SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study

ISARIC4C Investigators; Eleanor Parker; Jordan Thomas; Kelly J. Roper; Samreen Ijaz; Tansy Edwards; Federica Marchesin; Ksenia Katsanovskaja; Lauren Lett; Christopher Jones; Hayley E. Hardwick; Chris Davis; Elen Vink; Sarah E. McDonald; Shona C. Moore; Steve Dicks; Keerthana Jegatheesan; Nicola J. Cook; Joshua Hope; Peter Cherepanov; Myra O. McClure; J. Kenneth Baillie; Peter J. M. Openshaw; Lance Turtle; Antonia Ho; Malcolm G. Semple; William A. Paxton; Richard S. Tedder; Georgios Pollakis

doi:10.3389/fimmu.2023.1146702

SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study

ISARIC4C Investigators, Eleanor Parker, Jordan Thomas, Kelly J. Roper, Samreen Ijaz, Tansy Edwards, Federica Marchesin, Ksenia Katsanovskaja, Lauren Lett, Christopher Jones, Hayley E. Hardwick, Chris Davis, Elen Vink, Sarah E. McDonald, Shona C. Moore, Steve Dicks, Keerthana Jegatheesan, Nicola J. Cook, Joshua Hope, Peter CherepanovMyra O. McClure, J. Kenneth Baillie, Peter J. M. Openshaw, Lance Turtle, Antonia Ho, Malcolm G. Semple, William A. Paxton, Richard S. Tedder, Georgios Pollakis^*

^*Corresponding author for this work

Chemical Engineering

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Abstract

The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically naïve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.

Original language	English
Article number	1146702
Number of pages	12
Journal	Frontiers in immunology
Volume	14
DOIs	https://doi.org/10.3389/fimmu.2023.1146702
Publication status	Published - 15 Mar 2023

Bibliographical note

Funding Information:
This work is supported by grants from: the National Institute for Health Research (NIHR) [award CO-CIN-01], the Medical Research Council [grant MC_PC_19059, MR/V028979/1 and UKRI CV220-111], the Chief Scientist Office, Scotland, and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with the UK Health Security Agency (UK-HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], NIHR HPRU in Respiratory Infections at Imperial College London with UK-HSA [award 200927], Wellcome Trust and Department for International Development [215091/Z/18/Z], the Bill and Melinda Gates Foundation [OPP1209135], Liverpool Experimental Cancer Medicine Centre (Grant Reference: C18616/A25153), NIHR Biomedical Research Centre at Imperial College London [IS-BRC-1215-20013], EU Platform foR European Preparedness Against (Re-) emerging Epidemics (PREPARE) [FP7 project 602525]. We acknowledge the NIHR Clinical Research Network for providing infrastructure support for this research. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029). LT is supported by a Wellcome Trust clinical career development fellowship a [205228/Z/16/Z]. PO is supported by a NIHR Senior Investigator Award [award 201385]. For the purpose of Open Access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust or UK-HSA. UKRI support was provided through the following grant: MRC/UKRI grant MC_PC_19078 “nCoV: Serological detection of past SARS-CoV-2 infection by non-invasive sampling for field epidemiology and quantitative antibody detection".

PO is the Imperial College Lead Investigator of the EMINENT consortium, supported by the Medical Research Council UK MR/R502121/1. This grant supports collaborative testing of compounds developed by GlaxoSmithKline in UK universities. PO is also on advisory boards for Affnivax, Oxford Immunotech, Nestle and Pfizer in relation to immunity to viruses fees paid to Imperial College London. PO is also on an advisory board for Janssen/J&J.

Publisher Copyright:
Copyright © 2023 Parker, Thomas, Roper, Ijaz, Edwards, Marchesin, Katsanovskaja, Lett, Jones, Hardwick, Davis, Vink, McDonald, Moore, Dicks, Jegatheesan, Cook, Hope, Cherepanov, McClure, Baillie, Openshaw, Turtle, Ho, Semple, Paxton, Tedder, Pollakis and ISARIC4C Investigators.

