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Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial.
Lancet. 2021 12 18; 398(10318):2258-2276.Lct

Abstract

BACKGROUND

Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT).

METHODS

COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130.

FINDINGS

Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.

INTERPRETATION

All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination.

FUNDING

UK Vaccine Taskforce and National Institute for Health Research.

Authors+Show Affiliations

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.Imperial Clinical Trials Unit, Imperial College London, London, UK.Imperial Clinical Trials Unit, Imperial College London, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.Stockport NHS Foundation Trust, Stockport, UK.NIHR Liverpool and Broadgreen Clinical Research Facility, Liverpool, 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.NIHR Cambridge Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.NIHR Liverpool and Broadgreen Clinical Research Facility, Liverpool, UK.PHARMExcel, Welwyn Garden City, Hertfordshire, UK.NIHR/Wellcome Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK; MRC Clinical Trials Unit, University College London, London, UK.NIHR/Wellcome Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.Portsmouth Hospitals University NHS Trust, Portsmouth, UK.Queen Elizabeth University Hospital, NHS Greater Glasgow & Clyde, Glasgow, UK.Portsmouth Hospitals University NHS Trust, Portsmouth, UK.Wellcome-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.Cancer Research UK Oxford Centre, University of Oxford, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.University Hospitals Sussex NHS Foundation Trust, Brighton, UK.Department of Infectious Diseases and Tropical Medicine, London Northwest University Healthcare, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.The Adam Practice, Poole, UK.Stockport NHS Foundation Trust, Stockport, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.NIHR Leeds Clinical Research Facility, Leeds Teaching Hospitals Trust and University of Leeds, Leeds, UK.North Wales Clinical Research Facility, Betsi Cadwaladr University Health Board and Bangor University, Bangor, UK.Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, 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.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.University Hospitals of Leicester NHS Trust, University of Leicester, Leicester, UK.University Hospitals of Leicester NHS Trust, University of Leicester, Leicester, UK.NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.Bradford Institute for Health Research and Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK.Bradford Institute for Health Research and Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.University Hospitals Sussex NHS Foundation Trust, Brighton, UK.Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK.Department of Infectious Diseases and Tropical Medicine, London Northwest University Healthcare, London, UK.Queen Elizabeth University Hospital, NHS Greater Glasgow & Clyde, Glasgow, UK; MRC University of Glasgow Centre for Virus Research, Glasgow, UK.Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK.NIHR Leeds Clinical Research Facility, Leeds Teaching Hospitals Trust and University of Leeds, Leeds, 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.UK Health Security Agency, Porton Down, UK.UK Health Security Agency, Porton Down, UK.UK Health Security Agency, Colindale, London, UK.UK Health Security Agency, Colindale, London, 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; NIHR Oxford Biomedical Research Centre, Oxford, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, 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. Electronic address: s.faust@soton.ac.uk.No affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34863358

Citation

Munro, Alasdair P S., et al. "Safety and Immunogenicity of Seven COVID-19 Vaccines as a Third Dose (booster) Following Two Doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a Blinded, Multicentre, Randomised, Controlled, Phase 2 Trial." Lancet (London, England), vol. 398, no. 10318, 2021, pp. 2258-2276.
Munro APS, Janani L, Cornelius V, et al. Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet. 2021;398(10318):2258-2276.
Munro, A. P. S., Janani, L., Cornelius, V., Aley, P. K., Babbage, G., Baxter, D., Bula, M., Cathie, K., Chatterjee, K., Dodd, K., Enever, Y., Gokani, K., Goodman, A. L., Green, C. A., Harndahl, L., Haughney, J., Hicks, A., van der Klaauw, A. A., Kwok, J., ... Faust, S. N. (2021). Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet (London, England), 398(10318), 2258-2276. https://doi.org/10.1016/S0140-6736(21)02717-3
Munro APS, et al. Safety and Immunogenicity of Seven COVID-19 Vaccines as a Third Dose (booster) Following Two Doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a Blinded, Multicentre, Randomised, Controlled, Phase 2 Trial. Lancet. 2021 12 18;398(10318):2258-2276. PubMed PMID: 34863358.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. AU - Munro,Alasdair P S, AU - Janani,Leila, AU - Cornelius,Victoria, AU - Aley,Parvinder K, AU - Babbage,Gavin, AU - Baxter,David, AU - Bula,Marcin, AU - Cathie,Katrina, AU - Chatterjee,Krishna, AU - Dodd,Kate, AU - Enever,Yvanne, AU - Gokani,Karishma, AU - Goodman,Anna L, AU - Green,Christopher A, AU - Harndahl,Linda, AU - Haughney,John, AU - Hicks,Alexander, AU - van der Klaauw,Agatha A, AU - Kwok,Jonathan, AU - Lambe,Teresa, AU - Libri,Vincenzo, AU - Llewelyn,Martin J, AU - McGregor,Alastair C, AU - Minassian,Angela M, AU - Moore,Patrick, AU - Mughal,Mehmood, AU - Mujadidi,Yama F, AU - Murira,Jennifer, AU - Osanlou,Orod, AU - Osanlou,Rostam, AU - Owens,Daniel R, AU - Pacurar,Mihaela, AU - Palfreeman,Adrian, AU - Pan,Daniel, AU - Rampling,Tommy, AU - Regan,Karen, AU - Saich,Stephen, AU - Salkeld,Jo, AU - Saralaya,Dinesh, AU - Sharma,Sunil, AU - Sheridan,Ray, AU - Sturdy,Ann, AU - Thomson,Emma C, AU - Todd,Shirley, AU - Twelves,Chris, AU - Read,Robert C, AU - Charlton,Sue, AU - Hallis,Bassam, AU - Ramsay,Mary, AU - Andrews,Nick, AU - Nguyen-Van-Tam,Jonathan S, AU - Snape,Matthew D, AU - Liu,Xinxue, AU - Faust,Saul N, AU - ,, Y1 - 2021/12/02/ PY - 2021/11/04/received PY - 2021/11/17/revised PY - 2021/11/19/accepted PY - 2021/12/6/pubmed PY - 2022/1/4/medline PY - 2021/12/5/entrez SP - 2258 EP - 2276 JF - Lancet (London, England) JO - Lancet VL - 398 IS - 10318 N2 - BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. INTERPRETATION: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. FUNDING: UK Vaccine Taskforce and National Institute for Health Research. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/34863358/Safety_and_immunogenicity_of_seven_COVID_19_vaccines_as_a_third_dose__booster__following_two_doses_of_ChAdOx1_nCov_19_or_BNT162b2_in_the_UK__COV_BOOST_:_a_blinded_multicentre_randomised_controlled_phase_2_trial_ DB - PRIME DP - Unbound Medicine ER -