Immunogenicity and safety of DS-5670d, an mRNA-based COVID-19 vaccine targeting omicron XBB.1.5: Results from a phase 3, randomized, active-controlled study in adults and children aged >=12 years

BackgroundMany people worldwide have now acquired immune responses against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) following previous vaccination and/or infection. As a result, national vaccination programs are now implementing a simplified schedule of single-dose administration and seasonal boosters. In this phase 3 non-inferiority study, we assessed the immunogenicity and safety of a single dose of the lipid nanoparticle-messenger ribonucleic acid vaccine DS-5670d, a monovalent composition for the 2023/24 season, containing an omicron XBB.1.5-derived antigen. Methods and FindingsAdults and children aged [≥]12 years were stratified according to their history of both prior SARS-CoV-2 infection plus prior coronavirus disease 2019 (COVID-19) 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. In the combined ABC subpopulations (DS-5670d, n = 362 vs BNT162b2, n = 363), the adjusted geometric mean titer ratio of blood neutralizing activity against SARS-CoV-2 (omicron XBB.1.5) was 1.218 (95% confidence interval [CI], 1.059, 1.401) and the seroresponse rates were 87.3% (DS-5670d) and 82.9% (BNT162b2) with an adjusted difference of 4.5% (95% CI, -0.70, 9.71). Both results exceeded prespecified 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 differences in immunogenicity 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. ConclusionsA 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 RegistrationJapan Registry of Clinical Trials (jRCT2031230424) Author summaryWhy was this study done? O_LIThe global emergency response against the coronavirus disease 2019 (COVID-19) pandemic is now being superseded by annual immunization using an updated vaccine composition to reduce the disease burden associated with newly emerging variants. C_LIO_LIWe conducted a comparative study of two newly authorized updated vaccine compositions containing the antigen derived from omicron XBB.1.5, which was recommended for the 2023/24 season. C_LIO_LIWe intended to assess the immunogenicity and safety of a single dose of DS-5670d compared with BNT162b2 in Japanese adults and children aged [≥]12 years. C_LI What did the researchers do and find? O_LIIn persons who had received prior vaccination, or who had previously had COVID-19, or both, DS-5670d was non-inferior to BNT162b2 in terms of blood neutralizing activity and seroresponse rates, and immune responses were not influenced by age or sex. C_LIO_LIAmong unvaccinated persons, those who had been exposed to SARS-CoV-2 by prior infection achieved an adequate immune response following a single dose of DS-5670d; however, the group who had had no previous exposure at all was too small to properly evaluate. C_LIO_LIThere were no major differences in the frequency or severity of adverse events between the study vaccination groups, and there were no DS-5670d-related serious adverse events. C_LI What do these findings mean? O_LIDS-5670d was immunogenically non-inferior to BNT162b2, which has already been widely administered in Japan. C_LIO_LIThere were no new critical safety concerns associated with DS-5670d, suggesting that it could be a useful SARS-CoV-2 vaccine option. C_LIO_LITaken together, the results from this study of DS-5670d and those from previous studies evaluating other compositions of DS-5670, i.e., those containing antigens from different strains of SARS-CoV-2, provide corroborating evidence that the DS-5670 vaccine platform can be applied to produce effective and safe seasonal vaccines against future emerging strains. C_LI