Immunogenicity of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, in different booster settings

A self-amplifying mRNA (sa-mRNA) vaccine against COVID-19 (ARCT-154) was evaluated for immunogenicity in three clinical studies with four booster scenarios: first homologous booster, first heterologous booster, second heterologous booster, and a two-dose series in previously infected participants. Neutralizing antibody responses were measured four weeks after vaccination using pseudovirus microneutralization assays against the Wuhan-Hu-1 and SARS-CoV-2 variants. ARCT-154, administered as a homologous booster, resulted in a geometric mean fold-rise (GMFR) of 6.5 (95 % confidence interval, 5.6–7.5) and seroconversion rate (SCR) of 77 % (69.8–83.2), compared with 1.4 (0.9–2.2) and 17.3 % (8.2–30.3) with placebo. A first heterologous booster of ARCT-154 achieved a GMFR of 36.7 (17.4–77.5) and SCR of 91.7 % (61.5–99.8) against Wuhan-Hu-1, with GMFRs ranging from 20.0 to 29.4 for Beta, Delta, and Omicron BA.1 variants. When comparing ARCT-154 and BNT162b2 mRNA vaccine as a second booster dose, GMFRs against Wuhan-Hu-1 were 6.8 (6.0–7.6) and 4.4 (4.0–4.8), and SCRs were 66.1 % (61.1–70.9) and 51.2 % (46.0–56.4), respectively. Similar inter-group differences were shown for the Omicron BA.4/5 and persisted for ≥12 months. Following natural infection, one dose and two doses of ARCT-154 resulted in GMFR of 4.4 (2.2–7.0) and 6.2 (3.8–10.0), and SCR of 58.8 % (32.9–81.6) and 73.3 % (44.9–92.2) against Wuhan-Hu-1, respectively. Neutralizing antibodies remained elevated for at least 6 months. These results confirm that ARCT-154, administered as a homologous or heterologous booster after previous COVID-19 vaccination or natural exposure, provides robust, broad, and durable immune responses against SARS-CoV-2 viruses.