DS-5670d is a monovalent mRNA vaccine against SARS-CoV-2 with an antigen derived from the XBB.1.5 omicron. This randomized phase 3 study compared a single dose of DS-5670d (60 µg mRNA) with BNT162b2 (30 µg mRNA) in participants 12 years of age and older, stratified by prior infection and/or vaccination into subpopulations A–D. Primary endpoints were geometric mean titer (GMT) of neutralizing activity and serum response at day 29 in combined ABC subpopulations (DS-5670d n=362 vs. BNT162b2 n=363). The adjusted GMT ratio was 1.218 (95% CI: 1.059–1.401) and the difference in serum response was 4.5% (95% CI: −0.70 to 9.71), meeting non-inferiority criteria. Immunogenicity was also comparable in the entire ABCD population, without significant differences according to age, gender or vaccination status, including unvaccinated persons. Adverse events occurred similarly in both groups with no difference in severity. The main limitation was the short follow-up period. The DS-5670d vaccine was immunogenically non-inferior to BNT162b2 and safe in subjects with or without prior immunity.