Award Title: 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)
Funder: Department of Health and Social Care

Abstract: 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).

Lay Abstract: 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. Both of these vaccines are administered as a two-dose regimen, as is the adjuvanted protein COVID-19 vaccine from Novavax, NVXCoV2373, which is under rolling review of the MHRA at the time of writing.   The use of heterologous prime/boost (mix and match) schedules of COVID-19 vaccines has already been studied in COMCOV and COMCOV2, and a schedule with ChAdOx1 nCOV-19 as the first dose, followed by BNT162b2 as the second dose has been shown to be highly immunogenic and is now deployed routinely in non-elderly populations in Canada and many northern European countries.    Use of heterologous prime/boost schedules could also potentially be of benefit in an adolescent immunisation campaign. 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) that has been observed after the second dose of BNT162b2, especially in young men. Mixed schedules with alternative vaccines used for the second dose, or using half doses of COVID-19 vaccines, could be an alternative that allows protection against COVID-19 while avoiding a second full dose of BNT162b2, and could also help deploy existing stocks of vaccine as effectively as possible.   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) or NVXCoV2373 (full dose) or an alternative mRNA produced by Moderna (half dose).

Research Activity Codes: 3.4 VACCINES
Health Categories: INFECTION