COVID-19 is no longer a global pandemic but remains a public health problem and new vaccine formulations are still being developed to target newly emerging variants.1 Current guidelines recommend annu...

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). ### Competing Interest Statement YO, MK, YI, IO, TM and YY are full-time employees and TK is a board member of the study sponsor. YK received fees from Meiji Seika Pharma Co., Ltd., for medical consultation during this study. BFG and YZ are full-time employees of Arcturus Therapeutics, Inc., who developed the vaccine, JLW is an independent consultant working for Arcturus Therapeutics, Inc. Other authors have no conflicts to declare. ### Clinical Trial jRCT 2071220080 ### Funding Statement 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 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Hakata Clinic Institutional Review Board of Hakata CL gave ethical approval for this work Institutional review board of Shinanozaka clinic of Shinanozaka CL gave ethical approval for this work P-One Clinic, Keikokai Medical Corp Institutional Review Board of Higashi-Shinjuku CL gave ethical approval for this work P-One Clinic, Keikokai Medical Corp Institutional Review Board of P-One CL gave ethical approval for this work Medical Corporation Heishinkai OPHAC Hospital Institutional Review Board of Osaka Pharmacology Clinical Research Hospital gave ethical approval for this work Medical Corporation Heishinkai OPHAC Hospital Institutional Review Board of ToCROM gave ethical approval for this work Kobori Central Clinical Research Ethics Committee of Shin-Sapporo HP gave ethical approval for this work Kobori Central Clinical Research Ethics Committee of LUNA gave ethical approval for this work Kobori Central Clinical Research Ethics Committee of Medimesse Sakurajyuji gave ethical approval for this work Fukushima Medical University Hospital Institutional Review Board of Fukushima Medical HP gave ethical approval for this work Juntendo University Hospital Institutional Review Board of Juntendo HP gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript

Data from this large trial suggest that ARCT-154 is safe and well tolerated.

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