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

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.

• 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: Elsevier BV
• 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.