Immunogenicity of a booster dose of a bivalent (Asp614Gly and omicron BA.4/5 variant) self-amplifying mRNA SARS-CoV-2 booster vaccine versus the BNT162b2 omicron BA.4/5 mRNA vaccine: a randomised phase 3 trial.

Background: We previously showed that ARCT-154, a self-amplifying mRNA COVID-19 vaccine, had improved immunogenicity and antibody persistence compared with conventional mRNA or adenovirus vector vaccines. In this study, we compared ARCT-2301, a bivalent self-amplifying mRNA vaccine (Asp614Gly and omicron BA.4/5 variant), with the bivalent Comirnaty omicron BA.4-5 vaccine, to determine whether this improved response persisted in bivalent formulations against different SARS-CoV-2 variants.

Methods: This randomised, multicentre, phase 3, observer-masked, active-controlled comparative study was done at nine hospitals in Japan. Eligible participants were healthy Japanese adults, aged at least 18 years, who had previously received a full immunisation series of three to five doses of mRNA COVID-19 vaccines (Comirnaty or Spikevax [Moderna]), with the last dose received at least 3 months before screening for this trial. Participants were randomly assigned (1:1) to either ARCT-2301 or Comirnaty BA.4-5 mRNA vaccine using interactive computer-generated randomisation with a block size of four. Randomisation was stratified by gender (men vs women), age group (<65 years vs ≥65 years), type of vaccine used for last vaccination (bivalent omicron BA.1 vs bivalent omicron BA.4/5), and time since last COVID-19 vaccination (<5 months vs ≥5 months). ARCT-2301 was supplied in vials containing 100 μg lyophilised mRNA, 50 μg mRNA each coding for the full-length spike proteins of the ancestral Asp614Gly SARS-CoV-2 strain and omicron BA.4/5 variant. Immediately before use, each vial was reconstituted with 10 mL saline. The comparator original omicron BA.4/5 mRNA vaccine (Comirnaty BA.4-5) was supplied in ready-to-use vials containing a single dose of 30 μg mRNA in 0·3 mL volume. Both vaccines were administered by intramuscular injection in the deltoid of the non-dominant arm. The primary outcome of the study was to show non-inferiority of immunogenicity of ARCT-2301 versus Comirnaty BA.4-5 at day 29 as neutralising antibody geometric mean titres (GMT) and seroresponse rates against omicron BA.4/5. Primary analyses were done in a per-protocol manner. The trial is registered with the Japan Registry for Clinical Trials, jRCT2031230340.

Findings: Between Sept 29 and Nov 18, 2023, we enrolled 930 participants (451 men and 479 women) to receive a booster dose of ARCT-2301 (n=465) or Comirnaty BA.4-5 (n=465). The primary immunogenicity outcome to show that the antibody response at day 29 against omicron BA.4/5 elicited by ARCT-2301 was non-inferior to that elicited with Comirnaty BA.4-5 was achieved, both by GMT ratio (1·49, 95% CI 1·26-1·76) and difference in seroresponse rate (7·2%, 95% CI 0·6-13·7). Furthermore, the differences in antibody response between the groups showed superiority for ARCT-2301 against Wuhan-Hu-1 using both criteria, with a GMT ratio of 1·45 (95% CI 1·28-1·63) and a difference in seroresponse rate of 12·5% (95% CI 5·9-19·0), and omicron XBB.1.5, with a GMT ratio of 1·63 (95% CI 1·36-1·94) and a seroresponse rate difference of 16·7% (95% CI 10·1-23·2). Both vaccines were well-tolerated with mainly mild, transient solicited adverse events and no causally related severe or serious adverse events.

Interpretation: Boosting mRNA-immunised adults with ARCT-2301 induced superior immunogenicity compared with Comirnaty BA.4-5 against both Wuhan-Hu-1 and omicron BA.4/5 variant COVID-19, and elicited a higher response against omicron XBB.1.5. Both vaccines had similar tolerability profiles. Self-amplifying mRNA vaccines could provide a substantial contribution to pandemic preparedness and response, inducing robust immune responses with a lower dose of mRNA to allow wider and more equitable distribution.

Funding: Japanese Ministry of Health, Labour, and Welfare and Meiji Seika Pharma.