Evaluation of the Safety and Immunogenicity of Different COVID-19 Vaccine Combinations in Healthy Individuals: Study Protocol for a Randomized, Subject-blinded, Controlled Phase 3 Trial [PRIBIVAC]
Authors: Poh Xuan Ying , Lee Russel I , Lim Clarissa , Teo Jefanie , Rao Suma , Chia Po Ying , Ong Sean WX , Lee Tau Hong , Lin Ray , Ng Lisa FP , Chee Ren Ee , Lin Raymond TP , Wang Linfa , Renia Laurent , Lye David , Young Barnaby E 
Published: February 2022

Trials guidance: The Abstract should not exceed 350 words. Please minimize the use of abbreviations and do not cite references in the abstract. The abstract must include the following separate sections:• Background: Over 2021, COVID-19 vaccination programs worldwide focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore two mRNA vaccines (BNT162b2 and mRNA-1273) and the inactivated vaccine CoronaVac are currently authorized under the National Vaccination Programme for use as the primary vaccination series. More than 90% of the Singapore population has received at least one dose of a COVID-19 vaccine as of December 2021. With the demonstration that vaccine effectiveness wanes in the months after vaccination, and the emergence of Omicron which evades host immunity from prior infection and/or vaccination, attention in many countries has shifted to how best to maintain immunity through booster vaccinations. • Methods: The objectives of this phase 3, randomized, subject-blinded, controlled clinical trial are to assess the safety and immunogenicity of heterologous boost COVID-19 vaccine regimens (intervention groups 1-4) compared with a homologous boost regimen (control arm) in up to 600 adult volunteers. As non-mRNA vaccine candidates may enter the study at different time points depending on vaccine availability and local regulatory approval, participants will be randomized at equal probability to the available intervention arms at the time of randomization. Eligible participants will have received two doses of a homologous mRNA vaccine series with BNT162b2 or mRNA-1273 at least six months prior to enrolment. Participants will be excluded if they have a history of confirmed SARS or SARS-CoV-2 infection, are immunocompromised or pregnant. Participants will be monitored for adverse events and serious adverse events by physical examinations, laboratory tests and self-reporting. Blood samples will be collected at serial time points [Pre-vaccination/screening (Day -14 to Day 0), Day 7, Day 28, Day 180, Day 360 post-vaccination] for assessment of antibody and cellular immune parameters. Primary endpoint is the level of anti-SARS-CoV-2 spike immunoglobulins at Day 28 post-booster, and will be measured against wildtype SARS-CoV-2 and variants of concern. Comprehensive immune profiling of the humoral and cellular immune response to vaccination will be performed. • Discussion: This study will provide necessary data to understand the quantity, quality and persistence of the immune response to homologous and heterologous third booster dose of COVID-19 vaccines. This an important step in developing COVID-19 vaccination programs beyond the primary series. Trial registration: ClinicalTrials.gov NCT05142319, registered on 2 Dec 2021.