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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
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. The COV-BOOST trial i...
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| Published in: | The Lancet infectious diseases 2022-08, Vol.22 (8), p.1131-1141 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| container_title | The Lancet infectious diseases |
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| creator | Cathie, Katrina Chatterjee, Krishna Harndahl, Linda Owens, Daniel R Pacurar, Mihaela Saich, Stephen Thomson, Emma C Todd, Shirley Read, Robert C Munro, Alasdair P S Janani, Leila Cornelius, Victoria Aley, Parvinder K Dodd, Kate Qureshi, Ehsaan Harndahl, Linda Llewelyn, Martin J Mujadidi, Yama F Osanlou, Rostam Owens, Daniel R Regan, Karen Saich, Stephen Maallah, Mina Thomson, Emma C Todd, Shirley Faust, Saul N Tudor Jones, Lona Harrison, Elizabeth Burton, Katharine Storton, Kim Munusamy, Malathi Tandy, Bridget Cox, Stephen Barker, Dominique Hailstone, Jessica Bisnauthsing, Karen Abeywickrama, Movin Spence, Niamh Packham, Alice Aslam, Suahil McGreevy, Caitlin Borca, Alessandro Farooqi, Sadaf Hale, Colin Stackpoole, Michael Rashid-Gardner, Zalina Lyon, Rebecca McDonnell, Chloe Cole, Christine Brown, Claire Sabine, Charlette Turnbull, Iain Drake-Brockman, Rachael Smith, Catherine Kownacka, Alicia Hladkiwskyj, John Patel, Gita Barry, Joshua Longhurst, Beverley Richmond, Leah Fox, Lauren Graham, Victoria Knight, Chanice Choi, Bea Gouriet, Jade Macdonald, Jonathan Seaton, Andrew Gardside, Ben Bonnaud, Avril Keenan, Samantha Hall, Jane Newman, Joseph Haydock, Helen van Welsenes, Donald Cooper, Chris Tunstall, Simon Cutts, Rebecca Whittley, Sarah Adams, Kirsty Turner, Nicola Andrews, Antonette Stokes, Matthew Berry, Lisa Cullinane, James Haskell, Louise Romani, Rossana Fowler, Simon Marius, Phedra Summerton, Eloise Horsfall, Emily Burton, Holly Dineen, Emily Lakeman, Nicki Branney, Debbie Vamplew, Luke Wiselka, Martin Wenn, Victoria Renals, Valerie Ellis, Kate Hardy, Anna |
| description | 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.
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.
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 |
| doi_str_mv | 10.1016/S1473-3099(22)00271-7 |
| format | article |
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Chatterjee, Krishna ; Harndahl, Linda ; Owens, Daniel R ; Pacurar, Mihaela ; Saich, Stephen ; Thomson, Emma C ; Todd, Shirley ; Read, Robert C ; Munro, Alasdair P S ; Janani, Leila ; Cornelius, Victoria ; Aley, Parvinder K ; Dodd, Kate ; Qureshi, Ehsaan ; Harndahl, Linda ; Llewelyn, Martin J ; Mujadidi, Yama F ; Osanlou, Rostam ; Owens, Daniel R ; Regan, Karen ; Saich, Stephen ; Maallah, Mina ; Thomson, Emma C ; Todd, Shirley ; Faust, Saul N ; Tudor Jones, Lona ; Harrison, Elizabeth ; Burton, Katharine ; Storton, Kim ; Munusamy, Malathi ; Tandy, Bridget ; Cox, Stephen ; Barker, Dominique ; Hailstone, Jessica ; Bisnauthsing, Karen ; Abeywickrama, Movin ; Spence, Niamh ; Packham, Alice ; Aslam, Suahil ; McGreevy, Caitlin ; Borca, Alessandro ; Farooqi, Sadaf ; Hale, Colin ; Stackpoole, Michael ; Rashid-Gardner, Zalina ; Lyon, Rebecca ; McDonnell, Chloe ; Cole, Christine ; Brown, Claire ; Sabine, Charlette ; Turnbull, Iain ; Drake-Brockman, Rachael ; Smith, Catherine ; Kownacka, Alicia ; Hladkiwskyj, John ; Patel, Gita ; Barry, Joshua ; Longhurst, Beverley ; Richmond, Leah ; Fox, Lauren ; Graham, Victoria ; Knight, Chanice ; Choi, Bea ; Gouriet, Jade ; Macdonald, Jonathan ; Seaton, Andrew ; Gardside, Ben ; Bonnaud, Avril ; Keenan, Samantha ; Hall, Jane ; Newman, Joseph ; Haydock, Helen ; van Welsenes, Donald ; Cooper, Chris ; Tunstall, Simon ; Cutts, Rebecca ; Whittley, Sarah ; Adams, Kirsty ; Turner, Nicola ; Andrews, Antonette ; Stokes, Matthew ; Berry, Lisa ; Cullinane, James ; Haskell, Louise ; Romani, Rossana ; Fowler, Simon ; Marius, Phedra ; Summerton, Eloise ; Horsfall, Emily ; Burton, Holly ; Dineen, Emily ; Lakeman, Nicki ; Branney, Debbie ; Vamplew, Luke ; Wiselka, Martin ; Wenn, Victoria ; Renals, Valerie ; Ellis, Kate ; Hardy, Anna</creator><creatorcontrib>Cathie, Katrina ; Chatterjee, Krishna ; Harndahl, Linda ; Owens, Daniel R ; Pacurar, Mihaela ; Saich, Stephen ; Thomson, Emma C ; Todd, Shirley ; Read, Robert C ; Munro, Alasdair P S ; Janani, Leila ; Cornelius, Victoria ; Aley, Parvinder K ; Dodd, Kate ; Qureshi, Ehsaan ; Harndahl, Linda ; Llewelyn, Martin J ; Mujadidi, Yama F ; Osanlou, Rostam ; Owens, Daniel R ; Regan, Karen ; Saich, Stephen ; Maallah, Mina ; Thomson, Emma C ; Todd, Shirley ; Faust, Saul N ; Tudor Jones, Lona ; Harrison, Elizabeth ; Burton, Katharine ; Storton, Kim ; Munusamy, Malathi ; Tandy, Bridget ; Cox, Stephen ; Barker, Dominique ; Hailstone, Jessica ; Bisnauthsing, Karen ; Abeywickrama, Movin ; Spence, Niamh ; Packham, Alice ; Aslam, Suahil ; McGreevy, Caitlin ; Borca, Alessandro ; Farooqi, Sadaf ; Hale, Colin ; Stackpoole, Michael ; Rashid-Gardner, Zalina ; Lyon, Rebecca ; McDonnell, Chloe ; Cole, Christine ; Brown, Claire ; Sabine, Charlette ; Turnbull, Iain ; Drake-Brockman, Rachael ; Smith, Catherine ; Kownacka, Alicia ; Hladkiwskyj, John ; Patel, Gita ; Barry, Joshua ; Longhurst, Beverley ; Richmond, Leah ; Fox, Lauren ; Graham, Victoria ; Knight, Chanice ; Choi, Bea ; Gouriet, Jade ; Macdonald, Jonathan ; Seaton, Andrew ; Gardside, Ben ; Bonnaud, Avril ; Keenan, Samantha ; Hall, Jane ; Newman, Joseph ; Haydock, Helen ; van Welsenes, Donald ; Cooper, Chris ; Tunstall, Simon ; Cutts, Rebecca ; Whittley, Sarah ; Adams, Kirsty ; Turner, Nicola ; Andrews, Antonette ; Stokes, Matthew ; Berry, Lisa ; Cullinane, James ; Haskell, Louise ; Romani, Rossana ; Fowler, Simon ; Marius, Phedra ; Summerton, Eloise ; Horsfall, Emily ; Burton, Holly ; Dineen, Emily ; Lakeman, Nicki ; Branney, Debbie ; Vamplew, Luke ; Wiselka, Martin ; Wenn, Victoria ; Renals, Valerie ; Ellis, Kate ; Hardy, Anna ; COV-BOOST study group</creatorcontrib><description>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.
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.
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).
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.
