Publication date: Jul 12, 2023
Background Licensed mRNA vaccines demonstrated initial effectiveness against COVID-19 but require booster doses to broaden the anti-SARS-CoV-2 response. There is an unmet need for novel highly immunogenic and broadly protective vaccines. We compared immunogenicity and tolerability of ARCT-154, a novel self-amplifying mRNA vaccine with the mRNA vaccine, Comirnaty. Methods We compared immune responses to ARCT-154 and Comirnaty booster doses in healthy 18-77-year-old Japanese adults initially immunised with two doses of mRNA COVID-19 vaccine (Comirnaty or Spikevax) then a third dose of Comirnaty at least 3 months previously. Neutralising antibodies were measured before and 28 days after booster vaccination. The primary objective was to demonstrate non-inferiority of the immune response against Wuhan-Hu-1 SARS-CoV-2 virus as geometric mean titre (GMT) ratios and seroresponse rates (SRR) of neutralising antibodies; key secondary endpoints included the immune response against the Omicron BA.4/5 variant and vaccine tolerability assessed using participant-completed electronic diaries. Findings Between December 13, 2022 and February 25, 2023 we enrolled 828 participants randomised 1:1 to receive ARCT-154 (n = 420) or Comirnaty (n = 408) booster doses. Four weeks after boosting, ARCT-154 induced higher Wuhan-Hu-1 neutralising antibodies GMTs than Comirnaty (5641 [95% CI: 4321-7363] and 3934 [2993-5169], respectively), a GMT ratio of 1.43 (95% CI: 1.26-1.63), with SRR of 65.2% (60.2-69.9) and 51.6% (46.4-56.8) meeting the non-inferiority criteria. Respective anti-Omicron BA.4/5 GMTs were 2551 (1687-3859) and 1958 (1281-2993), a GMT ratio of 1.30 (95% CI: 1.07-1.58), with SRR of 69.9% (65.0-74.4) and 58.0% (52.8-63.1), meeting the superiority criteria for ARCT-154 over Comirnaty. Booster doses of either ARCT-154 or Comirnaty were equally well-tolerated with no causally-associated severe or serious adverse events; 94.8% and 96.8% of ARCT-154 and Comirnaty vaccinees reported local reactions and 65.7% and 62.5% had solicited systemic adverse events. Events were mainly mild in severity, occurring and resolving within 3-4 days of vaccination. Interpretation Immune responses four weeks after an ARCT-154 booster dose in mRNA-immunised adults were higher than after a Comirnaty booster, meeting non-inferiority criteria against the prototype Wuhan-Hu-1 virus, and superiority criteria against the Omicron BA.4/5 variant.