A single-blind, randomised, phase II multi-centre study to determine reactogenicity and immunogenicity of heterologous prime/boost COVID-19 vaccine schedules in adolescents (COMCOV-3)
Adolescents in the UK will receive either a full or half dose of a different COVID-19 vaccine as their second shot, to test whether this reduces the rare risk of heart inflammation while still protecting them from infection. This matters because the standard two-dose schedule of the Pfizer/BioNTech vaccine in young men has been linked to myocarditis or pericarditis at a rate of 67 per million second doses. The UK’s Joint Committee on Vaccination and Immunisation has already recommended a first dose for 16- and 17-year-olds, but decisions about the second dose remain open. The trial will compare four options: a full or half dose of Pfizer/BioNTech, a full dose of the Novavax vaccine, or a half dose of the Moderna vaccine, all given eight weeks after the first Pfizer/BioNTech shot. If successful, the research could give the NHS a safer, more flexible immunisation schedule for adolescents—potentially using lower doses or different vaccine types to maintain strong immune responses while cutting side effects. This would directly affect how vaccination programmes are rolled out for younger age groups, a population where infection rates have been high. The study builds on earlier COMCOV trials that showed mixed vaccine schedules work well in adults, but cannot use the Oxford/AstraZeneca vaccine in younger people due to blood-clot risks.
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The successful roll-out of COVID vaccines such as COVID-19 mRNA Vaccine BNT162b2 and the Oxford/AstraZeneca ChAdOx1 nCOV-19 vaccine has saved approximately 60 000 lives in the UK alone up to July 2021. While older age groups and others at most risk of disease have been prioritised in COVID-19 immunisation campaigns, recommendations for immunisation are now being extended to adolescents in many countries including the USA, Israel and Ireland, given the high rates of infection in this age group. The potential benefits (and costs) of extending the UK COVID-19 vaccine immunisation to adolescents in the UK is under active review by the JCVI, and on 4th August 2021 it was announced that a first dose of BNT162b2 was recommended for all 16 to 17 year-olds in the UK, with decisions about the timing and nature of the second dose to be decided. One concern regarding adolescent immunisation is a rare side effect of inflammation of the heart muscle (myocarditis) or lining of the heart (pericarditis), observed at a rate of 67 per million following the second dose of BNT162b2 administered to young men in the USA. The possibility of using alternatives to a full dose of BNT162b2 as the second dose of vaccine are therefore being considered. The use of heterologous prime/boost schedules of COVID-19 vaccines has been studied in COMCOV and COMCOV2, to facilitate flexible immunisation programmes. The COMCOV study showed a schedule with ChAdOx1 nCOV-19 as the first dose, followed by BNT162b2 as the second dose is highly immunogenic and is now deployed routinely in non-elderly populations in Canada and many northern European countries. However, restrictions on the use of ChAdOx1 nCOV-19 in younger adults due to concerns regarding vaccine induced thrombotic thrombocytopenia mean that this would not be a suitable option for a mixed schedule in adolescents. Another potential option for the second dose is NVXCoV2373, which is not yet licensed but under a rolling review from the MHRA. A phase 3 study of NVXCoV2373 showed it to be 89.7% effective at preventing SARS-CoV-2 infection in adults, without any significant safety concerns. A phase 3 study currently underway in the USA (NCT04611802) includes an adolescent cohort (N=3000), in which over 1400 participants have received NVXCoV2373 with no safety concerns raised (Novavax, personal communication). Furthermore, data generated in COMCOV2 has shown that a schedule employing BNT162b2 followed by NVXCoV2373 is no more reactogenic than a homologous BNT162b2/BNT162B2 schedule in participants aged over 50 years. An additional potential approach is use of a half dose vaccine, for either BNT162B2 or an alternative mRNA prodiced by Moderna, which would be expected to be less reactogenic than a full dose and allow greater numbers to be immunised with the available supply of vaccines. Accordingly, this study will determine the side effect profile, and the immune responses, following schedules using BNT162b2 as a first dose, and a second dose administered 8 weeks later of either BNT162b2 (full or half dose), NVXCoV2373 (full dose) or Moderna (half dose).
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