Reactogenicity and Immunogenicity following Heterologous and Homologous Third Dose COVID-19 vaccination in UK Adolescents (Com-COV3): A Randomised Controlled Non-Inferiority Trial

E Kelly¹, M Greenland¹, P de Whalley¹, G C Macaulay¹, P K Aley¹, E Plested¹, S Koleva¹, J Cotton¹, J Kinch¹, T Madupuri¹, R C Read², M Ramsay³, C Cameron⁴, Turner Dpj⁵, P Heath⁶, P Connor⁷, K Cathie⁸, S N Faust², Banerjee 1st⁹, K Man¹⁰, F Shackley¹¹, S O' Riordan¹², S Owens¹³, T Polychronakis¹⁴, H Trari Belhadef¹, Y Mujadidi¹, A Singha¹, L Cantrell¹, E Clutterbuck¹, R Anslow¹, T James¹⁵, B Hallis¹⁶, M Matheson¹⁶, L Chang¹⁷, T Lambe¹⁸, J S Nguyen-Van-Tam¹⁹, M D Snape¹, A M Minassian¹, X Liu²⁰

Affiliations

¹ Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK.
² 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.
³ Immunisation and Countermeasures Division, National Infection Service, Public Health England, London, UK.
⁴ Health Protection Scotland, Glasgow, UK.
⁵ University of Nottingham, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁶ Vaccine Institute, St. George's, University of London and St. George's University Hospitals NHS Trust, London, UK.
⁷ Noah's Ark Children's Hospital for Wales, University Hospital of Wales, Cardiff, UK.
⁸ NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁹ Royal Manchester Children's Hospital, Manchester University Hospitals Foundation Trust, UK.
¹⁰ Royal Free Hospital NHS Foundation Trust, London, UK.
¹¹ Sheffield's Children NHS Foundation Trust, Sheffield, UK.
¹² Leeds Teaching Hospital NHS Foundation Trust, Leeds, UK.
¹³ Newcastle Upon Tyne Hospitals NHS Foundation Trust, UK.
¹⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁵ Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁶ UK Health Security Agency, Porton Down, Salisbury, UK.
¹⁷ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁸ Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute, University of Oxford, Oxford, UK.
¹⁹ Population and Lifespan Health, University of Nottingham, Nottingham, UK.
²⁰ Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: Xinxue.liu@paediatrics.ox.ac.uk.

PMID: 41338394
DOI: 10.1016/j.jinf.2025.106663

Free article

Reactogenicity and Immunogenicity following Heterologous and Homologous Third Dose COVID-19 vaccination in UK Adolescents (Com-COV3): A Randomised Controlled Non-Inferiority Trial

E Kelly et al. J Infect. 2025.

Free article

. 2025 Dec 1:106663.

doi: 10.1016/j.jinf.2025.106663. Online ahead of print.

Authors

Affiliations

¹ Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK.
² 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.
³ Immunisation and Countermeasures Division, National Infection Service, Public Health England, London, UK.
⁴ Health Protection Scotland, Glasgow, UK.
⁵ University of Nottingham, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁶ Vaccine Institute, St. George's, University of London and St. George's University Hospitals NHS Trust, London, UK.
⁷ Noah's Ark Children's Hospital for Wales, University Hospital of Wales, Cardiff, UK.
⁸ NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁹ Royal Manchester Children's Hospital, Manchester University Hospitals Foundation Trust, UK.
¹⁰ Royal Free Hospital NHS Foundation Trust, London, UK.
¹¹ Sheffield's Children NHS Foundation Trust, Sheffield, UK.
¹² Leeds Teaching Hospital NHS Foundation Trust, Leeds, UK.
¹³ Newcastle Upon Tyne Hospitals NHS Foundation Trust, UK.
¹⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁵ Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁶ UK Health Security Agency, Porton Down, Salisbury, UK.
¹⁷ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁸ Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute, University of Oxford, Oxford, UK.
¹⁹ Population and Lifespan Health, University of Nottingham, Nottingham, UK.
²⁰ Oxford Vaccine Group, NIHR Oxford Biomedical Research Centre, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: Xinxue.liu@paediatrics.ox.ac.uk.

PMID: 41338394
DOI: 10.1016/j.jinf.2025.106663

Abstract

Background: The emergence of SARS-CoV2 variants combined with waning vaccine-induced immunity and breakthrough infections have highlighted the need for booster doses to maintain protection against SARS-CoV2 infection and disease.

