Microbe
Volume	30
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2021.11.013
State	Published - Jan 12 2022

Keywords

Beta variant
COVID-19
SARS-CoV-2
antibody
immune responses
neutralization
receptor-binding domain
spike protein
structure
vaccine

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10.1016/j.chom.2021.11.013

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Liu, C., Zhou, D., Nutalai, R., Duyvesteyn, H. M. E., Tuekprakhon, A., Ginn, H. M., Dejnirattisai, W., Supasa, P., Mentzer, A. J., Wang, B., Case, J. B., Zhao, Y., Skelly, D. T., Chen, R. E., Johnson, S. A., Ritter, T. G., Mason, C., Malik, T., Temperton, N., ... Screaton, G. R. (2022). The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants. Cell Host and Microbe, 30(1), 53-68.e12. https://doi.org/10.1016/j.chom.2021.11.013

@article{dc58ecc067c34110a71f1db593f4e140,

title = "The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants",

abstract = "Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.",

keywords = "Beta variant, COVID-19, SARS-CoV-2, antibody, immune responses, neutralization, receptor-binding domain, spike protein, structure, vaccine",

author = "Chang Liu and Daming Zhou and Rungtiwa Nutalai and Duyvesteyn, {Helen M.E.} and Aekkachai Tuekprakhon and Ginn, {Helen M.} and Wanwisa Dejnirattisai and Piyada Supasa and Mentzer, {Alexander J.} and Beibei Wang and Case, {James Brett} and Yuguang Zhao and Skelly, {Donal T.} and Chen, {Rita E.} and Johnson, {Sile Ann} and Ritter, {Thomas G.} and Chris Mason and Tariq Malik and Nigel Temperton and Paterson, {Neil G.} and Williams, {Mark A.} and Hall, {David R.} and Clare, {Daniel K.} and Andrew Howe and Goulder, {Philip J.R.} and Fry, {Elizabeth E.} and Diamond, {Michael S.} 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 number: 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), D.I.S. and E.E.F. by the UKRI MRC (MR/N00065X/1), J.B.C. by a Helen Hay Whitney Foundation postdoctoral fellowship, and M.S.D. by NIH (R01 AI157155) and the Defense Advanced Research Project Agency (HR001117S0019). D.I.S. and G.R.S. are Jenner Investigators. A.J.M. and D.T.S. are NIHR Academic Clinical Lecturers. We are also grateful for support from Schmidt Futures, the Red Avenue Foundation and the Oak Foundation. 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). Virus used for the neutralization assays was isolated by J.D. Doherty Centre, Melbourne, Australia. We acknowledge the rapid sharing of Victoria, Alpha, and Beta, which was isolated by scientists within the National Infection Service at PHE Porton Down, and Delta and B.1.525 viruses were kindly provided by W.B. and T.d.S. from the genotype to phenotype consortium G2P-UK. We thank the Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining Gamma virus. We acknowledge Diamond Light Source (DLS) for use of beamline I03 under Proposal lb27009 (COVID-19 Rapid Access). Huge thanks to teams at the DLS and Department of Structural Biology, Oxford University that have enabled work to continue during the pandemic. Electron microscopy experiments were conducted at both eBIC and the Oxford Particle Imaging Centre (OPIC) Electron Microscopy Facility. The computational aspects of this research were supported by the Wellcome Trust Core Award grant number 203141/Z/16/Z and the NIHR Oxford BRC. 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. This work was supported by the UK Department of Health & 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 Hyde Family Foundation. D.Z. performed BLI interaction analyses. D.Z. J.R. N.G.P. M.A.W. and D.R.H. prepared the crystals and enabled and performed X-ray data collection. H.M.E.D. D.K.C. and A.H. collected and analyzed cryo-EM data. J.R. E.E.F. and D.I.S. analyzed the structural results. G.R.S. J.M. P.S. Y.Z. D.Z. B.W. R.N. A.T. C.L. and D.Z. prepared S constructs, RBDs, ACE2, and mAbs, and C.L. W.D. P.S. R.N. and A.T. performed neutralization assays. H.M.G. performed mapping and cluster analysis and sequence and antigenic space analyses. A.J.M. D.T.S. S.A.J. T.G.R. C.M. T.M. and P.J.R.G. assisted with patient samples. J.B.C. and R.E.C. performed mouse experiments and clinical analyses. J.B.C. performed viral burden analyses. J.B.C. M.S.D. and G.R.S. designed mouse experiments and analyzed results, N.T. provided the SARS-CoV-2 lentiviral construct. G.R.S. and D.I.S. conceived the study; J.B.C. M.S.D. G.R.S. and D.I.S. wrote the initial manuscript draft with other authors providing editorial comments. All authors read and approved the manuscript. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. The University of Oxford has protected intellectual property disclosed in this publication. Funding Information: 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. This work was supported by the UK Department of Health & 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 Hyde Family Foundation . Funding Information: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 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 ), D.I.S. and E.E.F. by the UKRI MRC ( MR/N00065X/1 ), J.B.C. by a Helen Hay Whitney Foundation postdoctoral fellowship, and M.S.D. by NIH ( R01 AI157155 ) and the Defense Advanced Research Project Agency ( HR001117S0019 ). D.I.S. and G.R.S. are Jenner Investigators. A.J.M. and D.T.S. are NIHR Academic Clinical Lecturers. We are also grateful for support from Schmidt Futures , the Red Avenue Foundation and the Oak Foundation . 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 ). Virus used for the neutralization assays was isolated by J.D., Doherty Centre, Melbourne, Australia. We acknowledge the rapid sharing of Victoria, Alpha, and Beta, which was isolated by scientists within the National Infection Service at PHE Porton Down, and Delta and B.1.525 viruses were kindly provided by W.B. and T.d.S. from the genotype to phenotype consortium G2P-UK. We thank the Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining Gamma virus. We acknowledge Diamond Light Source (DLS) for use of beamline I03 under Proposal lb27009 (COVID-19 Rapid Access). Huge thanks to teams at the DLS and Department of Structural Biology, Oxford University that have enabled work to continue during the pandemic. Electron microscopy experiments were conducted at both eBIC and the Oxford Particle Imaging Centre (OPIC) Electron Microscopy Facility. The computational aspects of this research were supported by the Wellcome Trust Core Award grant number 203141/Z/16/Z and the NIHR Oxford BRC. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = jan,

