Clinical Trial

. 2022 Jan 1;399(10319):36-49.

doi: 10.1016/S0140-6736(21)02718-5. Epub 2021 Dec 6.

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

Arabella S V Stuart¹, Robert H Shaw¹, Xinxue Liu², Melanie Greenland², Parvinder K Aley², Nick J Andrews³, J C Cameron⁴, Sue Charlton⁵, Elizabeth A Clutterbuck², Andrea M Collins⁶, Tom Darton⁷, Tanya Dinesh², Christopher J A Duncan⁸, Anna England⁵, Saul N Faust⁹, Daniela M Ferreira⁶, Adam Finn¹⁰, Anna L Goodman¹¹, Christopher A Green¹², Bassam Hallis⁵, Paul T Heath¹³, Helen Hill⁶, Bryn M Horsington², Teresa Lambe¹⁴, Rajeka Lazarus¹⁵, Vincenzo Libri¹⁶, Patrick J Lillie¹⁷, Yama F Mujadidi², Ruth Payne⁷, Emma L Plested², Samuel Provstgaard-Morys², Maheshi N Ramasamy¹, Mary Ramsay¹⁸, Robert C Read⁹, Hannah Robinson², Gavin R Screaton¹⁹, Nisha Singh², David P J Turner²⁰, Paul J Turner²¹, Iason Vichos², Rachel White², Jonathan S Nguyen-Van-Tam²², Matthew D Snape²³; Com-COV2 Study Group

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
² Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
³ Statistics, Modelling and Economics Department, UK Health Security Agency, London, UK; Immunisation and Countermeasures Division, National Infection Service, UK Health Security Agency, London, UK.
⁴ Public Health Scotland, Glasgow, Scotland, UK.
⁵ UK Health Security Agency, Porton Down, Salisbury, UK.
⁶ Liverpool School of Tropical Medicine, Liverpool, UK.
⁷ 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.
⁸ The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
⁹ 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.
¹⁰ School of Population Health Sciences, and School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
¹¹ 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.
¹² NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
¹³ The Vaccine Institute, St George's University of London, London, UK.
¹⁴ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical, Science Oxford Institute, University of Oxford, Oxford, UK.
¹⁵ North Bristol NHS Trust, Bristol, UK.
¹⁶ NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁷ Infection Research Group, Hull University Teaching Hospitals NHS Trust, Hull, UK.
¹⁸ Immunisation and Countermeasures Division, National Infection Service, UK Health Security Agency, London, UK.
¹⁹ 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.
²⁰ University of Nottingham, Nottingham, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK.
²¹ National Heart and Lung Institute, Imperial College London, London, UK.
²² Division of Epidemiology and Public Health, University of Nottingham School of Medicine, Nottingham, UK.
²³ 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.

PMID: 34883053
PMCID: PMC8648333
DOI: 10.1016/S0140-6736(21)02718-5

Clinical Trial

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

Arabella S V Stuart et al. Lancet. 2022.

. 2022 Jan 1;399(10319):36-49.

doi: 10.1016/S0140-6736(21)02718-5. Epub 2021 Dec 6.

Authors

Affiliations

¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
² Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
³ Statistics, Modelling and Economics Department, UK Health Security Agency, London, UK; Immunisation and Countermeasures Division, National Infection Service, UK Health Security Agency, London, UK.
⁴ Public Health Scotland, Glasgow, Scotland, UK.
⁵ UK Health Security Agency, Porton Down, Salisbury, UK.
⁶ Liverpool School of Tropical Medicine, Liverpool, UK.
⁷ 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.
⁸ The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.
⁹ 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.
¹⁰ School of Population Health Sciences, and School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
¹¹ 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.
¹² NIHR/Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
¹³ The Vaccine Institute, St George's University of London, London, UK.
¹⁴ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical, Science Oxford Institute, University of Oxford, Oxford, UK.
¹⁵ North Bristol NHS Trust, Bristol, UK.
¹⁶ NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁷ Infection Research Group, Hull University Teaching Hospitals NHS Trust, Hull, UK.
¹⁸ Immunisation and Countermeasures Division, National Infection Service, UK Health Security Agency, London, UK.
¹⁹ 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.
²⁰ University of Nottingham, Nottingham, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK.
²¹ National Heart and Lung Institute, Imperial College London, London, UK.
²² Division of Epidemiology and Public Health, University of Nottingham School of Medicine, Nottingham, UK.
²³ 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.

