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

BackgroundLicensed 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(R). MethodsWe 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(R)) 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. FindingsBetween 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{middle dot}43 (95% CI: 1{middle dot}26-1{middle dot}63), with SRR of 65{middle dot}2% (60{middle dot}2-69{middle dot}9) and 51{middle dot}6% (46{middle dot}4-56{middle dot}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{middle dot}30 (95% CI: 1{middle dot}07-1{middle dot}58), with SRR of 69{middle dot}9% (65{middle dot}0-74{middle dot}4) and 58{middle dot}0% (52{middle dot}8-63{middle dot}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{middle dot}8% and 96{middle dot}8% of ARCT-154 and Comirnaty vaccinees reported local reactions and 65{middle dot}7% and 62{middle dot}5% had solicited systemic adverse events. Events were mainly mild in severity, occurring and resolving within 3-4 days of vaccination. InterpretationImmune 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. FundingThe 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 identifierThe study was registered on the Japan Registry for Clinical Trials (jRCT 2071220080).