BACKGROUNDPublic health concerns due to ongoing emergence of SARS-CoV-2 variants necessitates further development of improved COVID-19 vaccines. One major innovation are self-amplifying mRNA vaccines, such as ARCT-154 (Arcturus Therapeutics, Inc.), which induces superior immunogenicity compared with conventional mRNA in terms of magnitude, breadth and persistence of neutralizing antibodies.RESEARCH DESIGN AND METHODSIn a pivotal placebo-controlled trial in Vietnam combining phase 1, 2 and 3 cohorts, over 17,000 adults received at least one dose of ARCT-154. Here, we report the safety and reactogenicity observations made.RESULTSARCT-154 elicited more local reactions than the saline placebo, most reports of injection site pain were mild/moderate with only a few reporting severe pain. Most frequent solicited adverse events were fatigue, myalgia, headache, arthralgia and chills. Solicited local and systemic reactogenicity resolved within 7 days. Long-term follow-up has not revealed any safety concerns, with no reports of myocarditis or pericarditis. Acceptable tolerability of ARCT-154 was also observed in older participants and in those liable to severe consequences of COVID-19 due to underlying medical conditions. No serious consequences occurred in several pregnancies reported after vaccination, with normal outcomes when followed to term.CONCLUSIONSData from this large trial suggest that ARCT-154 is safe and well tolerated.