Keywords

COVID-19
disease
immunology
neutralisation
SARS-CoV-2
serology
virus

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Cite this

ISARIC4C Investigators, Parker, E., Thomas, J., Roper, K. J., Ijaz, S., Edwards, T., Marchesin, F., Katsanovskaja, K., Lett, L., Jones, C., Hardwick, H. E., Davis, C., Vink, E., McDonald, S. E., Moore, S. C., Dicks, S., Jegatheesan, K., Cook, N. J., Hope, J., ... Pollakis, G. (2023). SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study. Frontiers in immunology, 14, Article 1146702. https://doi.org/10.3389/fimmu.2023.1146702

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title = "SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study",

abstract = "The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically na{\"i}ve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.",

keywords = "COVID-19, disease, immunology, neutralisation, SARS-CoV-2, serology, virus",

author = "{ISARIC4C Investigators} and Eleanor Parker and Jordan Thomas and Roper, {Kelly J.} and Samreen Ijaz and Tansy Edwards and Federica Marchesin and Ksenia Katsanovskaja and Lauren Lett and Christopher Jones and Hardwick, {Hayley E.} and Chris Davis and Elen Vink and McDonald, {Sarah E.} and Moore, {Shona C.} and Steve Dicks and Keerthana Jegatheesan and Cook, {Nicola J.} and Joshua Hope and Peter Cherepanov and McClure, {Myra O.} and Baillie, {J. Kenneth} and Openshaw, {Peter J. M.} and Lance Turtle and Antonia Ho and Semple, {Malcolm G.} and Paxton, {William A.} and Tedder, {Richard S.} and Georgios Pollakis and Christopher Green",

note = "Funding Information: This work is supported by grants from: the National Institute for Health Research (NIHR) [award CO-CIN-01], the Medical Research Council [grant MC_PC_19059, MR/V028979/1 and UKRI CV220-111], the Chief Scientist Office, Scotland, and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with the UK Health Security Agency (UK-HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], NIHR HPRU in Respiratory Infections at Imperial College London with UK-HSA [award 200927], Wellcome Trust and Department for International Development [215091/Z/18/Z], the Bill and Melinda Gates Foundation [OPP1209135], Liverpool Experimental Cancer Medicine Centre (Grant Reference: C18616/A25153), NIHR Biomedical Research Centre at Imperial College London [IS-BRC-1215-20013], EU Platform foR European Preparedness Against (Re-) emerging Epidemics (PREPARE) [FP7 project 602525]. We acknowledge the NIHR Clinical Research Network for providing infrastructure support for this research. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029). LT is supported by a Wellcome Trust clinical career development fellowship a [205228/Z/16/Z]. PO is supported by a NIHR Senior Investigator Award [award 201385]. For the purpose of Open Access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust or UK-HSA. UKRI support was provided through the following grant: MRC/UKRI grant MC_PC_19078 “nCoV: Serological detection of past SARS-CoV-2 infection by non-invasive sampling for field epidemiology and quantitative antibody detection{"}. PO is the Imperial College Lead Investigator of the EMINENT consortium, supported by the Medical Research Council UK MR/R502121/1. This grant supports collaborative testing of compounds developed by GlaxoSmithKline in UK universities. PO is also on advisory boards for Affnivax, Oxford Immunotech, Nestle and Pfizer in relation to immunity to viruses fees paid to Imperial College London. PO is also on an advisory board for Janssen/J&J. Publisher Copyright: Copyright {\textcopyright} 2023 Parker, Thomas, Roper, Ijaz, Edwards, Marchesin, Katsanovskaja, Lett, Jones, Hardwick, Davis, Vink, McDonald, Moore, Dicks, Jegatheesan, Cook, Hope, Cherepanov, McClure, Baillie, Openshaw, Turtle, Ho, Semple, Paxton, Tedder, Pollakis and ISARIC4C Investigators. ",

