Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

OPTIC consortium; ISARIC4C consortium; Rungtiwa Nutalai; Daming Zhou; Aekkachai Tuekprakhon; Helen M. Ginn; Piyada Supasa; Chang Liu; Jiandong Huo; Alexander J. Mentzer; Helen M.E. Duyvesteyn; Aiste Dijokaite-Guraliuc; Donal Skelly; Thomas G. Ritter; Ali Amini; Sagida Bibi; Sandra Adele; Sile Ann Johnson; Bede Constantinides; Hermione Webster; Nigel Temperton; Paul Klenerman; Eleanor Barnes; Susanna J. Dunachie; Derrick Crook; Andrew J. Pollard; Teresa Lambe; Philip Goulder; Neil G. Paterson; Mark A. Williams; David R. Hall; Juthathip Mongkolsapaya; Elizabeth E. Fry; Wanwisa Dejnirattisai; Jingshan Ren; David I. Stuart; Gavin R. Screaton

doi:10.1016/j.cell.2022.05.014

Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

OPTIC consortium, ISARIC4C consortium, Rungtiwa Nutalai, Daming Zhou, Aekkachai Tuekprakhon, Helen M. Ginn, Piyada Supasa, Chang Liu, Jiandong Huo, Alexander J. Mentzer, Helen M.E. Duyvesteyn, Aiste Dijokaite-Guraliuc, Donal Skelly, Thomas G. Ritter, Ali Amini, Sagida Bibi, Sandra Adele, Sile Ann Johnson, Bede Constantinides, Hermione WebsterNigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Derrick Crook, Andrew J. Pollard, Teresa Lambe, Philip Goulder, Neil G. Paterson, Mark A. Williams, David R. Hall, Juthathip Mongkolsapaya, Elizabeth E. Fry, Wanwisa Dejnirattisai^*, Jingshan Ren^*, David I. Stuart^*, Gavin R. Screaton^*

^*Corresponding author for this work

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

Abstract

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

Original language	English
Pages (from-to)	2116-2131.e18
Number of pages	35
Journal	Cell
Volume	185
Issue number	12
Early online date	20 May 2022
DOIs	https://doi.org/10.1016/j.cell.2022.05.014
Publication status	Published - 9 Jun 2022

Bibliographical note

Acknowledgments:
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. We are also grateful for support from Schmidt Futures, the Red Avenue Foundation, and the Oak Foundation. G.R.S. was supported by Wellcome, H.M.E.D. and J.R. by Wellcome (101122/Z/13/Z), D.I.S. and E.E.F. by UKRI MRC (MR/N00065X/1). D.I.S. and G.R.S. are Jenner Investigators. This is a contribution from the UK Instruct-ERIC Center. A.J.M. is an NIHR-supported Academic Clinical Lecturer. Convalescent sampling was supported by the UKRI MRC (MC_PC_19059 awarded to the ISARIC-4C consortium, full contributor list available at https://isaric4c.net/about/authors/) and the National Institutes of Health and Oxford Biomedical Research Centre and an Oxfordshire Health Services Research Committee grant to A.J.M.. The Wellcome Center for Human Genetics is supported by Wellcome (grant 090532/Z/09/Z). Computational aspects were supported by the Wellcome (203141/Z/16/Z) and the NIHR Oxford BRC. SPR measurements were carried out at the Molecular Biophysics facility, University of Oxford. Diamond Light Source provided time on Beamlines I03 and I04 under Proposal lb27009 for COVID-19 Rapid Access. Electron microscopy was conducted at the Oxford Particle Imaging Centre (OPIC), founded by a Wellcome JIF award (060208/Z/00/Z), or COSMIC (Oxford). Computational aspects were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the NIHR Oxford BRC.

Oxford Vaccine work was supported by UKRI, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland’s NIHR Clinical Research Network. We thank the Oxford Protective T-cell Immunology for COVID-19 (OPTIC) Clinical team (Christopher Conlon, Alexandra Deeks, John Frater, Lisa Frending, Siobhan Gardiner, Anni Jämsén, Katie Jeffery, Tom Malone, Eloise Phillips, Lucy Rothwell, Lizzie Stafford) for participant sample collection and the Oxford Immunology Network Covid-19 Response T cell Consortium for laboratory support. We acknowledge rapid sharing of Victoria, B.1.1.7, and B.1.351 isolated by scientists in the National Infection Service at PHE Porton Down, and B.1.617.2 virus was kindly provided by Wendy Barclay and Thushan De-Silva. 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 (DHSC) 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 NIH (U19 I082360). S.J.D. is funded by an NIHR Global Research Professorship (NIHR300791). 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 DHSC, the National NIHR, the MRC, or Public Health, England.