Methods: Com-COV3 was a phase II, multicentre, randomised controlled trial, recruiting across 11 UK sites from June 2022 to June 2023, with follow up visits to February 2024. Healthy 12-15-year-olds who had received a two-30μg dose BNT162b2 primary regimen at least 90 days previously were randomised 1:1:1:1:1 to receive either BNT162b2 30μg, BNT162b2 10μg (adult vaccine formulation), BNT162b2 10μg (paediatric formulation), NVXCoV2373, or Meningococcal B vaccine (control). The primary objective was to determine if SARS-CoV-2 anti-spike antibody following a 10μg dose of the adult formulation of BNT162b2 was non-inferior to the paediatric formulation at 28 days post-third vaccination. The last five participants were randomised using a 1:3:3:1:1 ratio to prioritise recruitment to the study groups required for the co-primary endpoint. Although recruitment ceased early, the sample size required to fulfil the primary objective was met.

Findings: 281 participants were recruited (mean age 14 years old, 57% female). Adverse reactions were mostly mild-to-moderate. Local reactogenicity was mildest following NVXCoV2373. Frequency of adverse events was similar for both full dose and fractional dose BNT162b2 groups. Four serious adverse events occurred: three in the paediatric and one in the adult 10μg BNT162b2 group. Immunogenicity of 10μg BNT162b2 (adult) was both non-inferior and superior to that of 10μg BNT162b2 (paediatric); adjusted geometric mean ratio (aGMR) anti-spike IgG 1.50 (one-sided 95%CI 1.25 to ∞). Compared with 30μg BNT162b2, anti-spike IgG at day 28 post-third dose were similar in the 10μg BNT162b2 (adult) group [aGMR 0.93 (95%CI 0.75-1.14)] and significantly lower in the 10μg BNT162b2 (paediatric) [aGMR 0.64 (95%CI 0.52-0.78)] and NVXCoV2373 [aGMR 0.77 (95%CI 0.63-0.95)] groups. Compared with 30μg BNT162b2, levels of neutralising antibodies against Omicron BA.5 and XBB.15 were similar across vaccine groups.

Interpretation: All booster regimens evaluated elicited a robust immune response. 10μg fractional adult BNT162b2 vaccine demonstrated similar immunogenicity compared with 30μg BNT162b2 and superior immunogenicity compared with 10μg paediatric BNT162b2 vaccine. Fractional doses of the adult BNT162b2 vaccine are an alternative to the paediatric formulation for booster campaigns in adolescents.

Funding: National Institute for Health Research, Vaccine Task Force, and Coalition for Epidemic Preparedness Innovations.

Keywords: BNT162b2; COVID-19; NVXCoV2373; SARS-CoV-2; adolescents; boosters; breakthrough infection; heterologous; immunisation; immunogenicity; reactogenicity; vaccination.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MDS acted until September 2022 on behalf of the University of Oxford as an Investigator on research studies funded or supported by the vaccine manufacturers GlaxoSmithKline, Janssen, AstraZeneca, Novavax, MCM vaccines and Pfizer. He received no direct personal benefit for this work. From September 2022 he has been an employee at Moderna Biotech and holds stock options in this company. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, BioNTech, AstraZeneca, GlaxoSmithKline, Sanofi, Merck, Moderna, and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. KC acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator and/or providing consultative advice on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi, Iliad and Valneva. She receives no personal financial payment for this work. AMM acts on behalf of the University of Oxford as an investigator on research studies funded + /- sponsored by vaccine manufacturers including Pfizer, GlaxoSmithKline, Janssen, Valneva SE and Novavax. She receives no personal financial benefit for this work. PTH acts on behalf of St George’s University of London as an Investigator on clinical trials and studies of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Moderna, Novavax and Valneva. He receives no personal financial payment for this work. He is a member of the JCVI. JSN-V-T was seconded to the Department of Health and Social Care (DHSC) from October 2017-March 2022 as Deputy Chief Medical Officer, England, receiving no benefits, other than salary, for this work. Since leaving DHSC he has received a lecture fee from AstraZeneca and undertaken paid consulting for Moderna BioTech. The views expressed in this paper are those of its authors and not necessarily those of DHSC or JCVI.

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Reactogenicity and Immunogenicity following Heterologous and Homologous Third Dose COVID-19 vaccination in UK Adolescents (Com-COV3): A Randomised Controlled Non-Inferiority Trial

Affiliations

Reactogenicity and Immunogenicity following Heterologous and Homologous Third Dose COVID-19 vaccination in UK Adolescents (Com-COV3): A Randomised Controlled Non-Inferiority Trial

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Miscellaneous