UK Vaccine Task Force and National Institute for Health Research.</description><identifier>ISSN: 1473-3099</identifier><identifier>ISSN: 1474-4457</identifier><identifier>EISSN: 1474-4457</identifier><identifier>DOI: 10.1016/S1473-3099(22)00271-7</identifier><identifier>PMID: 35550261</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>2019-nCoV Vaccine mRNA-1273 ; Adverse events ; Aged ; Antibodies ; Antibodies, Viral ; BNT162 Vaccine ; ChAdOx1 nCoV-19 ; Clinical trials ; Coronaviruses ; COVID-19 ; COVID-19 - prevention & control ; COVID-19 vaccines ; COVID-19 Vaccines - adverse effects ; Dosage ; Enzyme-linked immunosorbent assay ; Female ; Humans ; Humoral immunity ; Hypothesis testing ; Immune response ; Immune response (cell-mediated) ; Immune system ; Immunogenicity ; Immunogenicity, Vaccine ; Immunoglobulin G ; Immunology ; Infections ; Infectious diseases ; Laboratories ; Lymphocytes T ; Male ; Middle Aged ; mRNA ; mRNA vaccines ; Observational studies ; Protein folding ; Proteins ; Randomization ; Safety ; SARS-CoV-2 ; Schedules ; Severe acute respiratory syndrome coronavirus 2 ; Spike protein ; Statistical analysis ; Vaccines</subject><ispartof>The Lancet infectious diseases, 2022-08, Vol.22 (8), p.1131-1141</ispartof><rights>2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license</rights><rights>Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.</rights><rights>2022. The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. This work is published under https://creativecommons.org/licenses/by/3.0/ (theLicense”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c547t-5c17a233c2e0ba2b9715de363507fb774a31707b5902d10d54f147582ad766523</citedby><cites>FETCH-LOGICAL-c547t-5c17a233c2e0ba2b9715de363507fb774a31707b5902d10d54f147582ad766523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,783,787,888,27938,27939</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35550261$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cathie, Katrina</creatorcontrib><creatorcontrib>Chatterjee, Krishna</creatorcontrib><creatorcontrib>Harndahl, Linda</creatorcontrib><creatorcontrib>Owens, Daniel R</creatorcontrib><creatorcontrib>Pacurar, Mihaela</creatorcontrib><creatorcontrib>Saich, Stephen</creatorcontrib><creatorcontrib>Thomson, Emma C</creatorcontrib><creatorcontrib>Todd, Shirley</creatorcontrib><creatorcontrib>Read, Robert C</creatorcontrib><creatorcontrib>Munro, Alasdair P S</creatorcontrib><creatorcontrib>Janani, Leila</creatorcontrib><creatorcontrib>Cornelius, Victoria</creatorcontrib><creatorcontrib>Aley, Parvinder K</creatorcontrib><creatorcontrib>Dodd, Kate</creatorcontrib><creatorcontrib>Qureshi, Ehsaan</creatorcontrib><creatorcontrib>Harndahl, Linda</creatorcontrib><creatorcontrib>Llewelyn, Martin J</creatorcontrib><creatorcontrib>Mujadidi, Yama F</creatorcontrib><creatorcontrib>Osanlou, Rostam</creatorcontrib><creatorcontrib>Owens, Daniel R</creatorcontrib><creatorcontrib>Regan, Karen</creatorcontrib><creatorcontrib>Saich, Stephen</creatorcontrib><creatorcontrib>Maallah, Mina</creatorcontrib><creatorcontrib>Thomson, Emma C</creatorcontrib><creatorcontrib>Todd, Shirley</creatorcontrib><creatorcontrib>Faust, Saul N</creatorcontrib><creatorcontrib>Tudor Jones, Lona</creatorcontrib><creatorcontrib>Harrison, Elizabeth</creatorcontrib><creatorcontrib>Burton, Katharine</creatorcontrib><creatorcontrib>Storton, Kim</creatorcontrib><creatorcontrib>Munusamy, Malathi</creatorcontrib><creatorcontrib>Tandy, Bridget</creatorcontrib><creatorcontrib>Cox, Stephen</creatorcontrib><creatorcontrib>Barker, Dominique</creatorcontrib><creatorcontrib>Hailstone, Jessica</creatorcontrib><creatorcontrib>Bisnauthsing, Karen</creatorcontrib><creatorcontrib>Abeywickrama, Movin</creatorcontrib><creatorcontrib>Spence, Niamh</creatorcontrib><creatorcontrib>Packham, Alice</creatorcontrib><creatorcontrib>Aslam, Suahil</creatorcontrib><creatorcontrib>McGreevy, Caitlin</creatorcontrib><creatorcontrib>Borca, Alessandro</creatorcontrib><creatorcontrib>Farooqi, Sadaf</creatorcontrib><creatorcontrib>Hale, Colin</creatorcontrib><creatorcontrib>Stackpoole, 