Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility

ISARIC4C Investigators; Carolina Rosadas; Maryam Khan; Eleanor Parker; Federica Marchesin; Ksenia Katsanovskaja; Macià Sureda-Vives; Natalia Fernandez; Paul Randell; Ruth Harvey; Alice Lilley; Benjamin H.L. Harris; Mohamed Zuhair; Michael Fertleman; Samreen Ijaz; Steve Dicks; Charlotte-Eve Short; Rachael Quinlan; Graham P. Taylor; Kai Hu; Paul Mckay; Annachiara Rosa; Chloe Roustan; Mark Zuckerman; Kate El Bouzidi; Graham Cooke; Barnaby Flower; Maya Moshe; Paul Elliott; Alexandra J. Spencer; Teresa Lambe; Sarah C. Gilbert; Hugh Kingston; J Kenneth  Baillie; Peter J.M. Openshaw; Malcolm G. Semple; Peter Cherepanov; Myra O. Mcclure; Richard S. Tedder

doi:10.1016/j.jviromet.2022.114475

Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility

ISARIC4C Investigators, Carolina Rosadas, Maryam Khan, Eleanor Parker, Federica Marchesin, Ksenia Katsanovskaja, Macià Sureda-Vives, Natalia Fernandez, Paul Randell, Ruth Harvey, Alice Lilley, Benjamin H.L. Harris, Mohamed Zuhair, Michael Fertleman, Samreen Ijaz, Steve Dicks, Charlotte-Eve Short, Rachael Quinlan, Graham P. Taylor, Kai HuPaul Mckay, Annachiara Rosa, Chloe Roustan, Mark Zuckerman, Kate El Bouzidi, Graham Cooke, Barnaby Flower, Maya Moshe, Paul Elliott, Alexandra J. Spencer, Teresa Lambe, Sarah C. Gilbert, Hugh Kingston, J Kenneth Baillie, Peter J.M. Openshaw, Malcolm G. Semple, Peter Cherepanov, Myra O. Mcclure, Richard S. Tedder^*

^*Corresponding author for this work

Chemical Engineering

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Abstract

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity.

The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD).

This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations.

The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

Original language	English
Article number	114475
Number of pages	11
Journal	Journal of Virological Methods
Volume	302
Early online date	22 Jan 2022
DOIs	https://doi.org/10.1016/j.jviromet.2022.114475
Publication status	Published - Apr 2022

Bibliographical note

Funding:
This work is variously supported by grants from: the National Institute for Health Research (NIHR; awardCO-CIN-01), theMedical Research Council (MRC; grantMC_PC_19059 andMC_PC_19078), MRC NIHR (grantCV220-111) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), 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 PHE (award 200927), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), theBill 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), and NIHR Clinical Research Network for providing infrastructure support for this research. This work is supported by the Francis Crick Institute, which receives its core funding fromCancer Research UK (FC001061), the UK Medical Research Council (FC001061), and theWellcome Trust (FC001061).

Keywords

Sars-CoV-2
ELISA
Receptor binding domain
Antibodies

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ISARIC4C Investigators, Rosadas, C., Khan, M., Parker, E., Marchesin, F., Katsanovskaja, K., Sureda-Vives, M., Fernandez, N., Randell, P., Harvey, R., Lilley, A., Harris, B. H. L., Zuhair, M., Fertleman, M., Ijaz, S., Dicks, S., Short, C.-E., Quinlan, R., Taylor, G. P., ... Tedder, R. S. (2022). Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility. Journal of Virological Methods, 302, Article 114475. https://doi.org/10.1016/j.jviromet.2022.114475

@article{e2354543bcda424aa55655d68943b4cd,

title = "Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility",

abstract = "Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity.The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD).This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations.The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.",

keywords = "Sars-CoV-2, ELISA, Receptor binding domain, Antibodies",

author = "{ISARIC4C Investigators} and Carolina Rosadas and Maryam Khan and Eleanor Parker and Federica Marchesin and Ksenia Katsanovskaja and Maci{\`a} Sureda-Vives and Natalia Fernandez and Paul Randell and Ruth Harvey and Alice Lilley and Harris, {Benjamin H.L.} and Mohamed Zuhair and Michael Fertleman and Samreen Ijaz and Steve Dicks and Charlotte-Eve Short and Rachael Quinlan and Taylor, {Graham P.} and Kai Hu and Paul Mckay and Annachiara Rosa and Chloe Roustan and Mark Zuckerman and {El Bouzidi}, Kate and Graham Cooke and Barnaby Flower and Maya Moshe and Paul Elliott and Spencer, {Alexandra J.} and Teresa Lambe and Gilbert, {Sarah C.} and Hugh Kingston and Baillie, {J Kenneth} and Openshaw, {Peter J.M.} and Semple, {Malcolm G.} and Peter Cherepanov and Mcclure, {Myra O.} and Tedder, {Richard S.} and Christopher Green",