day = "12",

doi = "10.1016/j.chom.2021.11.013",

language = "English",

volume = "30",

pages = "53--68.e12",

journal = "Cell Host and Microbe",

issn = "1931-3128",

number = "1",

}

Liu, C, Zhou, D, Nutalai, R, Duyvesteyn, HME, Tuekprakhon, A, Ginn, HM, Dejnirattisai, W, Supasa, P, Mentzer, AJ, Wang, B, Case, JB, Zhao, Y, Skelly, DT, Chen, RE, Johnson, SA, Ritter, TG, Mason, C, Malik, T, Temperton, N, Paterson, NG, Williams, MA, Hall, DR, Clare, DK, Howe, A, Goulder, PJR, Fry, EE, Diamond, MS, Mongkolsapaya, J, Ren, J, Stuart, DI & Screaton, GR 2022, 'The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants', Cell Host and Microbe, vol. 30, no. 1, pp. 53-68.e12. https://doi.org/10.1016/j.chom.2021.11.013

TY - JOUR

T1 - The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

AU - Liu, Chang

AU - Zhou, Daming

AU - Nutalai, Rungtiwa

AU - Duyvesteyn, Helen M.E.

AU - Tuekprakhon, Aekkachai

AU - Ginn, Helen M.

AU - Dejnirattisai, Wanwisa

AU - Supasa, Piyada

AU - Mentzer, Alexander J.

AU - Wang, Beibei

AU - Case, James Brett

AU - Zhao, Yuguang

AU - Skelly, Donal T.

AU - Chen, Rita E.

AU - Johnson, Sile Ann

AU - Ritter, Thomas G.

AU - Mason, Chris

AU - Malik, Tariq

AU - Temperton, Nigel

AU - Paterson, Neil G.

AU - Williams, Mark A.

AU - Hall, David R.

AU - Clare, Daniel K.

AU - Howe, Andrew

AU - Goulder, Philip J.R.

AU - Fry, Elizabeth E.

AU - Diamond, Michael S.