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Jade</creatorcontrib><creatorcontrib>Macdonald, Jonathan</creatorcontrib><creatorcontrib>Seaton, Andrew</creatorcontrib><creatorcontrib>Gardside, Ben</creatorcontrib><creatorcontrib>Bonnaud, Avril</creatorcontrib><creatorcontrib>Keenan, Samantha</creatorcontrib><creatorcontrib>Hall, Jane</creatorcontrib><creatorcontrib>Newman, Joseph</creatorcontrib><creatorcontrib>Haydock, Helen</creatorcontrib><creatorcontrib>van Welsenes, Donald</creatorcontrib><creatorcontrib>Cooper, Chris</creatorcontrib><creatorcontrib>Tunstall, Simon</creatorcontrib><creatorcontrib>Cutts, Rebecca</creatorcontrib><creatorcontrib>Whittley, Sarah</creatorcontrib><creatorcontrib>Adams, Kirsty</creatorcontrib><creatorcontrib>Turner, Nicola</creatorcontrib><creatorcontrib>Andrews, Antonette</creatorcontrib><creatorcontrib>Stokes, Matthew</creatorcontrib><creatorcontrib>Berry, Lisa</creatorcontrib><creatorcontrib>Cullinane, James</creatorcontrib><creatorcontrib>Haskell, Louise</creatorcontrib><creatorcontrib>Romani, Rossana</creatorcontrib><creatorcontrib>Fowler, Simon</creatorcontrib><creatorcontrib>Marius, Phedra</creatorcontrib><creatorcontrib>Summerton, Eloise</creatorcontrib><creatorcontrib>Horsfall, Emily</creatorcontrib><creatorcontrib>Burton, Holly</creatorcontrib><creatorcontrib>Dineen, Emily</creatorcontrib><creatorcontrib>Lakeman, Nicki</creatorcontrib><creatorcontrib>Branney, Debbie</creatorcontrib><creatorcontrib>Vamplew, Luke</creatorcontrib><creatorcontrib>Wiselka, Martin</creatorcontrib><creatorcontrib>Wenn, Victoria</creatorcontrib><creatorcontrib>Renals, Valerie</creatorcontrib><creatorcontrib>Ellis, Kate</creatorcontrib><creatorcontrib>Hardy, Anna</creatorcontrib><creatorcontrib>COV-BOOST study group</creatorcontrib><title>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</title><title>The Lancet infectious diseases</title><addtitle>Lancet Infect Dis</addtitle><description>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.
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.
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).
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.
UK Vaccine Task Force and National Institute for Health Research.</description><subject>2019-nCoV Vaccine mRNA-1273</subject><subject>Adverse events</subject><subject>Aged</subject><subject>Antibodies</subject><subject>Antibodies, Viral</subject><subject>BNT162 Vaccine</subject><subject>ChAdOx1 nCoV-19</subject><subject>Clinical trials</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>COVID-19 - prevention & control</subject><subject>COVID-19 vaccines</subject><subject>COVID-19 Vaccines - adverse effects</subject><subject>Dosage</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Female</subject><subject>Humans</subject><subject>Humoral immunity</subject><subject>Hypothesis testing</subject><subject>Immune response</subject><subject>Immune response (cell-mediated)</subject><subject>Immune system</subject><subject>Immunogenicity</subject><subject>Immunogenicity, Vaccine</subject><subject>Immunoglobulin G</subject><subject>Immunology</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Laboratories</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Middle Aged</subject><subject>mRNA</subject><subject>mRNA vaccines</subject><subject>Observational studies</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>Randomization</subject><subject>Safety</subject><subject>SARS-CoV-2</subject><subject>Schedules</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Spike