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Clinical Trial
. 2023 Sep;87(3):230-241.
doi: 10.1016/j.jinf.2023.06.007. Epub 2023 Jun 17.

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

Eimear Kelly  1 , Melanie Greenland  1 , Philip C S de Whalley  1 , Parvinder K Aley  1 , Emma L Plested  1 , Nisha Singh  1 , Stanislava Koleva  1 , Sharon Tonner  1 , Grace C Macaulay  1 , Robert C Read  2 , Mary Ramsay  3 , J Claire Cameron  4 , David P J Turner  5 , Paul T Heath  6 , Jolanta Bernatoniene  7 , Philip Connor  8 , Katrina Cathie  9 , Saul N Faust  2 , Indraneel Banerjee  10 , Liberty Cantrell  1 , Yama F Mujadidi  1 , Hanane Trari Belhadef  1 , Elizabeth A Clutterbuck  1 , Rachel Anslow  1 , Zara Valliji  1 , Tim James  11 , Bassam Hallis  12 , Ashley David Otter  12 , Teresa Lambe  13 , Jonathan S Nguyen-Van-Tam  14 , Angela M Minassian  15 , Xinxue Liu  1 , Matthew D Snape  1 ; Com-COV3 Study Group
Affiliations
Clinical Trial

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

Eimear Kelly et al. J Infect. 2023 Sep.

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.

Keywords: Adolescents; BNT162b2; Breakthrough infection; COVID-19; Heterologous; Immunisation; Immunity; NVXCoV2373; SARS-CoV-2; 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, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck 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 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 will undertake paid consulting for Moderna BioTech from 3rd May 2023. The views expressed in this paper are those of its authors and not necessarily those of DHSC or JCVI.

Figures

Fig. 1
Fig. 1
Severity of solicited adverse reactions in days 0-7 after second vaccination by study arm as self-reported in participant electronic diaries in the safety analysis population. BNT-30: BNT162b2 30 µg; BNT-10: BNT162b2 10 µg; NVX: NVX-CoV2373. The severity presented is the participant’s highest severity across 7 days following vaccination for each solicited adverse event. Fever: Mild: 38·0°C to <38·5°C; moderate: 38·5°C to <39°C; severe: ≥39·0°C. Feverish: Self-reported feeling of feverishness. For systemic symptoms, grading was classified as: Mild – easily tolerated with no limitation on normal activity; Moderate – some limitation of daily activity; Severe – unable to perform normal daily activity. There were two self-reported SARS-CoV-2 infections in days 0-7 after second vaccination both occurring in the NVX-CoV2373 study arm. The first participant self-reported 6 days after second vaccination had a grade 1 headache on day 6. The second participant self-reported 7 days after second vaccination had a grade 1 headache and grade 1 fatigue on day 5.
Fig. 2
Fig. 2
Immune responses at day 28 (humoral), and day 14 (cellular) after the second vaccination, by study arm and pre-second dose serostatus in the day 28 modified intention-to-treat populations. BNT-30: BNT162b2 30 µg; BNT-10: BNT162b2 10 µg; NVX: NVX-CoV2373; CI: confidence interval. Data presented are the geometric means, adjusted geometric mean ratios and their corresponding 95% confidence intervals. The boxes indicate the adjusted geometric mean ratio and the horizontal lines indicate the corresponding 95% confidence intervals. The geometric mean ratios between BNT-30 and either BNT-10 or NVX are adjusted for study site as a fixed effect. The vertical dotted line refers to an adjusted geometric mean ratio of one and indicates the line of no difference. A confidence interval that lies completely to one side and not intersecting the line of no difference indicates a significant difference in the geometric mean concentrations between the study arm and the reference BNT-30 study arm.
Fig. 3
Fig. 3
Neutralising activity against Omicron BA.1 and BA.2 variants by study arm and serostatus pre-second dose at 28 days after the second vaccination in the day 28 modified intention-to-treat population. BNT-30: BNT162b2 30 µg; BNT-10: BNT162b2 10 µg; NVX: NVX-CoV2373; CI: confidence interval. Data presented are the geometric means, adjusted geometric mean ratios and their corresponding 95% confidence intervals. The boxes indicate the adjusted geometric mean ratio and the horizontal lines indicate the corresponding 95% confidence intervals. The geometric mean ratios between BNT-30 and either BNT-10 or NVX are adjusted for study site as a fixed effect. The vertical dotted line refers to an adjusted geometric mean ratio of one and indicates the line of no difference. A confidence interval that lies completely to one side and not intersecting the line of no difference indicates a significant difference in the geometric mean concentrations between the study arm and the reference BNT-30 study arm.
Fig. 4
Fig. 4
Kaplan-Meier curves for risk of self-reported SARS-CoV-2 infections during follow-up. A: participants randomised before 29th November 2021; B: seronegative participants randomised before 29th November 2021; C: seropositive participants randomised before 29th November 2021; D: participants randomised to BNT-30 or BNT-10 during the recruitment period; E: seronegative participants randomised to BNT-30 or BNT-10 during the recruitment period; F: seropositive participants randomised to BNT-30 or BNT-10 during the recruitment period. BNT-30: BNT162b2 30 µg; BNT-10: BNT162b2 10 µg; NVX: NVX-CoV2373. Self-reported SARS-CoV-2 infections occurring from >14 days following second dose were considered an event. Participants were censored at the date of either: self-reported SARS-CoV-2 infection within 14 days of second dose inclusive, third dose vaccination in the community, withdrawal, day 236 visit, or 236 days after second vaccination if day 236 visit was missed and no infection was self-reported, whichever came first. A vertical step down on the curve indicates a self-reported SARS-CoV-2 infection and a tick mark on the curve indicates a censored event. Participants were randomised 1:1:1 at the time of their second vaccination to BNT-30, BNT-10, or NVX. After 29th November 2021, when UK national immunisation policy changed to offer all 12-to-15-year-olds a second dose of BNT, recruitment stopped and participants who had already received their first dose of BNT within the study were randomised 1:1 to receive 30 µg BNT162b2 or 10 µg BNT162b2 as a second dose.
Fig. 5
Fig. 5
Kinetics of SARS-CoV-2 anti-spike antibodies after second dose in the day 236 modified intention-to-treat population. A: all participants; B: seronegative participants; C: seropositive participants; D: seronegative participants with no infection between second dose and day 236 visit; E: seropositive participants with no infection between second dose and day 236 visit; F: seronegative participants with an infection between second dose and day 236 visit. BNT-30: BNT162b2 30 µg; BNT-10: BNT162b2 10 µg; NVX: NVX-CoV2373. Is it The boxplots display the distribution of SARS-CoV-2 anti-spike antibodies over time, outliers are not displayed. The lines display the change in the median over time. An infection could occur at any time between second dose and day 236 visit and was defined as either: a self-reported SARS-CoV-2 infection >14 days after second dose, a two-fold rise in anti-nucleocapsid IgG from second dose to 132 or from 132 to 236 days after second dose, a two-fold rise in anti-spike antibodies from 28 to 132 or from 132 to236 days after second dose, or anti-nucleocapsid IgG seroconversion from second dose to day 132 or from 132 to 236 days after second dose.
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