Real-world effectiveness and non-inferiority evaluation and comparison of mRNA- and protein-based COVID-19 vaccines: a randomized study protocol (BEEHIVE)

BackgroundSurveillance of COVID-19 vaccine effectiveness was extensive upon vaccine introduction; however, it slowed once pandemic status was withdrawn in May 2023. Continued monitoring of updated vaccine formulations is needed to ensure maintenance of vaccine effectiveness (VE) in the face of evolving viral strains. ObjectiveThe randomized, controlled BEEHIVE study (NCT06065176) was developed to assess real-world VE of the 2023-2024 Pfizer-BioNTech and Novavax COVID-19 vaccine formulations, which are directed to the XBB.1.5 SARS-CoV-2 variant. MethodsThis study was designed to enroll [~]1500 participants aged [≥]18 years from the Salt Lake City, Utah area who had previously received [≥]2 doses of an authorized mRNA-based COVID-19 vaccine, but not a dose of the 2023-2024 formulation. Study groups included two blinded groups randomized to receive the 2023-2024 formula of either the Novavax COVID-19 Vaccine or Pfizer-BioNTech COVID-19 Vaccine and a non-randomized comparator group of volunteers who chose not to receive a 2023-2024 vaccine dose during the study. Follow-up lasted 24 weeks and included symptom surveys and self-administered COVID-19 antigen testing, both occurring weekly. The primary aim was to compare VE (preventing symptomatic SARS-CoV-2 infection) between study-vaccinated participants and the comparator group. The secondary aim was to determine the relative VE of the Pfizer-BioNTech mRNA and Novavax 2023-2024 COVID-19 vaccines. Secondary objectives included assessment of how the number of prior COVID-19 vaccinations impacted VE of the 2023-2024 COVID-19 vaccines, predictors and associated factors for asymptomatic versus symptomatic infection and/or prolonged or severe illness, factors associated with post-COVID conditions (PCC), and knowledge, attitudes, and practices of participants related to COVID-19 vaccination. Participant engagement was maintained via online and text-based reminders and surveys, and researcher follow-up. ResultsParticipants were recruited from November 2023 through March 2024 with 452 and 457 randomized to the Novavax and Pfizer-BioNTech vaccine groups, respectively, and 279 enrolled into the comparator group. SARS-CoV-2 variants from the XBB, JN.1, KP.2, and KP.3 lineages were in circulation in the United States and Utah region during data collection. The study ended on September 30, 2024 with results expected to be published in 2025. ConclusionsData from the BEEHIVE study will provide valuable real-world VE data for a heterologous dose of the Novavax COVID-19 Vaccine and homologous or heterologous dose of the Pfizer-BioNTech COVID-19 Vaccine after an mRNA-based COVID-19 primary series. Trial RegistrationClinicaltrials.gov NCT06065176