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Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial
Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

BACKGROUND: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.

METHODS: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.

FINDINGS: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group).

INTERPRETATION: Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose.

FUNDING: UK Vaccine Task Force and National Institute for Health Research.

1473-3099
1131-1141
Munro, Alasdair P S
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Feng, Shuo
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Maallah, Mina
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Minassian, Angela M
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Moore, Patrick
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Osanlou, Rostam
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Owens, Daniel R
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Pacurar, Mihaela
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Palfreeman, Adrian
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Pan, Daniel
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Rampling, Tommy
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Regan, Karen
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Saich, Stephen
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Bawa, Tanveer
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Saralaya, Dinesh
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COV-BOOST study group
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Aley, Parvinder K
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Baxter, David
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Bula, Marcin
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Cathie, Katrina
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Chatterjee, Krishna
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Qureshi, Ehsaan
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Goodman, Anna L
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Green, Christopher A
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Harndahl, Linda
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Haughney, John
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Hicks, Alexander
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van der Klaauw, Agatha A
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Kanji, Nasir
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Libri, Vincenzo
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Llewelyn, Martin J
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McGregor, Alastair C
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Maallah, Mina
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Minassian, Angela M
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Moore, Patrick
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Holliday, Kyra
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Osanlou, Orod
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Osanlou, Rostam
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Owens, Daniel R
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Pacurar, Mihaela
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Palfreeman, Adrian
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Saralaya, Dinesh
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Read, Robert C
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Charlton, Sue
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Hallis, Bassam
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Ramsay, Mary
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Faust, Saul N
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Munro, Alasdair P S, Feng, Shuo, Janani, Leila, Cornelius, Victoria, Aley, Parvinder K, Babbage, Gavin and Faust, Saul N , COV-BOOST study group (2022) Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial. The Lancet Infectious Diseases, 22 (8), 1131-1141. (doi:10.1016/S1473-3099(22)00271-7).

Record type: Article

Abstract

BACKGROUND: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.

METHODS: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.

FINDINGS: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group).

INTERPRETATION: Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose.

FUNDING: UK Vaccine Task Force and National Institute for Health Research.

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e-pub ahead of print date: 9 May 2022
Published date: August 2022
Additional Information: Funding Information: The study is funded by the UK Government through the National Institute for Health Research (NIHR) and the Vaccine Task Force. The study sponsor is University Hospital Southampton NHS Foundation Trust, Southampton, UK. ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 used in this study were supplied by the UK Health Security Agency (previously Public Health England). The research is supported by the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, the NIHR Clinical Research Facilities and NIHR Clinical Research Network, and the NIHR-funded National Immunisation Schedule Evaluation Consortium . SNF and MDS are NIHR Senior Investigators. KCh is a Wellcome Trust Investigator (210755/Z/18/Z) and NIHR Senior Investigator Emeritus. The views expressed in this Article 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 and Heath Research Authority for their extraordinary efforts in rapidly reviewing submissions, their attention to detail, and their input into trial design. Specific thanks go to Kirsty Wydenbach, Lisa Campbell, David Jones, Graham McNaughton, Marie-Christine Bielsky, and David Brown at the UK Medicines and Healthcare products Regulatory Agency; to David Carpenter (Chair), Mike Proven (Vice-Chair), and all volunteer officers and members of the South Central, Berkshire Research Ethics Committee; and to Kevin Ahmed and all Heath Research Authority staff who supported the trial. The investigators express their gratitude to all trial participants for their contribution, the UK Vaccine Task Force (Jacinda Kemps), and the trial committees for their invaluable advice. Andrew Ustianowski (Chair), Chris Rogers, and Andrew Riordan serve as the independent members of the Data Monitoring and Safety Committee and RCR 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 Task Force. The study sponsor is University Hospital Southampton NHS Foundation Trust, Southampton, UK. ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 used in this study were supplied by the UK Health Security Agency (previously Public Health England). The research is supported by the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, the NIHR Clinical Research Facilities and NIHR Clinical Research Network, and the NIHR-funded National Immunisation Schedule Evaluation Consortium. SNF and MDS are NIHR Senior Investigators. KCh is a Wellcome Trust Investigator (210755/Z/18/Z) and NIHR Senior Investigator Emeritus. The views expressed in this Article 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 and Heath Research Authority for their extraordinary efforts in rapidly reviewing submissions, their attention to detail, and their input into trial design. Specific thanks go to Kirsty Wydenbach, Lisa Campbell, David Jones, Graham McNaughton, Marie-Christine Bielsky, and David Brown at the UK Medicines and Healthcare products Regulatory Agency; to David Carpenter (Chair), Mike Proven (Vice-Chair), and all volunteer officers and members of the South Central, Berkshire Research Ethics Committee; and to Kevin Ahmed and all Heath Research Authority staff who supported the trial. The investigators express their gratitude to all trial participants for their contribution, the UK Vaccine Task Force (Jacinda Kemps), and the trial committees for their invaluable advice. Andrew Ustianowski (Chair), Chris Rogers, and Andrew Riordan serve as the independent members of the Data Monitoring and Safety Committee and RCR is the Chair of the Trial Steering Committee. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Identifiers

Local EPrints ID: 467964
URI: http://eprints.soton.ac.uk/id/eprint/467964
ISSN: 1473-3099
PURE UUID: c361f535-3eda-4196-8de2-e608a693e0ea
ORCID for Robert C Read: ORCID iD orcid.org/0000-0002-4297-6728
ORCID for Saul N Faust: ORCID iD orcid.org/0000-0003-3410-7642

Catalogue record

Date deposited: 26 Jul 2022 17:10
Last modified: 17 Mar 2024 03:28

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Contributors

Author: Alasdair P S Munro
Author: Shuo Feng
Author: Leila Janani
Author: Victoria Cornelius
Author: Parvinder K Aley
Author: Gavin Babbage
Author: David Baxter
Author: Marcin Bula
Author: Katrina Cathie
Author: Krishna Chatterjee
Author: Kate Dodd
Author: Yvanne Enever
Author: Ehsaan Qureshi
Author: Anna L Goodman
Author: Christopher A Green
Author: Linda Harndahl
Author: John Haughney
Author: Alexander Hicks
Author: Agatha A van der Klaauw
Author: Nasir Kanji
Author: Vincenzo Libri
Author: Martin J Llewelyn
Author: Alastair C McGregor
Author: Mina Maallah
Author: Angela M Minassian
Author: Patrick Moore
Author: Mehmood Mughal
Author: Yama F Mujadidi
Author: Kyra Holliday
Author: Orod Osanlou
Author: Rostam Osanlou
Author: Daniel R Owens
Author: Mihaela Pacurar
Author: Adrian Palfreeman
Author: Daniel Pan
Author: Tommy Rampling
Author: Karen Regan
Author: Stephen Saich
Author: Tanveer Bawa
Author: Dinesh Saralaya
Author: Sunil Sharma
Author: Ray Sheridan
Author: Emma C Thomson
Author: Shirley Todd
Author: Chris Twelves
Author: Robert C Read ORCID iD
Author: Sue Charlton
Author: Bassam Hallis
Author: Mary Ramsay
Author: Saul N Faust ORCID iD
Corporate Author: COV-BOOST study group

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