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Detection and Quantification of Antibody to SARS-CoV-2 Receptor Binding Domain Provides Enhanced Sensitivity, Specificity and Utility

30 Pages Posted: 5 Jan 2021

See all articles by Richard S. Tedder

Richard S. Tedder

Imperial College London - Section of Infectious Diseases and Immunity

Eleanor Parker

Department of Infectious Disease, Imperial College London

Macià Sureda-Vives

Department of Infectious Disease, Imperial College London

Natalia Fernandez

Department of Infectious Disease, Imperial College London

Paul Randell

Department of Infection and Immunity, Imperial College Healthcare NHS Trust

Federica Marchesin

Department of Infectious Disease, Imperial College London

Ksenia Katsanovskaja

Department of Infectious Disease, Imperial College London

Ruth Harvey

Worldwide Influenza Centre, Francis Crick Institute

Alice Lilley

Worldwide Influenza Centre, Francis Crick Institute

Benjamin HL Harris

The Wellington Hospital

Mohamed Zuhair

The Wellington Hospital

Michael Fertleman

The Wellington Hospital

Samreen Ijaz

Blood Borne Virus Unit, National Infection Service, Colindale Public Health England

Steve Dicks

Blood Borne Virus Unit, National Infection Service, Colindale Public Health England

Charlotte-Eve Short

Department of Infectious Disease, Imperial College London

Rachael Quinlan

Department of Infectious Disease, Imperial College London

Graham P. Taylor

Department of Infectious Disease, Imperial College London

Paul McKay

Department of Infectious Disease, Imperial College London

Kai Hu

Department of Infectious Disease, Imperial College London

Annachiara Rosa

Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute

Chloe Roustan

Structural Biology Science Technology Platform, Francis Crick Institute

Mark Zuckerman

King's College London

Kate El Bouzidi

Department of Virology, King’s College Hospital

Graham S. Cooke

Imperial College London - Department of Infectious Disease

Barney Flower

Department of Infectious Disease, Imperial College London

Maya Moshe

Department of Infectious Disease, Imperial College London

Paul Elliott

Imperial College London - Department of Epidemiology and Biostatistics

Alexandra J. Spencer

Jenner Institute, University of Oxford

Teresa Lambe

University of Oxford - The Jenner Institute

Sarah C. Gilbert

University of Oxford - The Jenner Institute

Hugh Kingston

Department of Infection and Immunity, Imperial College Healthcare NHS Trust

J. Kenneth Baillie

University of Edinburgh - Roslin Institute

Peter Openshaw

Imperial College London - National Heart and Lung Institute

Malcolm Semple

University of Liverpool - Institute of Infection, Veterinary and Ecological Sciences

ISARIC4C Investigators Group

Independent

Peter Cherepanov

Department of Infectious Disease, Imperial College London

Myra McLure

Imperial College London - Department of Infectious Disease

More...

Abstract

Background: 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.

Methods: The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA) provides the most sensitive format. It has been exploited in a novel hybrid manner employing an S1 solid-phase preferentially presenting RBD once solid-phase bound, coupled with a labelled RBD conjugate, used in a two-step sequential assay.

Findings: This 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 neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine. The early response at presentation with illness, elevated responsiveness with disease severity, detection of asymptomatic seroconversion and persistence after the loss of antibody to the nucleoprotein (anti-NP) are all documented.

Trial Registration: The ISARIC WHO CCP-UK study was registered at https://www.isrctn.com/ISRCTN66726260 and designated an Urgent Public Health Research Study by NIHR.

Interpretation: The hybrid DABA displays the attributes necessary for an antibody test to be used in both clinical and reference serology. It allows the neutralising antibody response to be inferred early in infection and potentially in vaccine recipients. It is also of sufficient sensitivity to be used to provide serological confirmation of prior infection and provides a more secure measure for seroprevalence studies in the population generally than does anti-NP based on the Architect platform.

Funding: This work is variously supported by grants from: the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059 and MC_PC_19078), MRC NIHR (grant CV220-111) 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), 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), and NIHR Clinical Research Network for providing infrastructure support for this research.

Declaration of Interests: RST, MOM and PC report patent pending (Patent Application No. 2011047.4 for “SARS-CoV-2 antibody detection assay). All other authors declare no competing interests.

Ethics Approval Statement: The use of tissues was approved by the CDRTB Steering Committee in accordance with the responsibility delegated by the National Research Ethics Service (South Central Ethics Committee – C, NRES reference 15/SC/0089).