note = "Funding: This work is variously supported by grants from: the National Institute for Health Research (NIHR; awardCO-CIN-01), theMedical Research Council (MRC; grantMC_PC_19059 andMC_PC_19078), MRC NIHR (grantCV220-111) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), 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 PHE (award 200927), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), theBill 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), and NIHR Clinical Research Network for providing infrastructure support for this research. This work is supported by the Francis Crick Institute, which receives its core funding fromCancer Research UK (FC001061), the UK Medical Research Council (FC001061), and theWellcome Trust (FC001061).",

year = "2022",

month = apr,

doi = "10.1016/j.jviromet.2022.114475",

language = "English",

volume = "302",

journal = "Journal of Virological Methods",

issn = "0166-0934",

publisher = "Elsevier",

}

ISARIC4C Investigators, Rosadas, C, Khan, M, Parker, E, Marchesin, F, Katsanovskaja, K, Sureda-Vives, M, Fernandez, N, Randell, P, Harvey, R, Lilley, A, Harris, BHL, Zuhair, M, Fertleman, M, Ijaz, S, Dicks, S, Short, C-E, Quinlan, R, Taylor, GP, Hu, K, Mckay, P, Rosa, A, Roustan, C, Zuckerman, M, El Bouzidi, K, Cooke, G, Flower, B, Moshe, M, Elliott, P, Spencer, AJ, Lambe, T, Gilbert, SC, Kingston, H, Baillie, JK, Openshaw, PJM, Semple, MG, Cherepanov, P, Mcclure, MO & Tedder, RS 2022, 'Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility', Journal of Virological Methods, vol. 302, 114475. https://doi.org/10.1016/j.jviromet.2022.114475

TY - JOUR

T1 - Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility

AU - ISARIC4C Investigators

AU - Rosadas, Carolina

AU - Khan, Maryam

AU - Parker, Eleanor

AU - Marchesin, Federica

AU - Katsanovskaja, Ksenia

AU - Sureda-Vives, Macià

AU - Fernandez, Natalia

AU - Randell, Paul

AU - Harvey, Ruth

AU - Lilley, Alice

AU - Harris, Benjamin H.L.

AU - Zuhair, Mohamed

AU - Fertleman, Michael

AU - Ijaz, Samreen

AU - Dicks, Steve

AU - Short, Charlotte-Eve

AU - Quinlan, Rachael

AU - Taylor, Graham P.

AU - Hu, Kai

AU - Mckay, Paul

AU - Rosa, Annachiara

AU - Roustan, Chloe

AU - Zuckerman, Mark

AU - El Bouzidi, Kate

AU - Cooke, Graham

AU - Flower, Barnaby

AU - Moshe, Maya

AU - Elliott, Paul

AU - Spencer, Alexandra J.

AU - Lambe, Teresa

AU - Gilbert, Sarah C.

AU - Kingston, Hugh

AU - Baillie, J Kenneth

AU - Openshaw, Peter J.M.

AU - Semple, Malcolm G.

AU - Cherepanov, Peter

AU - Mcclure, Myra O.

AU - Tedder, Richard S.

AU - Green, Christopher

N1 - Funding: This work is variously supported by grants from: the National Institute for Health Research (NIHR; awardCO-CIN-01), theMedical Research Council (MRC; grantMC_PC_19059 andMC_PC_19078), MRC NIHR (grantCV220-111) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), 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 PHE (award 200927), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), theBill 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), and NIHR Clinical Research Network for providing infrastructure support for this research. This work is supported by the Francis Crick Institute, which receives its core funding fromCancer Research UK (FC001061), the UK Medical Research Council (FC001061), and theWellcome Trust (FC001061).

PY - 2022/4

Y1 - 2022/4

N2 - Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity.The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD).This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations.The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

AB - Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity.The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD).This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations.The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

KW - Sars-CoV-2

KW - ELISA

KW - Receptor binding domain

KW - Antibodies

U2 - 10.1016/j.jviromet.2022.114475

DO - 10.1016/j.jviromet.2022.114475

M3 - Article

SN - 0166-0934

VL - 302

JO - Journal of Virological Methods

JF - Journal of Virological Methods

M1 - 114475

ER -

Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility

Abstract

Bibliographical note

Keywords

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