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

Com-COV Study Group; 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; David P.J. Turner; Paul J. Turner; Laura L. Walker; Rachel White; Jonathan S. Nguyen-Van-Tam; Matthew D. Snape; Tommy Rampling; Natalie Baker; Kerry Godwin; Karen Buttigieg; Imam Shaik; Phill Brown; Lauren Allen; Stephanie Leung; Ross Fothergill; Chanice Knight; Paminder Lall

doi:10.1016/S0140-6736(21)01694-9

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

Com-COV Study Group, 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 HillTeresa 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, David P.J. Turner, Paul J. Turner, Laura L. Walker, Rachel White, Jonathan S. Nguyen-Van-Tam, Matthew D. Snape^*, Tommy Rampling, Natalie Baker, Kerry Godwin, Karen Buttigieg, Imam Shaik, Phill Brown, Lauren Allen, Stephanie Leung, Ross Fothergill, Chanice Knight, Paminder Lall

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

387 Citations (Scopus)

11 Downloads (Pure)

Abstract

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 ELI SA) at 28 days after boost, when comparing ChAd/BNTwith 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 (12906 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 infinity). 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 infinity). 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.

Original language	English
Pages (from-to)	856-869
Number of pages	14
Journal	The Lancet
Volume	398
Issue number	10303
Early online date	6 Aug 2021
DOIs	https://doi.org/10.1016/S0140-6736(21)01694-9
Publication status	Published - 4 Sept 2021

Bibliographical note

Funding Information: The study is funded by the UK Government through the National Institute for Health Research (NIHR) and the Vaccine Task Force. This research was supported by the NIHR Oxford Biomedical Research Centre and delivered through the NIHR-funded National Immunisation Schedule Evaluation Consortium. MDS and SNF are NIHR senior investigators. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The investigators express their gratitude for the contribution of all trial participants, and for the invaluable advice of the international data safety monitoring board. We additionally acknowledge the broader support from the various teams within the University of Oxford, including the Department of Paediatrics, Clinical Trials Research Governance, Research Contracts, and the Public Affairs Directorate.

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. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests.

Open Access: This is an Open Access article under the CC BY 4.0
license.

Publisher Copyright: Crown Copyright © 2021 Published by Elsevier Ltd.

Citation: Liu, Xinxue, et al. "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." The Lancet 398.10303 (2021): 856-869.

DOI: https://doi.org/10.1016/S0140-6736(21)01694-9

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Cite this

Com-COV Study Group, Liu, X., Shaw, R. H., Stuart, A. S. V., Greenland, M., Aley, P. K., Andrews, N. J., Cameron, J. C., Charlton, S., Clutterbuck, E. A., Collins, A. M., Dinesh, T., England, A., Faust, S. N., Ferreira, D. M., Finn, A., Green, C. A., Hallis, B., Heath, P. T., ... Lall, P. (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. The Lancet, 398(10303), 856-869. https://doi.org/10.1016/S0140-6736(21)01694-9

@article{3eeee93f6dc3467ca7ec526ef7ca38d7,

title = "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",

abstract = "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 ELI SA) at 28 days after boost, when comparing ChAd/BNTwith 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 (12906 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 infinity). 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 infinity). 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. ",

author = "{Com-COV Study Group} and Xinxue Liu and Shaw, {Robert H.} and Stuart, {Arabella S.V.} and Melanie Greenland and Aley, {Parvinder K.} and Andrews, {Nick J.} and Cameron, {J. Claire} and Sue Charlton and Clutterbuck, {Elizabeth A.} and Collins, {Andrea M.} and Tanya Dinesh and Anna England and Faust, {Saul N.} and Ferreira, {Daniela M.} and Adam Finn and Green, {Christopher A.} and Bassam Hallis and Heath, {Paul T.} and Helen Hill and Teresa Lambe and Rajeka Lazarus and Vincenzo Libri and Fei Long and Mujadidi, {Yama F.} and Plested, {Emma L.} and Samuel Provstgaard-Morys and Ramasamy, {Maheshi N.} and Mary Ramsay and Read, {Robert C.} and Hannah Robinson and Nisha Singh and Turner, {David P.J.} and Turner, {Paul J.} and Walker, {Laura L.} and Rachel White and Nguyen-Van-Tam, {Jonathan S.} and Snape, {Matthew D.} and Munro, {Alasdair P.S.} and Jazz Bartholomew and Laura Presland and Sarah Horswill and Sarah Warren and Sophie Varkonyi-Clifford and Tommy Rampling and Natalie Baker and Kerry Godwin and Karen Buttigieg and Imam Shaik and Phill Brown and Lauren Allen and Stephanie Leung and Ross Fothergill and Chanice Knight and Paminder Lall",

note = "Funding Information: The study is funded by the UK Government through the National Institute for Health Research (NIHR) and the Vaccine Task Force. This research was supported by the NIHR Oxford Biomedical Research Centre and delivered through the NIHR-funded National Immunisation Schedule Evaluation Consortium. MDS and SNF are NIHR senior investigators. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The investigators express their gratitude for the contribution of all trial participants, and for the invaluable advice of the international data safety monitoring board. We additionally acknowledge the broader support from the various teams within the University of Oxford, including the Department of Paediatrics, Clinical Trials Research Governance, Research Contracts, and the Public Affairs Directorate. 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. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests. Open Access: This is an Open Access article under the CC BY 4.0 license. Publisher Copyright: Crown Copyright {\textcopyright} 2021 Published by Elsevier Ltd. Citation: Liu, Xinxue, et al. {"}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.{"} The Lancet 398.10303 (2021): 856-869. DOI: https://doi.org/10.1016/S0140-6736(21)01694-9 ",