Keywords

SARS-CoV-2
COVID-19
Omicron
BA.1
BA.1.1
BA.2
antibody responses
crystallography
variants of concern
receptor binding domain
neutralization
immune escape

UN SDGs

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

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NutalaiR2022PotentFinal published version, 11.2 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

OPTIC consortium, ISARIC4C consortium, Nutalai, R., Zhou, D., Tuekprakhon, A., Ginn, H. M., Supasa, P., Liu, C., Huo, J., Mentzer, A. J., Duyvesteyn, H. M. E., Dijokaite-Guraliuc, A., Skelly, D., Ritter, T. G., Amini, A., Bibi, S., Adele, S., Johnson, S. A., Constantinides, B., ... Screaton, G. R. (2022). Potent cross-reactive antibodies following Omicron breakthrough in vaccinees. Cell, 185(12), 2116-2131.e18. https://doi.org/10.1016/j.cell.2022.05.014

@article{9b19b955e7ca40e78d9033eec907f22e,

title = "Potent cross-reactive antibodies following Omicron breakthrough in vaccinees",

abstract = "Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.",

keywords = "SARS-CoV-2, COVID-19, Omicron, BA.1, BA.1.1, BA.2, antibody responses, crystallography, variants of concern, receptor binding domain, neutralization, immune escape",

author = "{OPTIC consortium} and {ISARIC4C consortium} and Rungtiwa Nutalai and Daming Zhou and Aekkachai Tuekprakhon and Ginn, {Helen M.} and Piyada Supasa and Chang Liu and Jiandong Huo and Mentzer, {Alexander J.} and Duyvesteyn, {Helen M.E.} and Aiste Dijokaite-Guraliuc and Donal Skelly and Ritter, {Thomas G.} and Ali Amini and Sagida Bibi and Sandra Adele and Johnson, {Sile Ann} and Bede Constantinides and Hermione Webster and Nigel Temperton and Paul Klenerman and Eleanor Barnes and Dunachie, {Susanna J.} and Derrick Crook and Pollard, {Andrew J.} and Teresa Lambe and Philip Goulder and Paterson, {Neil G.} and Williams, {Mark A.} and Hall, {David R.} and Juthathip Mongkolsapaya and Fry, {Elizabeth E.} and Wanwisa Dejnirattisai and Jingshan Ren and Stuart, {David I.} and Screaton, {Gavin R.} and Christopher Green",

note = "Acknowledgments: 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. We are also grateful for support from Schmidt Futures, the Red Avenue Foundation, and the Oak Foundation. G.R.S. was supported by Wellcome, H.M.E.D. and J.R. by Wellcome (101122/Z/13/Z), D.I.S. and E.E.F. by UKRI MRC (MR/N00065X/1). D.I.S. and G.R.S. are Jenner Investigators. This is a contribution from the UK Instruct-ERIC Center. A.J.M. is an NIHR-supported Academic Clinical Lecturer. Convalescent sampling was supported by the UKRI MRC (MC_PC_19059 awarded to the ISARIC-4C consortium, full contributor list available at https://isaric4c.net/about/authors/) and the National Institutes of Health and Oxford Biomedical Research Centre and an Oxfordshire Health Services Research Committee grant to A.J.M.. The Wellcome Center for Human Genetics is supported by Wellcome (grant 090532/Z/09/Z). Computational aspects were supported by the Wellcome (203141/Z/16/Z) and the NIHR Oxford BRC. SPR measurements were carried out at the Molecular Biophysics facility, University of Oxford. Diamond Light Source provided time on Beamlines I03 and I04 under Proposal lb27009 for COVID-19 Rapid Access. Electron microscopy was conducted at the Oxford Particle Imaging Centre (OPIC), founded by a Wellcome JIF award (060208/Z/00/Z), or COSMIC (Oxford). Computational aspects were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the NIHR Oxford BRC. Oxford Vaccine work was supported by UKRI, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland{\textquoteright}s NIHR Clinical Research Network. We thank the Oxford Protective T-cell Immunology for COVID-19 (OPTIC) Clinical team (Christopher Conlon, Alexandra Deeks, John Frater, Lisa Frending, Siobhan Gardiner, Anni J{\"a}ms{\'e}n, Katie Jeffery, Tom Malone, Eloise Phillips, Lucy Rothwell, Lizzie Stafford) for participant sample collection and the Oxford Immunology Network Covid-19 Response T cell Consortium for laboratory support. We acknowledge rapid sharing of Victoria, B.1.1.7, and B.1.351 isolated by scientists in the National Infection Service at PHE Porton Down, and B.1.617.2 virus was kindly provided by Wendy Barclay and Thushan De-Silva. 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 (DHSC) 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 NIH (U19 I082360). S.J.D. is funded by an NIHR Global Research Professorship (NIHR300791). 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 DHSC, the National NIHR, the MRC, or Public Health, England.",

year = "2022",

month = jun,

day = "9",

doi = "10.1016/j.cell.2022.05.014",

language = "English",

volume = "185",

pages = "2116--2131.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

number = "12",

}

OPTIC consortium, ISARIC4C consortium, Nutalai, R, Zhou, D, Tuekprakhon, A, Ginn, HM, Supasa, P, Liu, C, Huo, J, Mentzer, AJ, Duyvesteyn, HME, Dijokaite-Guraliuc, A, Skelly, D, Ritter, TG, Amini, A, Bibi, S, Adele, S, Johnson, SA, Constantinides, B, Webster, H, Temperton, N, Klenerman, P, Barnes, E, Dunachie, SJ, Crook, D, Pollard, AJ, Lambe, T, Goulder, P, Paterson, NG, Williams, MA, Hall, DR, Mongkolsapaya, J, Fry, EE, Dejnirattisai, W, Ren, J, Stuart, DI & Screaton, GR 2022, 'Potent cross-reactive antibodies following Omicron breakthrough in vaccinees', Cell, vol. 185, no. 12, pp. 2116-2131.e18. https://doi.org/10.1016/j.cell.2022.05.014

