ABSTRACT
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.
Subject(s)
COVID-19ABSTRACT
Abstract: Background: In the prolonged COVID-19 pandemic, there remains a high need for the development of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine that can be used more safely and effectively to prevents the disease onset or severe disease. To satisfy such unmet need, we are currently developing the inactivated whole particle SARS-CoV-2 vaccine (KD-414) and conducted a phase 2/3 study in healthy adults in Japan to accumulate more immunogenicity and safety data of KD-414 using the dose selected based on the results of the phase 1/2 study. Methods: In an open-label uncontrolled phase 2/3 study, adults aged 18 years or older without a history of COVID-19 or COVID-19 vaccination received two intramuscular doses of KD-414 at a 28-day intervals, followed by one intramuscular dose 13 weeks after the second dose as the primary immunization. Safety data were collected after the first dose of KD-414 in all participants to evaluate the safety profile. In predetermined immunogenicity analysis subjects, the neutralizing antibody titers against the pseudovirus SARS-CoV-2 (Wuhan) before the first vaccination and after each vaccination with KD-414 were evaluated. Results: A total of 2500 adults aged 18 years or older were enrolled; 2474 of them received the vaccination up to the second dose, and 2081 completed the third vaccination. Regarding the safety, no deaths or serious adverse reactions were recorded from the first vaccination until 28 days after the third vaccination with KD-414. The incidence of adverse reactions (number of participants with onsets/number of participants in the safety analysis set) was 80.6% (2015/2500). Adverse reactions with an incidence of 10% or more included injection site pain, malaise, headache, injection site erythema, myalgia, and injection site induration. A total of 11 events of grade 3 or higher adverse reactions that prevented daily activities in 9 participants. There was no increasing tendency in the incidence of adverse reactions responding to the vaccinations. To evaluate immunogenicity, 295 first comers enrolled from five age ranges were allocated to the immunogenicity analysis subjects; 291 participants received the vaccination up to the second dose, and 249 participants completed the third vaccination. The geometric mean titers (95% confidence interval [CI]) of neutralizing antibody titers against pseudovirus SARS-CoV-2 (Wuhan) 28 days after the second vaccination and 28 days after the third vaccination with KD-414 were 139.6 (118.9 - 164.0) and 285.6 (244.3 - 334.0), respectively, showing an approximately two-fold increase after the third vaccination compared to that after the second vaccination. The geometric mean titers (95% CI) of neutralizing antibody titers after the third vaccination were 327.6 (269.8 - 397.9), 272.2 (211.5 - 350.4) and 128.0 (51.6 - 317.7) in participants aged 18 to 40 years, 41 to 64 years, and 65 years or older, respectively, showing an age-dependency. Conclusion: This study confirmed the favorable safety profile of KD-414 as a result of three vaccinations of KD-414 administered to over 2000 healthy Japanese participants aged 18 years or older. There were no particular differences in the types and incidences of adverse reactions between vaccinations, and no tendency of an increase in adverse reactions with an increase in the number of vaccinations. Similar to the phase 1/2 study, neutralizing antibody responses appeared to be age-dependent and the highest titers were observed in the age group of 18 - 40 years. A phase 3 study in adults aged 18 - 40 years (jRCT2031210679) and a phase 2/3 study in children aged 6 months - 18 years (jRCT2031220032) are currently ongoing.