year = "2021",

month = sep,

day = "4",

doi = "10.1016/S0140-6736(21)01694-9",

language = "English",

volume = "398",

pages = "856--869",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier B.V.",

number = "10303",

}

Com-COV Study Group, Liu, X, Shaw, RH, Stuart, ASV, Greenland, M, Aley, PK, Andrews, NJ, Cameron, JC, Charlton, S, Clutterbuck, EA, Collins, AM, Dinesh, T, England, A, Faust, SN, Ferreira, DM, Finn, A, Green, CA, Hallis, B, Heath, PT, Hill, H, Lambe, T, Lazarus, R, Libri, V, Long, F, Mujadidi, YF, Plested, EL, Provstgaard-Morys, S, Ramasamy, MN, Ramsay, M, Read, RC, Robinson, H, Singh, N, Turner, DPJ, Turner, PJ, Walker, LL, White, R, Nguyen-Van-Tam, JS, Snape, MD, Rampling, T, Baker, N , Godwin, K , Buttigieg, K , Shaik, I , Brown, P , Allen, L , Leung, S, Fothergill, R, Knight, C & Lall, P 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', The Lancet, vol. 398, no. 10303, pp. 856-869. https://doi.org/10.1016/S0140-6736(21)01694-9

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. / Com-COV Study Group; Liu, Xinxue; Shaw, Robert H. et al.
In: The Lancet, Vol. 398, No. 10303, 04.09.2021, p. 856-869.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV)

T2 - a single-blind, randomised, non-inferiority trial

AU - Com-COV Study Group

AU - Liu, Xinxue

AU - Shaw, Robert H.

AU - Stuart, Arabella S.V.

AU - Greenland, Melanie

AU - Aley, Parvinder K.

AU - Andrews, Nick J.

AU - Cameron, J. Claire

AU - Charlton, Sue

AU - Clutterbuck, Elizabeth A.

AU - Collins, Andrea M.

AU - Dinesh, Tanya

AU - England, Anna

AU - Faust, Saul N.

AU - Ferreira, Daniela M.

AU - Finn, Adam

AU - Green, Christopher A.

AU - Hallis, Bassam

AU - Heath, Paul T.

AU - Hill, Helen

AU - Lambe, Teresa

AU - Lazarus, Rajeka

AU - Libri, Vincenzo

AU - Long, Fei

AU - Mujadidi, Yama F.

AU - Plested, Emma L.

AU - Provstgaard-Morys, Samuel

AU - Ramasamy, Maheshi N.

AU - Ramsay, Mary

AU - Read, Robert C.

AU - Robinson, Hannah

AU - Singh, Nisha

AU - Turner, David P.J.

AU - Turner, Paul J.

AU - Walker, Laura L.

AU - White, Rachel

AU - Nguyen-Van-Tam, Jonathan S.

AU - Snape, Matthew D.

AU - Munro, Alasdair P.S.

AU - Bartholomew, Jazz

AU - Presland, Laura

AU - Horswill, Sarah

AU - Warren, Sarah

AU - Varkonyi-Clifford, Sophie

AU - Rampling, Tommy

AU - Baker, Natalie

AU - Godwin, Kerry

AU - Buttigieg, Karen

AU - Shaik, Imam

AU - Brown, Phill

AU - Allen, Lauren

AU - Leung, Stephanie

AU - Fothergill, Ross

AU - Knight, Chanice

AU - Lall, Paminder

N1 - Funding Information: The study is funded by the UK Government through the National Institute for Health Research (NIHR) and the Vaccine Task Force. This research was supported by the NIHR Oxford Biomedical Research Centre and delivered through the NIHR-funded National Immunisation Schedule Evaluation Consortium. MDS and SNF are NIHR senior investigators. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The investigators express their gratitude for the contribution of all trial participants, and for the invaluable advice of the international data safety monitoring board. We additionally acknowledge the broader support from the various teams within the University of Oxford, including the Department of Paediatrics, Clinical Trials Research Governance, Research Contracts, and the Public Affairs Directorate. 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. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests. Open Access: This is an Open Access article under the CC BY 4.0 license. Publisher Copyright: Crown Copyright © 2021 Published by Elsevier Ltd. Citation: Liu, Xinxue, et al. "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." The Lancet 398.10303 (2021): 856-869. DOI: https://doi.org/10.1016/S0140-6736(21)01694-9

PY - 2021/9/4

Y1 - 2021/9/4

N2 - 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 ELI SA) at 28 days after boost, when comparing ChAd/BNTwith 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 (12906 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 infinity). 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 infinity). 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.

AB - 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 ELI SA) at 28 days after boost, when comparing ChAd/BNTwith 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 (12906 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 infinity). 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 infinity). 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.

UR - http://www.scopus.com/inward/record.url?scp=85114018548&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(21)01694-9

DO - 10.1016/S0140-6736(21)01694-9

M3 - Article

C2 - 34370971

AN - SCOPUS:85114018548

SN - 0140-6736

VL - 398

SP - 856

EP - 869

JO - The Lancet

JF - The Lancet

IS - 10303

ER -

Com-COV Study Group, Liu X, Shaw RH, Stuart ASV, Greenland M, Aley PK et al. 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. The Lancet. 2021 Sept 4;398(10303):856-869. Epub 2021 Aug 6. doi: 10.1016/S0140-6736(21)01694-9

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

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