PMID: 34883053
PMCID: PMC8648333
DOI: 10.1016/S0140-6736(21)02718-5

Erratum in

Department of Error.
[No authors listed] [No authors listed] Lancet. 2022 Feb 26;399(10327):802. doi: 10.1016/S0140-6736(22)00321-X. Lancet. 2022. PMID: 35219392 Free PMC article. No abstract available.

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.

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Conflict of interest statement

Declaration of interests MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and chair of the WHO European Technical Advisory Group of Experts on Immunisation. He is an investigator or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer, and Sanofi, and of other vaccines from these and other manufacturers, including GlaxoSmithKline, VPI Pharmaceuticals, Takeda, and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator or provides consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva. He receives no personal financial payment for this work. PTH acts on behalf of St George's University of London as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva. He receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca, and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering the ChAd vaccine and is an occasional consultant to Vaccitech, unrelated to this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG benefits from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University's revenue sharing policy. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests.

Figures

**Figure 1**
Trial profile BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVX-CoV2373 vaccine, Novavax.

**Figure 2**
Correlation in the modified intention-to-treat population (A) SARS-CoV-2 anti-spike IgG and cellular response by IFN-γ ELISpot (the subset with cellular data only, n=582), (B) SARS-CoV-2 anti-spike IgG and live virus neutralising antibodies (the subset with live virus neutralising antibodies data only, n=289), (C) live virus neutralising antibodies and cellular response by IFN-γ ELISpot at 28 days after boost (the subset with live virus neutralising antibodies data only, n=289), (D) live virus neutralising antibodies tested at University of Oxford and those tested at Porton Down, UK Health Security Agency (the immunology cohort, n=123). Ellipses show the 95% CI for different vaccine schedules assuming multivariate normal distributions. Pearson correlation coefficients (95% CI) are presented for each vaccine schedule. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT₅₀=50% focus reduction neutralising antibody titre. m1273=mRNA-1273 vaccine, Moderna. NT₈₀=80% neutralising antibody titre. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot forming cells.

**Figure 3**
Kinetics of immunogenicity by vaccine schedule Cellular response data were available in around 60% of sites, the other study sites did not collect plasma samples due to logistical challenges; data presented at day 7 and day 14 were from the immunology cohort only. Data presented from day 0 and day 28 are for all participants in the modified intention-to-treat-population. Boxplots represent the median and 25th and 75th percentiles; the whiskers extend up to the largest value, not greater than 1·5 times the IQR beyond the box. (A) Anti-spike IgG and (B) T-cell response. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. m1273=mRNA−1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot-forming cells.

**Figure 4**
Severity of solicited local and systemic reactions in days 0–7 following boost vaccination by study arm as self-reported in participant electronic diaries Data are (A) local at vaccination site and (B) systemic. The severity presented is the participant's highest severity across 7 days after vaccination for each solicited adverse event. Fever was defined as mild if 38·0°C to <38·5°C, moderate if 38·5°C to <39°C, and severe if ≥39·0°C. Feverish was self-reported feeling of feverishness. For systemic symptoms, grading was classified as mild if easily tolerated with no limitation on normal activity; moderate if some limitation of daily activity; severe if unable to perform normal daily activity. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax.

See this image and copyright information in PMC

Comment in

Mixing mRNA, adenoviral, and spike-adjuvant vaccines for protection against COVID-19.
Richardson CD. Richardson CD. Lancet. 2022 Jan 1;399(10319):3-5. doi: 10.1016/S0140-6736(21)02757-4. Epub 2021 Dec 6. Lancet. 2022. PMID: 34883051 Free PMC article. No abstract available.
Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum.
Dejnirattisai W, Shaw RH, Supasa P, Liu C, Stuart AS, Pollard AJ, Liu X, Lambe T, Crook D, Stuart DI, Mongkolsapaya J, Nguyen-Van-Tam JS, Snape MD, Screaton GR; Com-COV2 study group. Dejnirattisai W, et al. Lancet. 2022 Jan 15;399(10321):234-236. doi: 10.1016/S0140-6736(21)02844-0. Epub 2021 Dec 20. Lancet. 2022. PMID: 34942101 Free PMC article. No abstract available.

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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

Affiliations

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

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