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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

Liu, Xinxue; Shaw, Robert H; Stuart, Arabella S V; Greenland, Melanie; Aley, Parvinder K; Andrews, Nick J; Cameron, J. Claire; Charlton, Sue; Clutterbuck, Elizabeth A; Collins, Andrea M; Dinesh, Tanya; England, Anna; Faust, Saul N; Ferreira, Daniela M; Finn, Adam; Green, Christopher A; Hallis, Bassam; Heath, Paul T; Hill, Helen; Lambe, Teresa; Lazarus, Rajeka; Libri, Vincenzo; Long, Fei; Mujadidi, Yama F; Plested, Emma L; Provstgaard-Morys, Samuel; Ramasamy, Maheshi N; Ramsay, Mary; Read, Robert C; Robinson, Hannah; Singh, Nisha; Turner, David P.J.; Turner, Paul J; Walker, Laura L; White, Rachel; Nguyen-Van-Tam, Jonathan S.; Snape, Matthew D; Munro, Alasdair P S; Bartholomew, Jazz; Presland, Laura; Horswill, Sarah; Warren, Sarah; Varkonyi-Clifford, Sophie; Saich, Stephen; Adams, Kirsty; Ricamara, Marivic; Turner, Nicola; Yee Ting, Nicole Y; Whittley, Sarah; Rampling, Tommy; Desai, Amisha; Brown, Claire H; Qureshi, Ehsaan; Gokani, Karishma; Naker, Kush; Kellett Wright, Johanna K; Willia...


Xinxue Liu

Robert H Shaw

Arabella S V Stuart

Melanie Greenland

Parvinder K Aley

Nick J Andrews

J. Claire Cameron

Sue Charlton

Elizabeth A Clutterbuck

Andrea M Collins

Tanya Dinesh

Anna England

Saul N Faust

Daniela M Ferreira

Adam Finn

Christopher A Green

Bassam Hallis

Paul T Heath

Helen Hill

Teresa Lambe

Rajeka Lazarus

Vincenzo Libri

Fei Long

Yama F Mujadidi

Emma L Plested

Samuel Provstgaard-Morys

Maheshi N Ramasamy

Mary Ramsay

Robert C Read

Hannah Robinson

Nisha Singh

Clinical Associate Professor

Paul J Turner

Laura L Walker

Rachel White

Matthew D Snape

Alasdair P S Munro

Jazz Bartholomew

Laura Presland

Sarah Horswill

Sarah Warren

Sophie Varkonyi-Clifford

Stephen Saich

Kirsty Adams

Marivic Ricamara

Nicola Turner

Nicole Y Yee Ting

Sarah Whittley

Tommy Rampling

Amisha Desai

Claire H Brown

Ehsaan Qureshi

Karishma Gokani

Kush Naker

Johanna K Kellett Wright

Rachel L Williams

Tawassal Riaz

Florentina D Penciu

Claudio Di Maso

Elizabeth G Howe

Iason Vichos

Mujtaba Ghulam Farooq

Rabiullah Noristani

Xin L Yao

Daniel Hammersley

Sue Belton

Simon Royal

Alberto San Francisco Ramos

Cecilia Hultin

Eva P Galiza

Farah Shiham


Hannah Sainsbury

Kelly Davies

Pauline Ambrose

Lisa Hitchins

Natalie Baker

Stephanie Leung

Ross Fothergill

Kerry Godwin

Karen Buttigieg

Imam Shaik

Phill Brown

Chanice Knight

Paminder Lall

Lauren Allen


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.


Liu, X., Shaw, R. H., Stuart, A. S. V., Greenland, M., Aley, P. K., Andrews, N. J., …Allen, L. (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. Lancet, 398(10303), 856-869.

Journal Article Type Article
Acceptance Date Aug 6, 2021
Online Publication Date Aug 6, 2021
Publication Date Sep 4, 2021
Deposit Date Aug 10, 2021
Publicly Available Date Aug 12, 2021
Journal The Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 398
Issue 10303
Pages 856-869
Public URL
Publisher URL