Immunogenicity and safety of self-amplifying mRNA COVID-19 vaccine (ARCT-2303), with or without co-administration of seasonal inactivated influenza vaccine in adults: a phase 3, randomised, controlled, observer-blind, multicentre study
Authors:
- Giles, Michelle L.
- Tabora, Charissa
- Baccarini, Carmen
- Barrientos, Leonela
- Vargas, Javier Cespedes
- Montellano, May Emmeline
- Nguyen, Paul
- Deshmukh, Sachin
- Neville, Munro
- Hohenboken, Matthew
- van Boxmeer, Josephine
- Jin, Hongfan
- Bugarini, Roberto
- Liu, Xuexuan
- Walson, Judd L.
- Verhoeven, Carole
- Smolenov, Igor
Details:
eClinicalMedicine, Volume 87, 2025-09-30
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Background A recently licenced self-amplifying mRNA (sa-mRNA) COVID-19 vaccine induces a robust, broad, and long-lasting immune response, extending the arsenal of efficacious COVID-19 countermeasures. We ran a clinical study to assess the benefits of vaccine strain update and the feasibility of co-administration with influenza vaccines. Methods Between March 27, 2024 and April 10, 2025, we performed a randomised, observer-blind, placebo-controlled, phase 3 study with 1499 adult participants to compare immune responses of sa-mRNA vaccine, encoding spike glycoprotein of the XBB.1.5 subvariant (ARCT-2303), with vaccine encoding the ancestral strain (ARCT-154), as measured by geometric mean titres of neutralising antibodies and SARS-CoV-2 neutralising antibody seroconversion rates against the Omicron XBB.1.5, and to assess the immunological non-inferiority of co-administered ARCT-2303 and influenza vaccines compared with separately administered vaccines, as measured by neutralising antibodies against Omicron XBB.1.5.6 and haemagglutinin inhibition against influenza vaccine strains. Reactogenicity (adverse events on Days 1–7) and safety (adverse events on Days 1–181) were also assessed. The trial was registered on ClinicalTrials.gov (identifier NCT06279871). Findings The geometric mean ratio (ARCT-2303/ARCT-154) of neutralising antibodies against Omicron XBB.1.5.6 on Day 29 was 2.7 (95% confidence interval (CI): 2.3–3.2), and the seroconversion rate difference was 28.4% (21.8–34.9); both met the prespecified superiority criteria. Concomitant administration of ARCT-2303 had no impact on the immune response to the quadrivalent influenza vaccine antigens, whether the non-adjuvanted vaccine given to 18‒64 year-old adults or the adjuvanted vaccine given to adults 65 years and older. The non-inferiority of the immune response against Omicron XBB.1.5.6 was also demonstrated when ARCT-2303 was co-administered or administered separately. Interpretation We conclude that ARCT-2303 induces a robust immune response against the vaccine variant of SARS-CoV-2 and can be co-administered with licenced influenza vaccines in adults with no impact on the safety or immunogenicity of either vaccine. Funding The study is funded by CSL under a collaboration agreement with Arcturus Therapeutics.