Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials

Abstract

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild-moderate transient AEs. 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 of 14.5 (95% CI: 13.6-15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. 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. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

Fig. 1. Study design.

The different phases (1, 2, 3a and 3b) of the study are shown with randomization of ARCT-154 and placebo groups, and timings of interventions.

Fig. 2. Study flow chart showing the disposition of participants throughout the various phases of the study.

Numbers and percentages are based on those randomized; participants could be excluded from the analysis sets for more than one reason. Analysis sets: ITT, Intent-to-treat; mITT, modified Intent-to-treat; PP, Per protocol set; RAS, Reactogenicity analysis set; SAS, Safety analysis set; IAS, immunogenicity analysis set. In Phase 1/2/3a 1 participant randomized to ARCT-154 received Placebo as Dose 1 giving 748 receiving ARCT-154 and 253 receiving Placebo as Dose 1. Phase 3b: 7 participants randomized to Placebo did not receive Dose 1 giving 8041 in the SAS Placebo group; two participants who received ARCT-154 as Dose 1 but placebo as Dose 2 were removed from the ARCT-154 Dose 2 SAS arm giving 7867, and 6 participants randomized to Placebo received incorrect investigational product and were removed from the Placebo Dose 2 SAS arm giving 7822.

Fig. 3

Solicited reactogenicity during 7 days after Doses 1 and 2 of ARCT-154 or placebo in the combined phase 1, 2 and 3a studies, with highest severity indicated as mild (Grade 1), moderate (Grade 2) or severe (Grade 3).

Fig. 4

Solicited reactogenicity during 7 days after Doses 1 and 2 of ARCT-154 or placebo in the phase 3b study, with highest severity indicated as mild (Grade 1), moderate (Grade 2) or severe (Grade 3).

Fig. 5. Neutralizing antibody responses before and after the two study vaccinations measured using two different assays.

Responses shown Geometric mean concentrations of neutralizing antibodies (with 95% CI bars) and with seroconversion rates (SCR) and geometric mean-fold rises (GMFR) from baseline indicated below. Values shown are for N participants (indicated in each column) at each timepoint.

Fig. 6

Cumulative incidence curves of COVID-19 of any severity (A), and severe COVID-19 (B) in vaccine and placebo groups from Day 36 (per protocol).