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

COV-BOOST study group

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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.

Original languageEnglish
Pages (from-to)2258-2276
Number of pages19
JournalThe Lancet
Volume398
Issue number10318
DOIs
Publication statusPublished - 18 Dec 2021

Bibliographical note

Funding Information:
KCa acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi, and Valneva. She receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton National Health Service (NHS) Foundation Trust as an investigator or providing consultative advice, or both, 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. 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 might benefit 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. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, Ciple, and Teva. 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. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Novavax, Medicago, and Sanofi. He received no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. MR has provided post marketing surveillance reports on vaccines for Pfizer and GlaxoSmithKline for which a cost recover charge is made. 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 vaccines. He received no personal financial payment for this work. All other authors declare no competing interests.

Funding Information:
The study is funded by the UK Government through the National Institute for Health Research (NIHR) and the Vaccine Taskforce. The study sponsor is University Hospital Southampton NHS Foundation Trust, Southampton, UK. ChAd, BNT, and m1273 used in this study were supplied by the UK Health Security Agency (previously Public Health England). NVX, VLA, Ad26, and CVn were supplied by the manufacturers, without charge. The research is supported by the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, the NIHR Clinical Research Network, and the NIHR funded National Immunisation Schedule Evaluation Consortium. SNF and MDS are NIHR Senior Investigators. KC is a Wellcome Trust Investigator (210755/Z/18/Z) and NIHR Senior Investigator Emeritus. 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 would like to thank the UK Medicines and Healthcare products Regulatory Agency (MHRA) and Heath Research Authority (HRA) for their extraordinary efforts in rapidly reviewing submissions, for their attention to detail and input into trial design. Specific thanks go to Kirsty Wydenbach, Lisa Campbell, David Jones, Graham McNaughton, Marie-Christine Bielsky, and David Brown at the MHRA; to David Carpenter and Mike Proven and all volunteer officers and members of the South Central, Berkshire Research Ethics Committee; and to Kevin Ahmed and all HRA staff who supported the trial. The investigators express their gratitude for the contribution of all trial participants, the UK Vaccine Taskforce (Jacinda Kemps, Kate Hilyard, and Kate Taylor) and the invaluable advice of the trial committees. Andrew Ustianowski, Chris Rogers, and Andrew Riordan served as the independent members of the data monitoring and safety committee. Robert Read is the chair of the trial steering committee.

Funding Information:
The study is funded by the UK Government through the National Institute for Health Research (NIHR) and the Vaccine Taskforce. The study sponsor is University Hospital Southampton NHS Foundation Trust, Southampton, UK. ChAd, BNT, and m1273 used in this study were supplied by the UK Health Security Agency (previously Public Health England). NVX, VLA, Ad26, and CVn were supplied by the manufacturers, without charge. The research is supported by the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, the NIHR Clinical Research Network, and the NIHR funded National Immunisation Schedule Evaluation Consortium. SNF and MDS are NIHR Senior Investigators. KC is a Wellcome Trust Investigator (210755/Z/18/Z) and NIHR Senior Investigator Emeritus. 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 would like to thank the UK Medicines and Healthcare products Regulatory Agency (MHRA) and Heath Research Authority (HRA) for their extraordinary efforts in rapidly reviewing submissions, for their attention to detail and input into trial design. Specific thanks go to Kirsty Wydenbach, Lisa Campbell, David Jones, Graham McNaughton, Marie-Christine Bielsky, and David Brown at the MHRA; to David Carpenter and Mike Proven and all volunteer officers and members of the South Central, Berkshire Research Ethics Committee; and to Kevin Ahmed and all HRA staff who supported the trial. The investigators express their gratitude for the contribution of all trial participants, the UK Vaccine Taskforce (Jacinda Kemps, Kate Hilyard, and Kate Taylor) and the invaluable advice of the trial committees. Andrew Ustianowski, Chris Rogers, and Andrew Riordan served as the independent members of the data monitoring and safety committee. Robert Read is the chair of the trial steering committee.

Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd.

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