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Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A randomised controlled trial

Kelly, Eimear; Greenland, Melanie; de Whalley, Philip C.S.; Aley, Parvinder K.; Plested, Emma L.; Singh, Nisha; Koleva, Stanislava; Tonner, Sharon; Macaulay, Grace C.; Read, Robert C.; Ramsay, Mary; Cameron, J. Claire; Turner, David P.J.; Heath, Paul T.; Bernatoniene, Jolanta; Connor, Philip; Cathie, Katrina; Faust, Saul N.; Banerjee, Indraneel; Cantrell, Liberty; Mujadidi, Yama F.; Belhadef, Hanane Trari; Clutterbuck, Elizabeth A.; Anslow, Rachel; Valliji, Zara; James, Tim; Hallis, Bassam; Otter, Ashley David; Lambe, Teresa; Nguyen-Van-Tam, Jonathan S.; Minassian, Angela M.; Liu, Xinxue; Snape, Matthew D.; Com-COV3 Study Group, Com-COV3 Study Group

Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A randomised controlled trial Thumbnail


Authors

Eimear Kelly

Melanie Greenland

Philip C.S. de Whalley

Parvinder K. Aley

Emma L. Plested

Nisha Singh

Stanislava Koleva

Sharon Tonner

Grace C. Macaulay

Robert C. Read

Mary Ramsay

J. Claire Cameron

DAVID TURNER david.turner@nottingham.ac.uk
Clinical Associate Professor

Paul T. Heath

Jolanta Bernatoniene

Philip Connor

Katrina Cathie

Saul N. Faust

Indraneel Banerjee

Liberty Cantrell

Yama F. Mujadidi

Hanane Trari Belhadef

Elizabeth A. Clutterbuck

Rachel Anslow

Zara Valliji

Tim James

Bassam Hallis

Ashley David Otter

Teresa Lambe

Jonathan S. Nguyen-Van-Tam

Angela M. Minassian

Xinxue Liu

Matthew D. Snape

Com-COV3 Study Group Com-COV3 Study Group



Abstract

Background: This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. Methods: A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. ‘Breakthrough infection’ analyses were exploratory. Findings: 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported ‘breakthrough infection’ compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a ‘breakthrough infection’ compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. Interpretation: Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. Funding: National Institute for Health Research and Vaccine Task Force. Trial Registration: International Standard Randomised Controlled Trial Number registry: 12348322.

Citation

Kelly, E., Greenland, M., de Whalley, P. C., Aley, P. K., Plested, E. L., Singh, N., …Com-COV3 Study Group, C. S. G. (2023). Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A randomised controlled trial. Journal of Infection, 87(3), 230-241. https://doi.org/10.1016/j.jinf.2023.06.007

Journal Article Type Article
Acceptance Date Jun 8, 2023
Online Publication Date Jun 17, 2023
Publication Date 2023-09
Deposit Date Jun 28, 2023
Publicly Available Date Jun 28, 2023
Journal Journal of Infection
Print ISSN 0163-4453
Electronic ISSN 1532-2742
Publisher British Infection Association
Peer Reviewed Peer Reviewed
Volume 87
Issue 3
Pages 230-241
DOI https://doi.org/10.1016/j.jinf.2023.06.007
Keywords Vaccines, Vaccination, Immunity, Heterologous, Adolescents, Immunisation, Breakthrough Infection, Covid-19, Sars-cov-2, Bnt162b2, Omicron, Nvxcov2373
Public URL https://nottingham-repository.worktribe.com/output/22400205
Publisher URL https://www.journalofinfection.com/article/S0163-4453(23)00330-4/fulltext
PMID 37331429
Additional Information Authors on behalf of the Com-COV3 Study Group.

This article is maintained by: Elsevier; Article Title: Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A Randomised Controlled Trial; Journal Title: Journal of Infection; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jinf.2023.06.007; Content Type: article; Copyright: © 2023 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association.

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