Title: Covid-19 heterologous prime/boost vaccine study
Funder: Department of Health and Social Care

Abstract: The COVID-19 pandemic has stimulated the development of a large number of potential COVID-19 vaccines (1, 2) and it is likely that at least two of these will be licensed and available during 2020/2021. Most vaccines in development are expected to be licensed as a two dose, homologous prime/boost schedule. Given the anticipated programmatic challenges of immunising large proportions of the population, there would be advantages to having flexible immunisation programmes where the second dose is not necessarily the same as the first dose, i.e. a permissive approach to using heterologous prime/boost schedules. Accordingly this study will determine the reactogenicity and immunogenicity of heterologous prime/boost schedules for candidate COVID-19 vaccines that are potentially to be deployed in the UK. The vaccines to be studied in this protocol will primarily be determined by those made available to the Department of Health and Social Care (DHSC) for population use. This will be an adaptive platform study, so as further vaccines get their licensure in the UK, they can be added to the trial, increasing the number of prime-boost vaccine permutations. The population to be studied will be adults over the age of 50 years; including those with comorbidities classified as mild/moderate/well controlled, as immunisation will most likely be prioritised for an older adult population with co-morbidities.Recruitment of individuals identifying as being of black and minority ethnicity will be prioritised. The sample size will be 460 participants, consisting of 4 group of 115. Vaccines will be given at 28 day intervals. All participants will have bloods tests at day 0, 28, 56, 112 and 365, and participants in the immunology sub-group (N=100, 25 per group) will have additional blood samples taken at day 7, 14, 35 and 42. The primary endpoint will be anti-SARS-CoV2 spike IgG at day 56 (1 month after the booster dose). This is a non-inferiority study, with the non-inferiority margin being a 0.63 fold-difference between the anti-SARS-CoV2 spike IgG geometric mean concentration in the heterologous boost arm and that in the homologous boost arm. The standard deviation of GMC on log scale (base 10) is 0.4 based on the current available data (1). Allowing for 25% of participants withdrawing or being sero-positive at baseline the sample size of 460 achieves 90% of power at one-sided 1% significance level.

Lay abstract: Multiple vaccines against COVID-19 disease are currently being tested. Some of them are likely to become available for use during 2020/2021. Most of them are expected to be licensed as a two-dose regimen, using the same vaccine for both the initial (prime) and subsequent (boost) dose. There are likely to be significant logistical challenges immunising large portions of the population. There would be significant advantages to having flexible immunisation programmes whereby the second vaccine dose is not necessarily the same as the first dose. Accordingly, this study will determine the safety as well as the immune responses to a variety of combinations of prime/boost schedules for candidate COVID-19 vaccines that are potentially to be deployed in the UK, to check whether or not they are suitable for use. The vaccines to be studied in this protocol will primarily be determined by those made available to the Department of Health and Social Care (DHSC) for population use. The study will start immunising participants when two licensed vaccines are available, and at this stage we will be ernolling 460 participants. There is the potential to increase the number of vaccines being studies to 3 or 4 vaccines, which would increase the number of possible combinations to 9 and 16 groups respectively.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION