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Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial

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

Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial Thumbnail


Authors

Arabella S V Stuart

Robert H Shaw

Xinxue Liu

Melanie Greenland

Parvinder K Aley

Nick J Andrews

J. C. Cameron

Sue Charlton

Elizabeth A Clutterbuck

Andrea M Collins

Tom Darton

Tanya Dinesh

Christopher J A Duncan

Anna England

Saul N Faust

Daniela M Ferreira

Adam Finn

Anna L Goodman

Christopher A Green

Bassam Hallis

Paul T Heath

Helen Hill

Bryn M Horsington

Teresa Lambe

Rajeka Lazarus

Vincenzo Libri

Patrick J Lillie

Yama F Mujadidi

Ruth Payne

Emma L Plested

Samuel Provstgaard-Morys

Maheshi N Ramasamy

Mary Ramsay

Robert C Read

Hannah Robinson

Gavin R Screaton

Nisha Singh

DAVID TURNER david.turner@nottingham.ac.uk
Clinical Associate Professor

Paul J Turner

Iason Vichos

Rachel White

Matthew D Snape



Abstract

Background: Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Methods: Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Findings: Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Interpretation: Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. Funding: UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

Journal Article Type Article
Acceptance Date Nov 19, 2021
Online Publication Date Dec 6, 2021
Publication Date Jan 1, 2022
Deposit Date Dec 23, 2021
Publicly Available Date Jan 20, 2022
Journal The Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Publisher Elsevier BV
Peer Reviewed Peer Reviewed
Volume 399
Issue 10319
Pages 36-49
DOI https://doi.org/10.1016/S0140-6736%2821%2902718-5
Keywords General Medicine
Public URL https://nottingham-repository.worktribe.com/output/7057628
Publisher URL https://www.sciencedirect.com/science/article/pii/S0140673621027185