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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.
Lancet Infect Dis. 2022 08; 22(8):1131-1141.LI

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.

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.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, 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, 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 and Clyde, Glasgow, UK.Wellcome-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.Wellcome-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, 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.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.NIHR Oxford Biomedical Research Centre, Oxford, UK.NIHR Leeds Clinical Research Facility, Leeds Teaching Hospitals Trust and University of Leeds, Leeds, UK.Public Health Wales, Betsi Cadwaladr University Health Board, Bangor University, Bangor, UK.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, 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, 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.Queen Elizabeth University Hospital, NHS Greater Glasgow and 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, Porton, UK.UK Health Security Agency, Porton Down, Porton, UK.UK Health Security Agency, Colindale, London, UK.UK Health Security Agency, Colindale, London, UK.Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.Division of Epidemiology and Public Health, University of Nottingham School of Medicine, University of Nottingham, 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
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35550261

Citation

Munro, Alasdair P S., et al. "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, vol. 22, no. 8, 2022, pp. 1131-1141.
Munro APS, Feng S, Janani L, et al. 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. Lancet Infect Dis. 2022;22(8):1131-1141.
Munro, A. P. S., Feng, S., Janani, L., Cornelius, V., Aley, P. K., Babbage, G., Baxter, D., Bula, M., Cathie, K., Chatterjee, K., Dodd, K., Enever, Y., Qureshi, E., Goodman, A. L., Green, C. A., Harndahl, L., Haughney, J., Hicks, A., van der Klaauw, A. A., ... Faust, S. N. (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. https://doi.org/10.1016/S1473-3099(22)00271-7
Munro APS, et al. 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. Lancet Infect Dis. 2022;22(8):1131-1141. PubMed PMID: 35550261.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Munro,Alasdair P S, AU - Feng,Shuo, 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 - Qureshi,Ehsaan, AU - Goodman,Anna L, AU - Green,Christopher A, AU - Harndahl,Linda, AU - Haughney,John, AU - Hicks,Alexander, AU - van der Klaauw,Agatha A, AU - Kanji,Nasir, AU - Libri,Vincenzo, AU - Llewelyn,Martin J, AU - McGregor,Alastair C, AU - Maallah,Mina, AU - Minassian,Angela M, AU - Moore,Patrick, AU - Mughal,Mehmood, AU - Mujadidi,Yama F, AU - Holliday,Kyra, 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 - Bawa,Tanveer, AU - Saralaya,Dinesh, AU - Sharma,Sunil, AU - Sheridan,Ray, 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 - Lambe,Teresa, AU - Nguyen-Van-Tam,Jonathan S, AU - Snape,Matthew D, AU - Liu,Xinxue, AU - Faust,Saul N, AU - ,, Y1 - 2022/05/09/ PY - 2022/04/12/received PY - 2022/04/19/revised PY - 2022/04/19/accepted PY - 2022/5/14/pubmed PY - 2022/7/27/medline PY - 2022/5/13/entrez SP - 1131 EP - 1141 JF - The Lancet. Infectious diseases JO - Lancet Infect Dis VL - 22 IS - 8 N2 - 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. SN - 1474-4457 UR - https://www.unboundmedicine.com/medline/citation/35550261/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_ DB - PRIME DP - Unbound Medicine ER -