Booster dose of self-amplifying SARS-CoV-2 RNA vaccine vs. mRNA vaccine: a phase 3 comparison of ARCT-154 with Comirnaty ®

SUMMARY 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. Funding The study was funded by the Japanese Ministry of Health, Labour, and Welfare following a public invitation to bid for an urgent improvement project for vaccine manufacturing systems, fourth invitation, Grant number: 1212-3. Clinical Trials registration and identifier The study was registered on the Japan Registry for Clinical Trials (jRCT 2071220080).