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Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study – A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines

Shaw, Robert H; Greenland, Melanie; Stuart, Arabella S V; Aley, Parvinder K; Andrews, Nick J; Cameron, J. Claire; Charlton, Sue; Clutterbuck, Elizabeth A; Collins, Andrea M; Darton, Tom; Dinesh, Tanya; Duncan, Christopher J A; Faust, Saul N; Ferreira, Daniela M; Finn, Adam; Goodman, Anna L; Green, Christopher A; Hallis, Bassam; Heath, Paul T; Hill, Helen; Lambe, Teresa; Libri, Vincenzo; Lillie, Patrick J; Morey, Ella; Mujadidi, Yama F; Payne, Ruth; Plested, Emma L; Provstgaard-Morys, Samuel; Ramasamy, Maheshi N; Mary Ramsay, Ffph; Read, Robert C; Hannah Robinson, R N; Screaton, Gavin R; Singh, Nisha; Turner, David P.J.; Turner, Paul J; White, Rachel; Nguyen-Van-Tam, Jonathan S.; Liu, Xinxue; Snape, Matthew D

Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study – A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines Thumbnail


Robert H Shaw

Melanie Greenland

Arabella S V Stuart

Parvinder K Aley

Nick J Andrews

J. Claire Cameron

Sue Charlton

Elizabeth A Clutterbuck

Andrea M Collins

Tom Darton

Tanya Dinesh

Christopher J A Duncan

Saul N Faust

Daniela M Ferreira

Adam Finn

Anna L Goodman

Christopher A Green

Bassam Hallis

Paul T Heath

Helen Hill

Teresa Lambe

Vincenzo Libri

Patrick J Lillie

Ella Morey

Yama F Mujadidi

Ruth Payne

Emma L Plested

Samuel Provstgaard-Morys

Maheshi N Ramasamy

Ffph Mary Ramsay

Robert C Read

R N Hannah Robinson

Gavin R Screaton

Nisha Singh

Clinical Associate Professor

Paul J Turner

Rachel White

Xinxue Liu

Matthew D Snape


Background: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development. Methods: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose ‘ChAd’ (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or ‘BNT’ (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8–12 weeks later with either the homologous vaccine, or ‘Mod’ (mRNA-1273, Spikevax, Moderna) or ‘NVX’ (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration. Findings: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies. Interpretation: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics. ISRCTN:27841311 EudraCT:2021-001275-16.

Journal Article Type Article
Acceptance Date Mar 31, 2023
Online Publication Date Apr 6, 2023
Publication Date 2023-06
Deposit Date Apr 19, 2023
Publicly Available Date Apr 19, 2023
Journal Journal of infection
Print ISSN 0163-4453
Electronic ISSN 1532-2742
Peer Reviewed Peer Reviewed
Volume 86
Issue 6
Pages 574-583
Keywords Protein, Antibody, Vaccine, Adenovirus vector, Vaccination, Persistence, T cell, Adjuvant, Cellular, Humoral, Subgroup, Heterologous, T-cell, immunology, homologous, Tcell, Sars-cov2, Covid, Mrna Lipid Nanoparticle
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Related Public URLs
PMID 37028454


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