Real-World Effectiveness and Noninferiority Evaluation and Comparison of Messenger RNA–Based and Protein-Based COVID-19 Vaccines: Protocol for the BEEHIVE Randomized Study With a Hybrid Effectiveness Design

TL;DR

This study aims to compare the real-world effectiveness of two updated COVID-19 vaccines in preventing symptomatic infections.

Contribution

The study introduces a hybrid design to evaluate and compare the effectiveness of mRNA and protein-based vaccines in a real-world setting.

Findings

The study will assess the effectiveness of the 2023-2024 formulations of Pfizer–BioNTech and Novavax vaccines.

It will examine how prior vaccination history affects the effectiveness of updated vaccines.

The study will identify factors influencing asymptomatic infection and post-COVID conditions.

Abstract

Surveillance of COVID-19 vaccine effectiveness (VE) was extensive upon vaccine introduction; however, it declined after the withdrawal of pandemic status in May 2023. Continued monitoring of updated vaccine formulations is needed to ensure the maintenance of VE in the face of evolving viral strains.

The Booster Epidemiological Evaluation of Health, Illness and Vaccine Efficacy (BEEHIVE) study (NCT06065176), a randomized trial with a hybrid design, was developed to assess the real-world VE of the 2023-2024 Pfizer–BioNTech and Novavax COVID-19 vaccine formulations targeting the XBB.1.5 SARS-CoV-2 variant.

This study was designed to enroll approximately 1500 participants aged ≥18 years from the Salt Lake City, Utah, area who had previously received ≥2 doses of an authorized messenger RNA (mRNA)–based COVID-19 vaccine but had not received a dose of the 2023-2024 formulation. The study used a randomized, hybrid design comprising 2 blinded groups assigned to receive the 2023-2024 formula of either the Novavax COVID-19 vaccine or the Pfizer–BioNTech COVID-19 vaccine and a nonrandomized, observational control 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 (defined as prevention of symptomatic SARS-CoV-2 infection) between study-vaccinated participants and the control 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 assessing how the number of previous COVID-19 vaccinations impacted VE of the 2023-2024 COVID-19 vaccines; identifying predictors and associated factors for asymptomatic versus symptomatic infection and/or prolonged or severe illness; examining factors associated with post–COVID-19 conditions; and evaluating participants’ knowledge, attitudes, and practices related to COVID-19 vaccination. Participant engagement was maintained via online and text-based reminders and surveys, as well as researcher follow-up.

Participants were recruited from November 2023 through March 2024, with 452 and 457 participants randomized to the Novavax and Pfizer–BioNTech vaccine groups, respectively, and 279 participants enrolled in the control group. SARS-CoV-2 variants from the XBB, JN.1, KP.2, and KP.3 lineages were in circulation in the United States and the Utah region during data collection. The study ended on September 9, 2024, with results expected to be published in 2026.

Data from this study will provide valuable real-world VE data for a dose of the Novavax COVID-19 vaccine or the Pfizer–BioNTech COVID-19 vaccine after an mRNA-based COVID-19 primary series.

ClinicalTrials.gov NCT06065176; https://www.clinicaltrials.gov/study/NCT06065176

RR1-10.2196/80858

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