Background <p>Although the emergency phase of the COVID-19 pandemic is over, attention has remained focused towards ongoing vaccination programs and the protection of high risk populations. The DS-5670 lipid nanoparticle-mRNA vaccine platform contains SARS-CoV-2 spike protein receptor-binding domain (RBD)-derived antigen(s). We conducted studies to provide supporting evidence for DS-5670 as a source of seasonal boosters using RBD antigens from variant strains and different valency compositions.</p> Methods <p>Randomized, active-comparator, non-inferiority studies evaluated monovalent DS-5670a (original strain RBD; Study 146 in 4518 adults ≥18 years) or bivalent DS-5670a/b (original and omicron BA.4-5 RBDs; Study 212 in 701 participants ≥12 years) as boosters. Primary efficacy endpoints were the GMFR in serum neutralization titers against SARS-CoV-2 (original strain) at 4 weeks (day 29) after study drug administration (Study 146), and the GMT and seroresponse rate of anti-SARS-CoV-2 (omicron BA.5 strain) serum neutralization titers on day 29 (Study 212).</p> Results <p>We show that both studies exceed non-inferiority margins. In Study 146, day 29 adjusted geometric mean fold-rise ratios for DS-5670a are 1.464 (97.5% confidence intervals 1.112, 1.927) vs BNT162b2 and 1.772 (1.335, 2.353) vs mRNA-1273. In Study 212, day 29 adjusted geometric mean titer ratio (DS-5670a/b vs bivalent BNT162b2) is 1.712 (95% confidence intervals, 1.509, 1.944); the between-group difference in seroresponse is 21.4% (13.8, 28.6). Both DS-5670 compositions are effective against symptomatic COVID-19, with broad neutralization activity across omicron sub-lineages. No serious adverse events are associated with DS-5670 in either study.</p> Conclusions <p>This platform can be utilized to produce new vaccines against future SARS-CoV-2 variants.</p>