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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.
Lancet. 2022 01 01; 399(10319):36-49.Lct

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.

Authors+Show Affiliations

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Statistics, Modelling and Economics Department, UK Health Security Agency, London, UK; Immunisation and Countermeasures Division, National Infection Service, UK Health Security Agency, London, UK.Public Health Scotland, Glasgow, Scotland, UK.UK Health Security Agency, Porton Down, Salisbury, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Liverpool School of Tropical Medicine, Liverpool, UK.Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.UK Health Security Agency, Porton Down, Salisbury, UK.NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.Liverpool School of Tropical Medicine, Liverpool, UK.School of Population Health Sciences, and School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.Department of Infection, and NIHR BRC, Guy's and St Thomas' NHS Foundation Trust, London, UK; MRC Clinical Trials Unit, University College London, London, UK.NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.UK Health Security Agency, Porton Down, Salisbury, UK.The Vaccine Institute, St George's University of London, London, UK.Liverpool School of Tropical Medicine, Liverpool, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical, Science Oxford Institute, University of Oxford, Oxford, UK.North Bristol NHS Trust, Bristol, UK.NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.Infection Research Group, Hull University Teaching Hospitals NHS Trust, Hull, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.Immunisation and Countermeasures Division, National Infection Service, UK Health Security Agency, London, UK.NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Chinese Academy of Medical, Science Oxford Institute, University of Oxford, Oxford, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.University of Nottingham, Nottingham, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK.National Heart and Lung Institute, Imperial College London, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Division of Epidemiology and Public Health, University of Nottingham School of Medicine, Nottingham, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford NIHR-Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address: matthew.snape@paediatrics.ox.ac.uk.No affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Equivalence Trial
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

34883053

Citation

Stuart, Arabella S V., et al. "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." Lancet (London, England), vol. 399, no. 10319, 2022, pp. 36-49.
Stuart ASV, Shaw RH, Liu X, et al. 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. Lancet. 2022;399(10319):36-49.
Stuart, A. S. V., Shaw, R. H., Liu, X., Greenland, M., Aley, P. K., Andrews, N. J., Cameron, J. C., Charlton, S., Clutterbuck, E. A., Collins, A. M., Darton, T., Dinesh, T., Duncan, C. J. A., England, A., Faust, S. N., Ferreira, D. M., Finn, A., Goodman, A. L., Green, C. A., ... Snape, M. D. (2022). 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. Lancet (London, England), 399(10319), 36-49. https://doi.org/10.1016/S0140-6736(21)02718-5
Stuart ASV, et al. 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. Lancet. 2022 01 1;399(10319):36-49. PubMed PMID: 34883053.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Stuart,Arabella S V, AU - Shaw,Robert H, AU - Liu,Xinxue, AU - Greenland,Melanie, AU - Aley,Parvinder K, AU - Andrews,Nick J, AU - Cameron,J C, AU - Charlton,Sue, AU - Clutterbuck,Elizabeth A, AU - Collins,Andrea M, AU - Darton,Tom, AU - Dinesh,Tanya, AU - Duncan,Christopher J A, AU - England,Anna, AU - Faust,Saul N, AU - Ferreira,Daniela M, AU - Finn,Adam, AU - Goodman,Anna L, AU - Green,Christopher A, AU - Hallis,Bassam, AU - Heath,Paul T, AU - Hill,Helen, AU - Horsington,Bryn M, AU - Lambe,Teresa, AU - Lazarus,Rajeka, AU - Libri,Vincenzo, AU - Lillie,Patrick J, AU - Mujadidi,Yama F, AU - Payne,Ruth, AU - Plested,Emma L, AU - Provstgaard-Morys,Samuel, AU - Ramasamy,Maheshi N, AU - Ramsay,Mary, AU - Read,Robert C, AU - Robinson,Hannah, AU - Screaton,Gavin R, AU - Singh,Nisha, AU - Turner,David P J, AU - Turner,Paul J, AU - Vichos,Iason, AU - White,Rachel, AU - Nguyen-Van-Tam,Jonathan S, AU - Snape,Matthew D, AU - ,, Y1 - 2021/12/06/ PY - 2021/10/27/received PY - 2021/11/15/revised PY - 2021/11/19/accepted PY - 2021/12/10/pubmed PY - 2022/1/27/medline PY - 2021/12/9/entrez SP - 36 EP - 49 JF - Lancet (London, England) JO - Lancet VL - 399 IS - 10319 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/34883053/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_ DB - PRIME DP - Unbound Medicine ER -