protein</subject><subject>Statistical analysis</subject><subject>Vaccines</subject><issn>1473-3099</issn><issn>1474-4457</issn><issn>1474-4457</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqFUk1vGyEQ3X6pSd3-hFZIvTiStwUWlmwOrRz3K1IUS7WbK2KBtYl2wQXsNP--7DqN6l56AmbevDfDvCx7jeA7BFH5foEIK_ICVtUY4xMIMUM5e5wdpzDJCaHs6XDfQ46yFyHcQIgYguR5dlRQSiEu0fGjJwvR6Hg3AabrttattDXS9G9hFfBayPgQA64B51dLVOIaD-nu-9U0R5gVYDa_vviUowrshJTG6gBWZqctEAE0buvjOlcuaFA7F6L2fbBt3a2xKxBvHehzoWefradq_gsBO3PXPZvzh4ICxLXxaig46GacGsjP5_PF8uQsobptG43UNno9AXVrrNJqAjZrkcrwBPjE5ToTtALRG9G-zJ41og361f05yn58-bycfcsv518vZtPLXFLCYk4lYgIXhcQa1gLXFUNU6aIsKGRNzRgRBWKQ1bSCWCGoKGnSAugpFoqVJcXFKPuw591s606roUHR8o03nfB33AnDDzPWrPnK7XgFT0mZlEfZ-J7Au59bHSJPU0jdtsJqtw0clyVhFaJFr_X2H-hNWoRN4yVUhSGBZEDRPUp6F4LXzUMzCPLeZnywGe89xDHmg804S3Vv_p7koeqPrxLg4x6g03_ujPY8SKOt1Mp4LSNXzvxH4jePFt2f</recordid><startdate>202208</startdate><enddate>202208</enddate><creator>Cathie, 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Group</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202208</creationdate><title>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</title><author>Cathie, Katrina ; Chatterjee, Krishna ; Harndahl, Linda ; Owens, Daniel R ; Pacurar, Mihaela ; Saich, Stephen ; Thomson, Emma C ; Todd, Shirley ; Read, Robert C ; Munro, Alasdair P S ; Janani, Leila ; Cornelius, Victoria ; Aley, Parvinder K ; Dodd, Kate ; Qureshi, Ehsaan ; Harndahl, Linda ; Llewelyn, Martin J ; Mujadidi, Yama F ; Osanlou, Rostam ; Owens, Daniel R ; Regan, Karen ; Saich, Stephen ; Maallah, Mina ; Thomson, Emma C ; Todd, Shirley ; Faust, Saul N ; Tudor Jones, Lona ; Harrison, Elizabeth ; Burton, Katharine ; Storton, Kim ; Munusamy, Malathi ; Tandy, Bridget ; Cox, Stephen ; Barker, Dominique ; Hailstone, Jessica ; Bisnauthsing, Karen ; Abeywickrama, Movin ; Spence, Niamh ; Packham, Alice ; Aslam, Suahil ; McGreevy, Caitlin ; Borca, Alessandro ; Farooqi, Sadaf ; Hale, Colin ; Stackpoole, Michael ; Rashid-Gardner, Zalina ; Lyon, Rebecca ; McDonnell, Chloe ; Cole, Christine ; Brown, Claire ; Sabine, Charlette ; Turnbull, Iain ; Drake-Brockman, Rachael ; Smith, Catherine ; Kownacka, Alicia ; Hladkiwskyj, John ; Patel, Gita ; Barry, Joshua ; Longhurst, Beverley ; Richmond, Leah ; Fox, Lauren ; Graham, Victoria ; Knight, Chanice ; Choi, Bea ; Gouriet, Jade ; Macdonald, Jonathan ; Seaton, Andrew ; Gardside, Ben ; Bonnaud, Avril ; Keenan, Samantha ; Hall, Jane ; Newman, Joseph ; Haydock, Helen ; van Welsenes, Donald ; Cooper, Chris ; Tunstall, Simon ; Cutts, Rebecca ; Whittley, Sarah ; Adams, Kirsty ; Turner, Nicola ; Andrews, Antonette ; Stokes, Matthew ; Berry, Lisa ; Cullinane, James ; Haskell, Louise ; Romani, Rossana ; Fowler, Simon ; Marius, Phedra ; Summerton, Eloise ; Horsfall, Emily ; Burton, Holly ; Dineen, Emily ; Lakeman, Nicki ; Branney, Debbie ; Vamplew, Luke ; Wiselka, Martin ; Wenn, Victoria ; Renals, Valerie ; Ellis, Kate ; Hardy, 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Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Lancet infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cathie, Katrina</au><au>Chatterjee, Krishna</au><au>Harndahl, Linda</au><au>Owens, Daniel R</au><au>Pacurar, Mihaela</au><au>Saich, Stephen</au><au>Thomson, Emma C</au><au>Todd, Shirley</au><au>Read, Robert C</au><au>Munro, Alasdair P S</au><au>Janani, Leila</au><au>Cornelius, Victoria</au><au>Aley, Parvinder K</au><au>Dodd, Kate</au><au>Qureshi, Ehsaan</au><au>Harndahl, Linda</au><au>Llewelyn, Martin J</au><au>Mujadidi, Yama F</au><au>Osanlou, Rostam</au><au>Owens, Daniel R</au><au>Regan, Karen</au><au>Saich, Stephen</au><au>Maallah, Mina</au><au>Thomson, Emma C</au><au>Todd, Shirley</au><au>Faust, Saul N</au><au>Tudor