Immunogenicity and safety of DS-5670d, an omicron XBB.1.5-targeting COVID-19 mRNA vaccine: A phase 3, randomized, active-controlled study.

BACKGROUND: DS-5670d is a monovalent lipid nanoparticle-messenger ribonucleic acid vaccine against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), containing an omicron XBB.1.5-derived antigen. This phase 3 non-inferiority study assessed the immunogenicity and safety of a single dose of DS-5670d according to participant immune status. METHODS AND FINDINGS: Participants aged ≥12 years were stratified according to their history of both prior SARS-CoV-2 infection plus prior coronavirus disease 2019 vaccination (subpopulation A), prior infection only (subpopulation B), prior vaccination only (subpopulation C), or no history of either infection or vaccination (subpopulation D), and randomly assigned (1:1) to receive DS-5670d or monovalent BNT162b2 omicron XBB.1.5. The primary efficacy endpoint was geometric mean titer (GMT) of blood neutralizing activity against SARS-CoV-2 (omicron XBB.1.5) and seroresponse rate at day 29 after study vaccine administration in the combined ABC subpopulations (DS-5670d, n = 362 versus BNT162b2, n = 363). Prespecified non-inferiority margins required that the lower limit of the 95% confidence interval (CI) exceeded 0.67 for the GMT ratio and -10% for the difference in seroresponse. The adjusted GMT ratio was 1.218 (95% confidence interval [CI], 1.059, 1.401). Seroresponse rates were 87.3% (DS-5670d) and 82.9% (BNT162b2); adjusted difference 4.5% (95% CI, -0.70, 9.71). Both results exceeded the non-inferiority margins and the study met the primary endpoint. Immunogenicity data in the overall ABCD population also met non-inferiority criteria. There were no apparent immunogenicity differences according to age or sex, and analyses suggested that even unvaccinated persons achieved an adequate immune response following a single dose of DS-5670d. There were no major differences in the incidence or severity of adverse events between the study vaccination groups. The main study limitation was the short duration of follow-up. CONCLUSIONS: A single dose of DS-5670d was immunogenically non-inferior to BNT162b2 and acceptably safe in persons with or without a history of prior infection and/or vaccination. Trial registration Japan Registry of Clinical Trials (jRCT2031230424).