Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium; Scottish National Blood Transfusion Service (SNBTS) consortium; International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators; Anna L. Mcnaughton; Robert S. Paton; Matthew Edmans; Jonathan Youngs; Judith Wellens; Prabhjeet Phalora; Alex Fyfe; Sandra Belij-Rammerstorfer; Jai S. Bolton; Jonathan Ball; George W. Carnell; Wanwisa Dejnirattisai; Christina Dold; David W. Eyre; Philip Hopkins; Alison Howarth; Kreepa Kooblall; Hannah Klim; Susannah Leaver; Lian Ni Lee; César López-Camacho; Sheila F. Lumley; Derek C. Macallan; Alexander J. Mentzer; Nicholas M. Provine; Jeremy Ratcliff; Jose Slon-Compos; Donal Skelly; Lucas Stolle; Piyada Supasa; Nigel Temperton; Chris Walker; Beibei Wang; Duncan Wyncoll; Peter Simmonds; Teresa Lambe; J Kenneth  Baillie; Malcolm G. Semple; Peter J.M. Openshaw; Uri Obolski; Marc Turner; Miles Carroll; Juthathip Mongkolsapaya; Gavin Screaton; Stephen H. Kennedy; Lisa Jarvis; Eleanor Barnes; Susanna Dunachie; José Lourenço; Philippa C. Matthews; Tihana Bicanic; Paul Klenerman; Sunetra Gupta; Craig P. Thompson

doi:10.1172/jci.insight.156372

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium, Scottish National Blood Transfusion Service (SNBTS) consortium, International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators, Anna L. Mcnaughton, Robert S. Paton, Matthew Edmans, Jonathan Youngs, Judith Wellens, Prabhjeet Phalora, Alex Fyfe, Sandra Belij-Rammerstorfer, Jai S. Bolton, Jonathan Ball, George W. Carnell, Wanwisa Dejnirattisai, Christina Dold, David W. Eyre, Philip Hopkins, Alison Howarth, Kreepa KooblallHannah Klim, Susannah Leaver, Lian Ni Lee, César López-Camacho, Sheila F. Lumley, Derek C. Macallan, Alexander J. Mentzer, Nicholas M. Provine, Jeremy Ratcliff, Jose Slon-Compos, Donal Skelly, Lucas Stolle, Piyada Supasa, Nigel Temperton, Chris Walker, Beibei Wang, Duncan Wyncoll, Peter Simmonds, Teresa Lambe, J Kenneth Baillie, Malcolm G. Semple, Peter J.M. Openshaw, Uri Obolski, Marc Turner, Miles Carroll, Juthathip Mongkolsapaya, Gavin Screaton, Stephen H. Kennedy, Lisa Jarvis, Eleanor Barnes, Susanna Dunachie, José Lourenço, Philippa C. Matthews, Tihana Bicanic, Paul Klenerman, Sunetra Gupta, Craig P. Thompson^*

^*Corresponding author for this work

Chemical Engineering

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Abstract

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.

Original language	English
Article number	e156372
Number of pages	17
Journal	JCI Insight
Volume	7
Issue number	13
Early online date	24 May 2022
DOIs	https://doi.org/10.1172/jci.insight.156372
Publication status	Published - 8 Jul 2022

Bibliographical note

Acknowledgments:
We would like to express our gratitude and acknowledge the contribution of the staff at Oxford University Hospitals NHS Foundation Trust, SNBTS, and St George’s University Hospitals NHS Foundation Trust (London) who were involved in the provision and preparation of samples analyzed in this project. We acknowledge the wider support of the ISARIC4C, OPTIC, and SNBTS research consortia. This work was supported by the Medical Research Council (MRC; grant MC_PC_19059). ME was supported by The Leona M. and Harry B. Helmsley Charitable Trust on May 31, 2021, for the project titled “International study of COVID-19 Antibody Response Under Sustained immune suppression in IBD.” RP was supported by funds provided under Professor RW Snow’s Wellcome Trust Principal Fellowship (number 212176). MSD (USA) provided loan of equipment, reagents, and technical support. JSB was supported by funding from the Biotechnology and Biological Sciences Research Council (grant number BB/M011224/1). CPT was funded by an European Research Council research grant, UNIFLUVAC, and by 2 MRC Confidence in Concept grants (Ref: BR00140). ALM is funded by a National Institute for Health Research (NIHR) Research Capability Funding grant (CO-CIN-01). ALM, RP, and SG were supported by the Georg and Emily von Opel Foundation. HK is supported by Future of Humanity Institute at the University of Oxford DPhil Scholarship program. DWE is funded by the Robertson Foundation. PK was funded by a Wellcome Trust grant (ref. 222426/Z/21/Z). EB is supported by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The funders played no role in the design, execution, or reporting of the study.

