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Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

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 (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Funding: UK Vaccine Task Force and National Institute for Health Research.

Aged, Antibodies, Viral/blood, BNT162 Vaccine, COVID-19 Vaccines/administration & dosage, COVID-19/prevention & control, ChAdOx1 nCoV-19, Equivalence Trials as Topic, Female, Humans, Immunization Schedule, Immunogenicity, Vaccine, Immunoglobulin G/blood, Intention to Treat Analysis, Male, Middle Aged, Single-Blind Method, Spike Glycoprotein, Coronavirus/immunology
0140-6736
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Liu, Xinxue
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Shaw, Robert H.
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Long, Fei
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Mujadidi, Yama F.
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Plested, Emma L.
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et al.
Com-COV Study Group
Liu, Xinxue
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Shaw, Robert H.
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Stuart, Arabella S.V.
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Greenland, Melanie
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Aley, Parvinder K.
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Andrews, Nick J.
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Cameron, J. Claire
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Charlton, Sue
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Clutterbuck, Elizabeth A.
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Collins, Andrea M.
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Dinesh, Tanya
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England, Anna
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Faust, Saul N.
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Ferreira, Daniela M.
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Finn, Adam
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Green, Christopher A.
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Hallis, Bassam
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Heath, Paul T.
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Ramsay, Mary
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Read, Robert C.
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Presland, Laura
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Horswill, Sarah
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Warren, Sarah
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Varkonyi-Clifford, Sophie
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Adams, Kirsty
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Ricamara, Marivic
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Turner, Nicola
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Yee Ting, Nicole Y.
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Whittley, Sarah
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Sainsbury, Hannah
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Liu, Xinxue, Shaw, Robert H., Stuart, Arabella S.V., Greenland, Melanie, Aley, Parvinder K., Andrews, Nick J., Nguyen-Van-Tam, Jonathan S. and Snape, Matthew D. , et al. and Com-COV Study Group (2021) Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial. The Lancet, 398 (10303), 856-869. (doi:10.1016/S0140-6736(21)01694-9).

Record type: Article

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 (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Funding: UK Vaccine Task Force and National Institute for Health Research.

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More information

e-pub ahead of print date: 6 August 2021
Published date: 4 September 2021
Keywords: Aged, Antibodies, Viral/blood, BNT162 Vaccine, COVID-19 Vaccines/administration & dosage, COVID-19/prevention & control, ChAdOx1 nCoV-19, Equivalence Trials as Topic, Female, Humans, Immunization Schedule, Immunogenicity, Vaccine, Immunoglobulin G/blood, Intention to Treat Analysis, Male, Middle Aged, Single-Blind Method, Spike Glycoprotein, Coronavirus/immunology

Identifiers

Local EPrints ID: 453649
URI: http://eprints.soton.ac.uk/id/eprint/453649
ISSN: 0140-6736
PURE UUID: ac2b3c66-6c13-4e0c-ac8f-e474faa36e64
ORCID for Saul N. Faust: ORCID iD orcid.org/0000-0003-3410-7642
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

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Date deposited: 20 Jan 2022 17:43
Last modified: 18 Mar 2024 03:21

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Contributors

Author: Xinxue Liu
Author: Robert H. Shaw
Author: Arabella S.V. Stuart
Author: Melanie Greenland
Author: Parvinder K. Aley
Author: Nick J. Andrews
Author: J. Claire Cameron
Author: Sue Charlton
Author: Elizabeth A. Clutterbuck
Author: Andrea M. Collins
Author: Tanya Dinesh
Author: Anna England
Author: Saul N. Faust ORCID iD
Author: Daniela M. Ferreira
Author: Adam Finn
Author: Christopher A. Green
Author: Bassam Hallis
Author: Paul T. Heath
Author: Helen Hill
Author: Teresa Lambe
Author: Rajeka Lazarus
Author: Vincenzo Libri
Author: Fei Long
Author: Yama F. Mujadidi
Author: Emma L. Plested
Author: Samuel Provstgaard-Morys
Author: Maheshi N. Ramasamy
Author: Mary Ramsay
Author: Robert C. Read ORCID iD
Author: Hannah Robinson
Author: Nisha Singh
Author: David P.J. Turner
Author: Paul J. Turner
Author: Laura L. Walker
Author: Rachel White
Author: Jonathan S. Nguyen-Van-Tam
Author: Matthew D. Snape
Author: Alasdair P.S. Munro
Author: Jazz Bartholomew
Author: Laura Presland
Author: Sarah Horswill
Author: Sarah Warren
Author: Sophie Varkonyi-Clifford
Author: Stephen Saich
Author: Kirsty Adams
Author: Marivic Ricamara
Author: Nicola Turner
Author: Nicole Y. Yee Ting
Author: Sarah Whittley
Author: Hannah Sainsbury
Corporate Author: et al.
Corporate Author: Com-COV Study Group

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