TY - JOUR

T1 - Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

AU - OPTIC consortium

AU - ISARIC4C consortium

AU - Nutalai, Rungtiwa

AU - Zhou, Daming

AU - Tuekprakhon, Aekkachai

AU - Ginn, Helen M.

AU - Supasa, Piyada

AU - Liu, Chang

AU - Huo, Jiandong

AU - Mentzer, Alexander J.

AU - Duyvesteyn, Helen M.E.

AU - Dijokaite-Guraliuc, Aiste

AU - Skelly, Donal

AU - Ritter, Thomas G.

AU - Amini, Ali

AU - Bibi, Sagida

AU - Adele, Sandra

AU - Johnson, Sile Ann

AU - Constantinides, Bede

AU - Webster, Hermione

AU - Temperton, Nigel

AU - Klenerman, Paul

AU - Barnes, Eleanor

AU - Dunachie, Susanna J.

AU - Crook, Derrick

AU - Pollard, Andrew J.

AU - Lambe, Teresa

AU - Goulder, Philip

AU - Paterson, Neil G.

AU - Williams, Mark A.

AU - Hall, David R.

AU - Mongkolsapaya, Juthathip

AU - Fry, Elizabeth E.

AU - Dejnirattisai, Wanwisa

AU - Ren, Jingshan

AU - Stuart, David I.

AU - Screaton, Gavin R.

AU - Green, Christopher

N1 - Acknowledgments: 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. We are also grateful for support from Schmidt Futures, the Red Avenue Foundation, and the Oak Foundation. G.R.S. was supported by Wellcome, H.M.E.D. and J.R. by Wellcome (101122/Z/13/Z), D.I.S. and E.E.F. by UKRI MRC (MR/N00065X/1). D.I.S. and G.R.S. are Jenner Investigators. This is a contribution from the UK Instruct-ERIC Center. A.J.M. is an NIHR-supported Academic Clinical Lecturer. Convalescent sampling was supported by the UKRI MRC (MC_PC_19059 awarded to the ISARIC-4C consortium, full contributor list available at https://isaric4c.net/about/authors/) and the National Institutes of Health and Oxford Biomedical Research Centre and an Oxfordshire Health Services Research Committee grant to A.J.M.. The Wellcome Center for Human Genetics is supported by Wellcome (grant 090532/Z/09/Z). Computational aspects were supported by the Wellcome (203141/Z/16/Z) and the NIHR Oxford BRC. SPR measurements were carried out at the Molecular Biophysics facility, University of Oxford. Diamond Light Source provided time on Beamlines I03 and I04 under Proposal lb27009 for COVID-19 Rapid Access. Electron microscopy was conducted at the Oxford Particle Imaging Centre (OPIC), founded by a Wellcome JIF award (060208/Z/00/Z), or COSMIC (Oxford). Computational aspects were supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z and the NIHR Oxford BRC. Oxford Vaccine work was supported by UKRI, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland’s NIHR Clinical Research Network. We thank the Oxford Protective T-cell Immunology for COVID-19 (OPTIC) Clinical team (Christopher Conlon, Alexandra Deeks, John Frater, Lisa Frending, Siobhan Gardiner, Anni Jämsén, Katie Jeffery, Tom Malone, Eloise Phillips, Lucy Rothwell, Lizzie Stafford) for participant sample collection and the Oxford Immunology Network Covid-19 Response T cell Consortium for laboratory support. We acknowledge rapid sharing of Victoria, B.1.1.7, and B.1.351 isolated by scientists in the National Infection Service at PHE Porton Down, and B.1.617.2 virus was kindly provided by Wendy Barclay and Thushan De-Silva. 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 (DHSC) 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 NIH (U19 I082360). S.J.D. is funded by an NIHR Global Research Professorship (NIHR300791). 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 DHSC, the National NIHR, the MRC, or Public Health, England.

PY - 2022/6/9

Y1 - 2022/6/9

N2 - Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

AB - Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

KW - SARS-CoV-2

KW - COVID-19

KW - Omicron

KW - BA.1

KW - BA.1.1

KW - BA.2

KW - antibody responses

KW - crystallography

KW - variants of concern

KW - receptor binding domain

KW - neutralization

KW - immune escape

U2 - 10.1016/j.cell.2022.05.014

DO - 10.1016/j.cell.2022.05.014

M3 - Article

SN - 0092-8674

VL - 185

SP - 2116-2131.e18

JO - Cell

JF - Cell

IS - 12

ER -

Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

Abstract

Bibliographical note

Keywords

UN SDGs

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