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Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium, Scottish National Blood Transfusion Service (SNBTS) consortium, International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators, Mcnaughton, A. L., Paton, R. S., Edmans, M., Youngs, J., Wellens, J., Phalora, P., Fyfe, A., Belij-Rammerstorfer, S., Bolton, J. S., Ball, J., Carnell, G. W., Dejnirattisai, W., Dold, C., Eyre, D. W., Hopkins, P., Howarth, A., ... Thompson, C. P. (2022). Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses. JCI Insight, 7(13), Article e156372. https://doi.org/10.1172/jci.insight.156372

Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium ; Scottish National Blood Transfusion Service (SNBTS) consortium ; International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators et al. / Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses. In: JCI Insight. 2022 ; Vol. 7, No. 13.

@article{289d76d1eaea470c959d73da7ac7f825,

title = "Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses",

abstract = "The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.",

author = "{Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium} and {Scottish National Blood Transfusion Service (SNBTS) consortium} and {International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators} and Mcnaughton, {Anna L.} and Paton, {Robert S.} and Matthew Edmans and Jonathan Youngs and Judith Wellens and Prabhjeet Phalora and Alex Fyfe and Sandra Belij-Rammerstorfer and Bolton, {Jai S.} and Jonathan Ball and Carnell, {George W.} and Wanwisa Dejnirattisai and Christina Dold and Eyre, {David W.} and Philip Hopkins and Alison Howarth and Kreepa Kooblall and Hannah Klim and Susannah Leaver and Lee, {Lian Ni} and C{\'e}sar L{\'o}pez-Camacho and Lumley, {Sheila F.} and Macallan, {Derek C.} and Mentzer, {Alexander J.} and Provine, {Nicholas M.} and Jeremy Ratcliff and Jose Slon-Compos and Donal Skelly and Lucas Stolle and Piyada Supasa and Nigel Temperton and Chris Walker and Beibei Wang and Duncan Wyncoll and Peter Simmonds and Teresa Lambe and Baillie, {J Kenneth} and Semple, {Malcolm G.} and Openshaw, {Peter J.M.} and Uri Obolski and Marc Turner and Miles Carroll and Juthathip Mongkolsapaya and Gavin Screaton and Kennedy, {Stephen H.} and Lisa Jarvis and Eleanor Barnes and Susanna Dunachie and Jos{\'e} Louren{\c c}o and Matthews, {Philippa C.} and Tihana Bicanic and Paul Klenerman and Sunetra Gupta and Thompson, {Craig P.} and Christopher Green",

note = "Acknowledgments: We would like to express our gratitude and acknowledge the contribution of the staff at Oxford University Hospitals NHS Foundation Trust, SNBTS, and St George{\textquoteright}s University Hospitals NHS Foundation Trust (London) who were involved in the provision and preparation of samples analyzed in this project. We acknowledge the wider support of the ISARIC4C, OPTIC, and SNBTS research consortia. This work was supported by the Medical Research Council (MRC; grant MC_PC_19059). ME was supported by The Leona M. and Harry B. Helmsley Charitable Trust on May 31, 2021, for the project titled “International study of COVID-19 Antibody Response Under Sustained immune suppression in IBD.” RP was supported by funds provided under Professor RW Snow{\textquoteright}s Wellcome Trust Principal Fellowship (number 212176). MSD (USA) provided loan of equipment, reagents, and technical support. JSB was supported by funding from the Biotechnology and Biological Sciences Research Council (grant number BB/M011224/1). CPT was funded by an European Research Council research grant, UNIFLUVAC, and by 2 MRC Confidence in Concept grants (Ref: BR00140). ALM is funded by a National Institute for Health Research (NIHR) Research Capability Funding grant (CO-CIN-01). ALM, RP, and SG were supported by the Georg and Emily von Opel Foundation. HK is supported by Future of Humanity Institute at the University of Oxford DPhil Scholarship program. DWE is funded by the Robertson Foundation. PK was funded by a Wellcome Trust grant (ref. 222426/Z/21/Z). EB is supported by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The funders played no role in the design, execution, or reporting of the study.",

year = "2022",

month = jul,

day = "8",

doi = "10.1172/jci.insight.156372",

language = "English",

volume = "7",

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publisher = "American Society for Clinical Investigation",

number = "13",

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Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium, Scottish National Blood Transfusion Service (SNBTS) consortium, International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators, Mcnaughton, AL, Paton, RS, Edmans, M, Youngs, J, Wellens, J, Phalora, P, Fyfe, A, Belij-Rammerstorfer, S, Bolton, JS, Ball, J, Carnell, GW, Dejnirattisai, W, Dold, C, Eyre, DW, Hopkins, P, Howarth, A, Kooblall, K, Klim, H, Leaver, S, Lee, LN, López-Camacho, C, Lumley, SF, Macallan, DC, Mentzer, AJ, Provine, NM, Ratcliff, J, Slon-Compos, J, Skelly, D, Stolle, L, Supasa, P, Temperton, N, Walker, C, Wang, B, Wyncoll, D, Simmonds, P, Lambe, T, Baillie, JK, Semple, MG, Openshaw, PJM, Obolski, U, Turner, M, Carroll, M, Mongkolsapaya, J, Screaton, G, Kennedy, SH, Jarvis, L, Barnes, E, Dunachie, S, Lourenço, J, Matthews, PC, Bicanic, T, Klenerman, P, Gupta, S & Thompson, CP 2022, 'Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses', JCI Insight, vol. 7, no. 13, e156372. https://doi.org/10.1172/jci.insight.156372

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses. / Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium; Scottish National Blood Transfusion Service (SNBTS) consortium; International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators et al.
In: JCI Insight, Vol. 7, No. 13, e156372, 08.07.2022.

