Safety and immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine

Abstract Combination of waning immunity and lower effectiveness of approved COVID-19 vaccines against SARS-CoV-2 variants necessitates new vaccines. We evaluated the safety, immunogenicity and efficacy of a novel self-amplifying mRNA COVID-19 vaccine against the D614G variant, ARCT-154, in an integrated phase 1/2/3a/3b, randomized, observer-blind trial in Vietnamese adults. Two doses of ARCT-154 or placebo 28 days apart were well tolerated with mild to moderate transient adverse events. Four weeks after the second dose 94.1% (95% CI: 92.1–95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline titers of 14.5 (95% CI: 13.6–15.5). Most cases of confirmed COVID-19 eligible for efficacy analysis were due to the Delta variant. Absolute efficacy of ARCT-154 was 56.6% (95% CI: 48.7–63.3) against any COVID-19, and 95.3% (80.5–98.9) against severe COVID-19. We show ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease and COVID-associated death.