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Safety and Immunogenicity Report from the Com-COV Study – a Single-Blind Randomised Non-Inferiority Trial Comparing Heterologous And Homologous Prime-Boost Schedules with An Adenoviral Vectored and mRNA COVID-19 Vaccine

45 Pages Posted: 25 Jun 2021

See all articles by Xinxue Liu

Xinxue Liu

University of Oxford - Oxford Vaccine Group

Robert H. Shaw

University of Oxford - Oxford Vaccine Group

Arabella SV Stuart

University of Oxford - Oxford Vaccine Group

Melanie Greenland

University of Oxford - Oxford Vaccine Group

Tanya Dinesh

University of Oxford - Oxford Vaccine Group

Samuel Provstgaard-Morys

University of Oxford - Oxford Vaccine Group

Elizabeth Clutterbuck

University of Oxford - Oxford Vaccine Group

Maheshi N. Ramasamy

University of Oxford - Oxford Vaccine Group

Parvinder K. Aley

University of Oxford - Oxford Vaccine Group

Yama Farooq Mujadidi

University of Oxford - Oxford Vaccine Group

Fei Long

University of Oxford - Oxford Vaccine Group

Emma Plested

University of Oxford - Oxford Vaccine Group

Hannah Robinson

University of Oxford - Oxford Vaccine Group

Nisha Singh

University of Oxford - Oxford Vaccine Group

Laura L. Walker

University of Oxford - Oxford Vaccine Group

Rachel White

University of Oxford - Oxford Vaccine Group

Nick Andrews

Public Health England Colindale

J. Claire Cameron

Government of the United Kingdom - Public Health Scotland

Andrea M. Collins

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Daniela M. Ferreira

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Helen C. Hill

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Christopher A. Green

University Hospitals Birmingham NHS Foundation Trust

Bassam Hallis

Public Health England - National Infection Service

Paul T. Heath

University of London - St George's Vaccine Institute

Saul N. Faust

University of Southampton - NIHR Southampton Clinical Research Facility and Biomedical Research Centre

Adam Finn

University Hospitals Bristol and Weston NHS Foundation Trust; University of Bristol - Cellular and Molecular Medicine

Teresa Lambe

University of Oxford - The Jenner Institute

Rajeka Lazarus

Government of the United Kingdom - North Bristol NHS Trust

Vincenzo Libri

NIHR UCLH Clinical Research Facility

Mary E. Ramsay

Public Health England - Immunisation, Hepatitis, and Blood Safety Department

Robert C. Read

University of Southampton - University Hospital Southampton NHS Foundation Trust

David P. J. Turner

Nottingham University Hospitals NHS Trust

Paul J. Turner

Imperial College London - National Heart & Lung Institute

Jonathan S. Nguyen-Van-Tam

University of Nottingham - Division of Epidemiology and Public Health

Matthew D. Snape

University of Oxford - Oxford Vaccine Group

Com-COV Study Group

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Abstract

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation, however we have previously reported that heterologous schedules incorporating an adenoviral-vectored vaccine (ChAd, Vaxzevria, Astrazeneca) and an mRNA vaccine (BNT, Comirnaty, Pfizer) at a 4-week interval are more reactogenic than homologous schedules. Here we report the immunogenicity of these schedules. 

Methods: Com-COV (ISRCTN: 69254139, EudraCT: 2020-005085-33) is a participant-blind, non-inferiority trial evaluating vaccine reactogenicity and immunogenicity. Adults ≥ 50 years, including those with well-controlled comorbidities, were randomised across eight groups to receive ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals.

The primary endpoint is geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG levels (ELISA) at one-month post boost between heterologous and homologous schedules given the same prime vaccine. We tested non-inferiority of GMR using a margin of 0.63. The primary analysis was on a per-protocol population, who were seronegative at baseline. Safety analyses were performed amongst participants receiving at least one dose of study vaccines.

Findings: In February 2021, 830 participants were enrolled and randomised, including 463 with a 28-day prime-boost interval whose results are reported in this paper. Participant mean age was 57.8 years, 45.8% were female, and 25.3% from ethnic minorities.The geometric mean concentration (GMC) of day 28 post-boost SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12,906 ELU/ml) was non-inferior to that in ChAd/ChAd recipients (1,392 ELU/ml) with a geometric mean ratio (GMR) of 9.2 (one-sided 97.5% CI: 7.5, ∞). In participants primed with BNT, we failed to show non-inferiority of the heterologous schedule (BNT/ChAd, GMC 7,133 ELU/ml) against the homologous schedule (BNT/BNT, GMC 14,080 ELU/ml) with a GMR of 0.51 (one-sided 97.5% CI: 0.43, ∞). Geometric mean of T cell response at 28 days post boost in the ChAd/BNT group was 185 SFC/106 PBMCs (spot forming cells/106 peripheral blood mononuclear cells) compared to 50, 80 and 99 SFC/106 PBMCs for ChAd/ChAd, BNT/BNT, and BNT/ChAd, respectively. There were four serious adverse events across all groups, none of which were considered related to immunisation.

Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the GMCs of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. These data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.

Trial Registration: The trial is registered at www.isrctn.com as ISRCTN: 69254139.