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

TY - JOUR

T1 - Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

AU - Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium

AU - Scottish National Blood Transfusion Service (SNBTS) consortium

AU - International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators

AU - Mcnaughton, Anna L.

AU - Paton, Robert S.

AU - Edmans, Matthew

AU - Youngs, Jonathan

AU - Wellens, Judith

AU - Phalora, Prabhjeet

AU - Fyfe, Alex

AU - Belij-Rammerstorfer, Sandra

AU - Bolton, Jai S.

AU - Ball, Jonathan

AU - Carnell, George W.

AU - Dejnirattisai, Wanwisa

AU - Dold, Christina

AU - Eyre, David W.

AU - Hopkins, Philip

AU - Howarth, Alison

AU - Kooblall, Kreepa

AU - Klim, Hannah

AU - Leaver, Susannah

AU - Lee, Lian Ni

AU - López-Camacho, César

AU - Lumley, Sheila F.

AU - Macallan, Derek C.

AU - Mentzer, Alexander J.

AU - Provine, Nicholas M.

AU - Ratcliff, Jeremy

AU - Slon-Compos, Jose

AU - Skelly, Donal

AU - Stolle, Lucas

AU - Supasa, Piyada

AU - Temperton, Nigel

AU - Walker, Chris

AU - Wang, Beibei

AU - Wyncoll, Duncan

AU - Simmonds, Peter

AU - Lambe, Teresa

AU - Baillie, J Kenneth

AU - Semple, Malcolm G.

AU - Openshaw, Peter J.M.

AU - Obolski, Uri

AU - Turner, Marc

AU - Carroll, Miles

AU - Mongkolsapaya, Juthathip

AU - Screaton, Gavin

AU - Kennedy, Stephen H.

AU - Jarvis, Lisa

AU - Barnes, Eleanor

AU - Dunachie, Susanna

AU - Lourenço, José

AU - Matthews, Philippa C.

AU - Bicanic, Tihana

AU - Klenerman, Paul

AU - Gupta, Sunetra

AU - Thompson, Craig P.

AU - Green, Christopher

N1 - Acknowledgments: We would like to express our gratitude and acknowledge the contribution of the staff at Oxford University Hospitals NHS Foundation Trust, SNBTS, and St George’s University Hospitals NHS Foundation Trust (London) who were involved in the provision and preparation of samples analyzed in this project. We acknowledge the wider support of the ISARIC4C, OPTIC, and SNBTS research consortia. This work was supported by the Medical Research Council (MRC; grant MC_PC_19059). ME was supported by The Leona M. and Harry B. Helmsley Charitable Trust on May 31, 2021, for the project titled “International study of COVID-19 Antibody Response Under Sustained immune suppression in IBD.” RP was supported by funds provided under Professor RW Snow’s Wellcome Trust Principal Fellowship (number 212176). MSD (USA) provided loan of equipment, reagents, and technical support. JSB was supported by funding from the Biotechnology and Biological Sciences Research Council (grant number BB/M011224/1). CPT was funded by an European Research Council research grant, UNIFLUVAC, and by 2 MRC Confidence in Concept grants (Ref: BR00140). ALM is funded by a National Institute for Health Research (NIHR) Research Capability Funding grant (CO-CIN-01). ALM, RP, and SG were supported by the Georg and Emily von Opel Foundation. HK is supported by Future of Humanity Institute at the University of Oxford DPhil Scholarship program. DWE is funded by the Robertson Foundation. PK was funded by a Wellcome Trust grant (ref. 222426/Z/21/Z). EB is supported by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The funders played no role in the design, execution, or reporting of the study.

PY - 2022/7/8

Y1 - 2022/7/8

N2 - The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.

AB - The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.

U2 - 10.1172/jci.insight.156372

DO - 10.1172/jci.insight.156372

M3 - Article

SN - 2379-3708

VL - 7

JO - JCI Insight

JF - JCI Insight

IS - 13

M1 - e156372

ER -

Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium, Scottish National Blood Transfusion Service (SNBTS) consortium, International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators, Mcnaughton AL, Paton RS, Edmans M et al. Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses. JCI Insight. 2022 Jul 8;7(13):e156372. Epub 2022 May 24. doi: 10.1172/jci.insight.156372

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

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