Jones, Lona</au><au>Harrison, Elizabeth</au><au>Burton, Katharine</au><au>Storton, Kim</au><au>Munusamy, Malathi</au><au>Tandy, Bridget</au><au>Cox, Stephen</au><au>Barker, Dominique</au><au>Hailstone, Jessica</au><au>Bisnauthsing, Karen</au><au>Abeywickrama, Movin</au><au>Spence, Niamh</au><au>Packham, Alice</au><au>Aslam, Suahil</au><au>McGreevy, Caitlin</au><au>Borca, Alessandro</au><au>Farooqi, Sadaf</au><au>Hale, Colin</au><au>Stackpoole, Michael</au><au>Rashid-Gardner, Zalina</au><au>Lyon, Rebecca</au><au>McDonnell, Chloe</au><au>Cole, Christine</au><au>Brown, Claire</au><au>Sabine, Charlette</au><au>Turnbull, Iain</au><au>Drake-Brockman, Rachael</au><au>Smith, Catherine</au><au>Kownacka, Alicia</au><au>Hladkiwskyj, John</au><au>Patel, Gita</au><au>Barry, Joshua</au><au>Longhurst, Beverley</au><au>Richmond, Leah</au><au>Fox, Lauren</au><au>Graham, Victoria</au><au>Knight, Chanice</au><au>Choi, Bea</au><au>Gouriet, Jade</au><au>Macdonald, Jonathan</au><au>Seaton, Andrew</au><au>Gardside, Ben</au><au>Bonnaud, Avril</au><au>Keenan, Samantha</au><au>Hall, Jane</au><au>Newman, Joseph</au><au>Haydock, Helen</au><au>van Welsenes, Donald</au><au>Cooper, Chris</au><au>Tunstall, Simon</au><au>Cutts, Rebecca</au><au>Whittley, Sarah</au><au>Adams, Kirsty</au><au>Turner, Nicola</au><au>Andrews, Antonette</au><au>Stokes, Matthew</au><au>Berry, Lisa</au><au>Cullinane, James</au><au>Haskell, Louise</au><au>Romani, Rossana</au><au>Fowler, Simon</au><au>Marius, Phedra</au><au>Summerton, Eloise</au><au>Horsfall, Emily</au><au>Burton, Holly</au><au>Dineen, Emily</au><au>Lakeman, Nicki</au><au>Branney, Debbie</au><au>Vamplew, Luke</au><au>Wiselka, Martin</au><au>Wenn, Victoria</au><au>Renals, Valerie</au><au>Ellis, Kate</au><au>Hardy, Anna</au><aucorp>COV-BOOST study group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>The Lancet infectious diseases</jtitle><addtitle>Lancet Infect Dis</addtitle><date>2022-08</date><risdate>2022</risdate><volume>22</volume><issue>8</issue><spage>1131</spage><epage>1141</epage><pages>1131-1141</pages><issn>1473-3099</issn><issn>1474-4457</issn><eissn>1474-4457</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Undefined-3</notes><notes>Contributed equally as last authors</notes><notes>Contributed equally as first authors</notes><notes>Members of the COV-BOOST study group can be found in appendix 1</notes><abstract>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.
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.
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).
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.
UK Vaccine Task Force and National Institute for Health Research.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>35550261</pmid><doi>10.1016/S1473-3099(22)00271-7</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1473-3099 |
| ispartof | The Lancet infectious diseases, 2022-08, Vol.22 (8), p.1131-1141 |
| issn | 1473-3099 1474-4457 1474-4457 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9084623 |
| source | ScienceDirect Freedom Collection |
| subjects | 2019-nCoV Vaccine mRNA-1273 Adverse events Aged Antibodies Antibodies, Viral BNT162 Vaccine ChAdOx1 nCoV-19 Clinical trials Coronaviruses COVID-19 COVID-19 - prevention & control COVID-19 vaccines COVID-19 Vaccines - adverse effects Dosage Enzyme-linked immunosorbent assay Female Humans Humoral immunity Hypothesis testing Immune response Immune response (cell-mediated) Immune system Immunogenicity Immunogenicity, Vaccine Immunoglobulin G Immunology Infections Infectious diseases Laboratories Lymphocytes T Male Middle Aged mRNA mRNA vaccines Observational studies Protein folding Proteins Randomization Safety SARS-CoV-2 Schedules Severe acute respiratory syndrome coronavirus 2 Spike protein Statistical analysis Vaccines |
| title | 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 |
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