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Objectives: We conducted a randomised controlled trial (RCT) to compare immunogenicity, reactogenicity and safety one month after a fourth COVID-19 mRNA or protein vaccine dose., Methods: This RCT recruited healthy adults in Melbourne, Australia, who had previously received three COVID-19 vaccine doses at least six months prior and had no SARS-CoV-2 infection in the last three months. The participants were randomised (1:1) to receive the bivalent mRNA vaccine (mRNA-1273.214/mRNA-1273.222, hereafter Moderna) or protein vaccine (NVX-CoV-2373, hereafter Novavax) as a fourth dose. A self-selected control group who elected not to receive an additional dose were also included. The co-primary endpoints compared immunogenicity at 28 days post-vaccination measured as binding antibodies (IgG against Ancestral and Omicron subvariants; BA.1, BA.4/5 and JN.1) between the two vaccine groups, and reactogenicity within one-week post-vaccination., Clinicaltrials: gov Identifier: NCT05543356., Results: Between Feb 28 and Oct 4, 2023, 496 participants were enrolled into the study. Participants were randomised into either the bivalent mRNA Moderna (n=177) or protein Novavax (n=176) vaccine groups, with n=143 allocated to the control group. The geometric mean ratio (GMR) of anti-Spike binding IgG antibody levels were higher for the Moderna vaccine compared to the Novavax vaccine at 28 days post-vaccination for all variants tested, including Ancestral (GMR: 2.11, 95% CI: 1.88 - 2.37), BA.1 (GMR: 2.32, 95% CI 2.04 - 2.63), BA.4/5 (GMR: 2.32, 95% CI: 2.04 - 2.65), and JN.1 (GMR: 2.40, 95% CI: 2.14 - 2.70). The frequency of any local and systemic reactions (grades 1-4) was higher for the Moderna vaccine (159/177; 89.8%) compared to the Novavax vaccine (130/176; 73.9%). Serious reactions (grade 3-4) between the groups were similar (11/177; 6.2%, versus 9/176; 5.1%, respectively)., Conclusion: At day 28 post-vaccination, higher immunogenicity was observed following Moderna vaccination compared to Novavax vaccination when given as a fourth dose in healthy adults for Ancestral and Omicron subvariants, including JN.1. However, local and systemic reactogenicity was higher in the Moderna vaccine group compared with the Novavax vaccine group. These results may have important implications for ongoing booster strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)