year = "2023",

month = mar,

day = "15",

doi = "10.3389/fimmu.2023.1146702",

language = "English",

volume = "14",

journal = "Frontiers in immunology",

issn = "1664-3224",

publisher = "Frontiers",

}

ISARIC4C Investigators, Parker, E, Thomas, J, Roper, KJ, Ijaz, S, Edwards, T, Marchesin, F, Katsanovskaja, K, Lett, L, Jones, C, Hardwick, HE, Davis, C, Vink, E, McDonald, SE, Moore, SC, Dicks, S, Jegatheesan, K, Cook, NJ, Hope, J, Cherepanov, P, McClure, MO, Baillie, JK, Openshaw, PJM, Turtle, L, Ho, A, Semple, MG, Paxton, WA, Tedder, RS & Pollakis, G 2023, 'SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study', Frontiers in immunology, vol. 14, 1146702. https://doi.org/10.3389/fimmu.2023.1146702

TY - JOUR

T1 - SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19

T2 - An ISARIC4C prospective study

AU - ISARIC4C Investigators

AU - Parker, Eleanor

AU - Thomas, Jordan

AU - Roper, Kelly J.

AU - Ijaz, Samreen

AU - Edwards, Tansy

AU - Marchesin, Federica

AU - Katsanovskaja, Ksenia

AU - Lett, Lauren

AU - Jones, Christopher

AU - Hardwick, Hayley E.

AU - Davis, Chris

AU - Vink, Elen

AU - McDonald, Sarah E.

AU - Moore, Shona C.

AU - Dicks, Steve

AU - Jegatheesan, Keerthana

AU - Cook, Nicola J.

AU - Hope, Joshua

AU - Cherepanov, Peter

AU - McClure, Myra O.

AU - Baillie, J. Kenneth

AU - Openshaw, Peter J. M.

AU - Turtle, Lance

AU - Ho, Antonia

AU - Semple, Malcolm G.

AU - Paxton, William A.

AU - Tedder, Richard S.

AU - Pollakis, Georgios

AU - Green, Christopher

N1 - Funding Information: This work is supported by grants from: the National Institute for Health Research (NIHR) [award CO-CIN-01], the Medical Research Council [grant MC_PC_19059, MR/V028979/1 and UKRI CV220-111], the Chief Scientist Office, Scotland, and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with the UK Health Security Agency (UK-HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], NIHR HPRU in Respiratory Infections at Imperial College London with UK-HSA [award 200927], Wellcome Trust and Department for International Development [215091/Z/18/Z], the Bill and Melinda Gates Foundation [OPP1209135], Liverpool Experimental Cancer Medicine Centre (Grant Reference: C18616/A25153), NIHR Biomedical Research Centre at Imperial College London [IS-BRC-1215-20013], EU Platform foR European Preparedness Against (Re-) emerging Epidemics (PREPARE) [FP7 project 602525]. We acknowledge the NIHR Clinical Research Network for providing infrastructure support for this research. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029). LT is supported by a Wellcome Trust clinical career development fellowship a [205228/Z/16/Z]. PO is supported by a NIHR Senior Investigator Award [award 201385]. For the purpose of Open Access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust or UK-HSA. UKRI support was provided through the following grant: MRC/UKRI grant MC_PC_19078 “nCoV: Serological detection of past SARS-CoV-2 infection by non-invasive sampling for field epidemiology and quantitative antibody detection". PO is the Imperial College Lead Investigator of the EMINENT consortium, supported by the Medical Research Council UK MR/R502121/1. This grant supports collaborative testing of compounds developed by GlaxoSmithKline in UK universities. PO is also on advisory boards for Affnivax, Oxford Immunotech, Nestle and Pfizer in relation to immunity to viruses fees paid to Imperial College London. PO is also on an advisory board for Janssen/J&J. Publisher Copyright: Copyright © 2023 Parker, Thomas, Roper, Ijaz, Edwards, Marchesin, Katsanovskaja, Lett, Jones, Hardwick, Davis, Vink, McDonald, Moore, Dicks, Jegatheesan, Cook, Hope, Cherepanov, McClure, Baillie, Openshaw, Turtle, Ho, Semple, Paxton, Tedder, Pollakis and ISARIC4C Investigators.

PY - 2023/3/15

Y1 - 2023/3/15

N2 - The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically naïve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.

AB - The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically naïve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.

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KW - immunology

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SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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