Funding: Funded by the UK Vaccine Task Force (VTF) and National Institute for Health Research (NIHR)

Declaration of Interest: MDS acts on behalf of the University of Oxford as an Investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and Chair of the WHO European Technical Advisory Group of Experts (ETAGE) on Immunisation. He is an investigator and/or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer and Sanofi and of other vaccines from these and other manufacturers including GSK, VPI, Takeda and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. PTH acts on behalf of St. George’s University of London as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an Investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva vaccines, and receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and is an occasional consultant to Vaccitech unrelated to this work. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19

Ethical Approval: The trial was reviewed and approved by the South-Central Berkshire Research Ethics Committee (21/SC/0022), the University of Oxford, and the Medicines and Healthcare Products Regulatory Agency MHRA). An independent data safety monitoring board (DSMB) reviewed safety data, and local trial- site physicians provided oversight of all adverse events in real-time.

Suggested Citation

Liu, Xinxue and Shaw, Robert H. and Stuart, Arabella SV and Greenland, Melanie and Dinesh, Tanya and Provstgaard-Morys, Samuel and Clutterbuck, Elizabeth and Ramasamy, Maheshi N. and Aley, Parvinder K. and Farooq Mujadidi, Yama and Long, Fei and Plested, Emma and Robinson, Hannah and Singh, Nisha and Walker, Laura L. and White, Rachel and Andrews, Nick and Cameron, J. Claire and Collins, Andrea M. and Ferreira, Daniela M. and Hill, Helen C. and Green, Christopher A. and Hallis, Bassam and Heath, Paul T. and Faust, Saul N. and Finn, Adam and Lambe, Teresa and Lazarus, Rajeka and Libri, Vincenzo and Ramsay, Mary E. and Read, Robert C. and Turner, David P. J. and Turner, Paul J. and Nguyen-Van-Tam, Jonathan S. and Snape, Matthew D. and Group, Com-COV Study, Safety and Immunogenicity Report from the Com-COV Study – a Single-Blind Randomised Non-Inferiority Trial Comparing Heterologous And Homologous Prime-Boost Schedules with An Adenoviral Vectored and mRNA COVID-19 Vaccine. Available at SSRN: https://ssrn.com/abstract=3874014 or http://dx.doi.org/10.2139/ssrn.3874014

Xinxue Liu

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Robert H. Shaw

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Arabella SV Stuart

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Melanie Greenland

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Tanya Dinesh

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Samuel Provstgaard-Morys

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Elizabeth Clutterbuck

University of Oxford - Oxford Vaccine Group

Maheshi N. Ramasamy

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Parvinder K. Aley

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Yama Farooq Mujadidi

University of Oxford - Oxford Vaccine Group

Fei Long

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Emma Plested

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Hannah Robinson

University of Oxford - Oxford Vaccine Group

Nisha Singh

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Laura L. Walker

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Rachel White

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Nick Andrews

Public Health England Colindale ( email )

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

J. Claire Cameron

Government of the United Kingdom - Public Health Scotland ( email )

United States

Andrea M. Collins

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Liverpool
United Kingdom

Daniela M. Ferreira

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Liverpool
United Kingdom

Helen C. Hill

Liverpool School of Tropical Medicine - Department of Clinical Sciences

Liverpool
United Kingdom

Christopher A. Green

University Hospitals Birmingham NHS Foundation Trust

Mindelsohn Way
Edgbaston
Birmingham, B15 2TH
United Kingdom

Bassam Hallis

Public Health England - National Infection Service ( email )

United Kingdom

Paul T. Heath

University of London - St George's Vaccine Institute ( email )

Senate House
Malet Street
London, WC1E 7HU
United Kingdom

Saul N. Faust

University of Southampton - NIHR Southampton Clinical Research Facility and Biomedical Research Centre ( email )

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Adam Finn

University Hospitals Bristol and Weston NHS Foundation Trust

University of Bristol,
Senate House, Tyndall Avenue
Bristol, BS8 ITH
United Kingdom

University of Bristol - Cellular and Molecular Medicine ( email )

United Kingdom

Teresa Lambe

University of Oxford - The Jenner Institute ( email )

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

Rajeka Lazarus

Government of the United Kingdom - North Bristol NHS Trust ( email )

Bristol
United Kingdom

Vincenzo Libri

NIHR UCLH Clinical Research Facility

London
United Kingdom

Mary E. Ramsay

Public Health England - Immunisation, Hepatitis, and Blood Safety Department ( email )

United Kingdom

Robert C. Read

University of Southampton - University Hospital Southampton NHS Foundation Trust

University Rd.
Southampton SO17 1BJ, SO17 1LP
United Kingdom

David P. J. Turner

Nottingham University Hospitals NHS Trust ( email )

Nottingham
United Kingdom

Paul J. Turner

Imperial College London - National Heart & Lung Institute

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Jonathan S. Nguyen-Van-Tam

University of Nottingham - Division of Epidemiology and Public Health

University Park
Nottingham, NG8 1BB
United Kingdom

Matthew D. Snape (Contact Author)

University of Oxford - Oxford Vaccine Group

Mansfield Road
Oxford, OX1 4AU
United Kingdom

No contact information is available for Com-COV Study Group

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