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Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

Shaw, Robert H; Liu, Xinxue; Stuart, Arabella S V; Greenland, Melanie; Aley, Parvinder K; Andrews, Nick J; Cameron, J. Claire; Charlton, Sue; Clutterbuck, Elizabeth A; Collins, Andrea M; Dejnirattisai, Wanwisa; Dinesh, Tanya; 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; Morey, Ella R; 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; 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; Gok...

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial Thumbnail


Robert H Shaw

Xinxue Liu

Arabella S V Stuart

Melanie Greenland

Parvinder K Aley

Nick J Andrews

J. Claire Cameron

Sue Charlton

Elizabeth A Clutterbuck

Andrea M Collins

Wanwisa Dejnirattisai

Tanya Dinesh

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

Ella R Morey

Samuel Provstgaard-Morys

Maheshi N Ramasamy

Mary Ramsay

Robert C Read

Hannah Robinson

Gavin R Screaton

Nisha Singh

Clinical Associate Professor

Paul J Turner

Iason Vichos

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

Amy Carson

Claudio Di Maso

Gracie Mead

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

Rebecca Crook

Marcin Bula

Fred Fyles

Hassan Burhan

Flora Maelin

Elen Hughes

Emmanuel Okenyi


Background: Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods: Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings: Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation: These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding: UK Vaccine Taskforce and National Institute for Health and Care Research.


Shaw, R. H., Liu, X., Stuart, A. S. V., Greenland, M., Aley, P. K., Andrews, N. J., …Okenyi, E. (2022). Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial. Lancet Respiratory Medicine, 10(11), 1049-1060.

Journal Article Type Article
Acceptance Date May 15, 2022
Online Publication Date Jun 9, 2022
Publication Date Nov 1, 2022
Deposit Date Aug 4, 2022
Publicly Available Date Aug 4, 2022
Journal The Lancet Respiratory Medicine
Print ISSN 2213-2600
Electronic ISSN 2213-2619
Publisher Elsevier BV
Peer Reviewed Peer Reviewed
Volume 10
Issue 11
Pages 1049-1060
Keywords Pulmonary and Respiratory Medicine
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