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

## TL;DR

A new mRNA vaccine, DS-5670d, was found to be as effective and safe as BNT162b2 in boosting immunity against the omicron XBB.1.5 variant of SARS-CoV-2 in people with or without prior infection or vaccination.

## Contribution

This study provides evidence that DS-5670d is non-inferior to BNT162b2 in terms of immunogenicity and safety in a diverse population with varying prior exposure to SARS-CoV-2.

## Key findings

- DS-5670d achieved a GMT ratio of 1.218, exceeding the non-inferiority margin of 0.67 compared to BNT162b2.
- Seroresponse rates were 87.3% for DS-5670d and 82.9% for BNT162b2, with a 4.5% adjusted difference.
- Unvaccinated individuals with prior SARS-CoV-2 infection achieved adequate immune responses after a single dose of DS-5670d.

## Abstract

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.

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.

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)

The initial 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.

Since many people have acquired basic immunity to SARS-CoV-2 and the vaccination program has been shifted to a seasonal single-dose regimen, we 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.

We 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.

In 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.

Among 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.

There 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.

DS-5670d was immunogenically non-inferior to BNT162b2, which has already been widely administered in Japan, and there were no new critical safety concerns associated with DS-5670d, suggesting that it could be a useful SARS-CoV-2 vaccine option.

Taken 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.

The main limitation of our study was that the length was fairly short, and we cannot yet draw any conclusions about the long-term protection provided by DS-5670d, or the long-term safety profile.

In this phase 3, randomized, active-controlled study, Fumihiko Takeshita and colleagues assess the non-inferiority of COVID-19 vaccine DS-5670d compared to BNT162b2, as well as its safety profile.