Written informed consent was obtained from all patients. Ethical approval was given by the South Central–Oxford C Research Ethics Committee in England (reference: 13/SC/0149), Scotland A Research Ethics Committee (reference: 20/SS/0028) and World Health Organization Ethics Review Committee (RPC571 and RPC572l; 25 April 2013)

Suggested Citation

Tedder, Richard S. and Parker, Eleanor and Sureda-Vives, Macià and Fernandez, Natalia and Randell, Paul and Marchesin, Federica and Katsanovskaja, Ksenia and Harvey, Ruth and Lilley, Alice and Harris, Benjamin HL and Zuhair, Mohamed and Fertleman, Michael and Ijaz, Samreen and Dicks, Steve and Short, Charlotte-Eve and Quinlan, Rachael and Taylor, Graham P. and McKay, Paul and Hu, Kai and Rosa, Annachiara and Roustan, Chloe and Zuckerman, Mark and El Bouzidi, Kate and Cooke, Graham S. and Flower, Barney and Moshe, Maya and Elliott, Paul and Spencer, Alexandra J. and Lambe, Teresa and Gilbert, Sarah C. and Kingston, Hugh and Baillie, J. Kenneth and Openshaw, Peter and Semple, Malcolm and Group, ISARIC4C Investigators and Cherepanov, Peter and McLure, Myra, Detection and Quantification of Antibody to SARS-CoV-2 Receptor Binding Domain Provides Enhanced Sensitivity, Specificity and Utility. Available at SSRN: https://ssrn.com/abstract=3739821 or http://dx.doi.org/10.2139/ssrn.3739821

Richard S. Tedder (Contact Author)

Imperial College London - Section of Infectious Diseases and Immunity ( email )

London
United Kingdom

Eleanor Parker

Department of Infectious Disease, Imperial College London ( email )

Macià Sureda-Vives

Department of Infectious Disease, Imperial College London ( email )

Natalia Fernandez

Department of Infectious Disease, Imperial College London

Paul Randell

Department of Infection and Immunity, Imperial College Healthcare NHS Trust ( email )

Federica Marchesin

Department of Infectious Disease, Imperial College London ( email )

Ksenia Katsanovskaja

Department of Infectious Disease, Imperial College London ( email )

Ruth Harvey

Worldwide Influenza Centre, Francis Crick Institute ( email )

Alice Lilley

Worldwide Influenza Centre, Francis Crick Institute ( email )

Benjamin HL Harris

The Wellington Hospital ( email )

Mohamed Zuhair

The Wellington Hospital ( email )

Michael Fertleman

The Wellington Hospital ( email )

Samreen Ijaz

Blood Borne Virus Unit, National Infection Service, Colindale Public Health England ( email )

Steve Dicks

Blood Borne Virus Unit, National Infection Service, Colindale Public Health England ( email )

Charlotte-Eve Short

Department of Infectious Disease, Imperial College London ( email )

Rachael Quinlan

Department of Infectious Disease, Imperial College London ( email )

Graham P. Taylor

Department of Infectious Disease, Imperial College London ( email )

Paul McKay

Department of Infectious Disease, Imperial College London

Kai Hu

Department of Infectious Disease, Imperial College London

Annachiara Rosa

Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute ( email )

Chloe Roustan

Structural Biology Science Technology Platform, Francis Crick Institute ( email )

Mark Zuckerman

King's College London

Strand
London, England WC2R 2LS
United Kingdom

Kate El Bouzidi

Department of Virology, King’s College Hospital ( email )

Graham S. Cooke

Imperial College London - Department of Infectious Disease ( email )

Exhibition Road
London, SW7 2AZ
United Kingdom

Barney Flower

Department of Infectious Disease, Imperial College London ( email )

Maya Moshe

Department of Infectious Disease, Imperial College London ( email )

Paul Elliott

Imperial College London - Department of Epidemiology and Biostatistics ( email )

St Mary's Campus
Norfolk Pl, Paddington
London, W2 1QN
United Kingdom

Alexandra J. Spencer

Jenner Institute, University of Oxford ( email )

Teresa Lambe

University of Oxford - The Jenner Institute ( email )

Old Road Campus Research Building Roosevelt Drive
Oxford, Oxfordshire OX3 7DQ
United Kingdom

Sarah C. Gilbert

University of Oxford - The Jenner Institute ( email )

Old Road Campus Research Building Roosevelt Drive
Oxford, Oxfordshire OX3 7DQ
United Kingdom

Hugh Kingston

Department of Infection and Immunity, Imperial College Healthcare NHS Trust ( email )

J. Kenneth Baillie

University of Edinburgh - Roslin Institute ( email )

United Kingdom

HOME PAGE: http://baillielab.net

Peter Openshaw

Imperial College London - National Heart and Lung Institute ( email )

Malcolm Semple

University of Liverpool - Institute of Infection, Veterinary and Ecological Sciences ( email )

Institute in The Park
Alder Hey Children's Hospital
Liverpool, L12 2AP
United Kingdom

HOME PAGE: http://https://www.liverpool.ac.uk/translational-medicine/staff/malcolm-semple/

Peter Cherepanov

Department of Infectious Disease, Imperial College London ( email )

Myra McLure

Imperial College London - Department of Infectious Disease ( email )

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