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 number: 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), D.I.S. and E.E.F. by the UKRI MRC (MR/N00065X/1), J.B.C. by a Helen Hay Whitney Foundation postdoctoral fellowship, and M.S.D. by NIH (R01 AI157155) and the Defense Advanced Research Project Agency (HR001117S0019). D.I.S. and G.R.S. are Jenner Investigators. A.J.M. and D.T.S. are NIHR Academic Clinical Lecturers. We are also grateful for support from Schmidt Futures, the Red Avenue Foundation and the Oak Foundation. 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). Virus used for the neutralization assays was isolated by J.D. Doherty Centre, Melbourne, Australia. We acknowledge the rapid sharing of Victoria, Alpha, and Beta, which was isolated by scientists within the National Infection Service at PHE Porton Down, and Delta and B.1.525 viruses were kindly provided by W.B. and T.d.S. from the genotype to phenotype consortium G2P-UK. We thank the Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining Gamma virus. We acknowledge Diamond Light Source (DLS) for use of beamline I03 under Proposal lb27009 (COVID-19 Rapid Access). Huge thanks to teams at the DLS and Department of Structural Biology, Oxford University that have enabled work to continue during the pandemic. Electron microscopy experiments were conducted at both eBIC and the Oxford Particle Imaging Centre (OPIC) Electron Microscopy Facility. The computational aspects of this research were supported by the Wellcome Trust Core Award grant number 203141/Z/16/Z and the NIHR Oxford BRC. 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. This work was supported by the UK Department of Health & 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 Hyde Family Foundation. D.Z. performed BLI interaction analyses. D.Z. J.R. N.G.P. M.A.W. and D.R.H. prepared the crystals and enabled and performed X-ray data collection. H.M.E.D. D.K.C. and A.H. collected and analyzed cryo-EM data. J.R. E.E.F. and D.I.S. analyzed the structural results. G.R.S. J.M. P.S. Y.Z. D.Z. B.W. R.N. A.T. C.L. and D.Z. prepared S constructs, RBDs, ACE2, and mAbs, and C.L. W.D. P.S. R.N. and A.T. performed neutralization assays. H.M.G. performed mapping and cluster analysis and sequence and antigenic space analyses. A.J.M. D.T.S. S.A.J. T.G.R. C.M. T.M. and P.J.R.G. assisted with patient samples. J.B.C. and R.E.C. performed mouse experiments and clinical analyses. J.B.C. performed viral burden analyses. J.B.C. M.S.D. and G.R.S. designed mouse experiments and analyzed results, N.T. provided the SARS-CoV-2 lentiviral construct. G.R.S. and D.I.S. conceived the study; J.B.C. M.S.D. G.R.S. and D.I.S. wrote the initial manuscript draft with other authors providing editorial comments. All authors read and approved the manuscript. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. The University of Oxford has protected intellectual property disclosed in this publication. Funding Information: 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. This work was supported by the UK Department of Health & 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 Hyde Family Foundation . Funding Information: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 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 ), D.I.S. and E.E.F. by the UKRI MRC ( MR/N00065X/1 ), J.B.C. by a Helen Hay Whitney Foundation postdoctoral fellowship, and M.S.D. by NIH ( R01 AI157155 ) and the Defense Advanced Research Project Agency ( HR001117S0019 ). D.I.S. and G.R.S. are Jenner Investigators. A.J.M. and D.T.S. are NIHR Academic Clinical Lecturers. We are also grateful for support from Schmidt Futures , the Red Avenue Foundation and the Oak Foundation . 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 ). Virus used for the neutralization assays was isolated by J.D., Doherty Centre, Melbourne, Australia. We acknowledge the rapid sharing of Victoria, Alpha, and Beta, which was isolated by scientists within the National Infection Service at PHE Porton Down, and Delta and B.1.525 viruses were kindly provided by W.B. and T.d.S. from the genotype to phenotype consortium G2P-UK. We thank the Secretariat of National Surveillance, Ministry of Health Brazil for assistance in obtaining Gamma virus. We acknowledge Diamond Light Source (DLS) for use of beamline I03 under Proposal lb27009 (COVID-19 Rapid Access). Huge thanks to teams at the DLS and Department of Structural Biology, Oxford University that have enabled work to continue during the pandemic. Electron microscopy experiments were conducted at both eBIC and the Oxford Particle Imaging Centre (OPIC) Electron Microscopy Facility. The computational aspects of this research were supported by the Wellcome Trust Core Award grant number 203141/Z/16/Z and the NIHR Oxford BRC. Publisher Copyright: © 2021 The Author(s)

PY - 2022/1/12

Y1 - 2022/1/12

N2 - Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.

AB - Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.

KW - Beta variant

KW - COVID-19

KW - SARS-CoV-2

KW - antibody

KW - immune responses

KW - neutralization

KW - receptor-binding domain

KW - spike protein

KW - structure

KW - vaccine

UR - http://www.scopus.com/inward/record.url?scp=85121345277&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2021.11.013

DO - 10.1016/j.chom.2021.11.013

M3 - Article

C2 - 34921776

AN - SCOPUS:85121345277

SN - 1931-3128

VL - 30

SP - 53-68.e12

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 1

ER -

The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

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