Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 20:87:103428.
doi: 10.1016/j.eclinm.2025.103428. eCollection 2025 Sep.

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

Michelle L Giles  1 , Charissa Tabora  2 , Carmen Baccarini  3 , Leonela Barrientos  4 , Javier Cespedes Vargas  5 , May Emmeline Montellano  6 , Paul Nguyen  7 , Sachin Deshmukh  8 , Munro Neville  9 , Matthew Hohenboken  10 , Josephine van Boxmeer  10 , Hongfan Jin  3 , Roberto Bugarini  3 , Xuexuan Liu  3 , Judd L Walson  11 , Carole Verhoeven  3 , Igor Smolenov  3
Affiliations

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

Michelle L Giles et al. EClinicalMedicine. .

Abstract

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.

Keywords: COVID-19 vaccine; Co-administration; Immunogenicity; Safety; Self-amplifying mRNA.

PubMed Disclaimer

Conflict of interest statement

C Baccarini, H Jin, R Bugarini, X Liu, C Verhoeven, and I Smolenov are full-time employees of the vaccine manufacturer, Arcturus Therapeutics, and hold the company's stock options. M Hohenboken and J van Boxmeer are full-time employees of the vaccine marketing authorisation holder, CSL and own CSL's stock. JL Walson is an independent consultant working for Arcturus Therapeutics and a member of the Scientific Advisory Board of Arcturus Therapeutics. Dr. ML Giles, C Tabora, L Barrientos, JC Vargas, ME Montellano, P Nguyen, S Deshmukh, and M Neville are investigators of the study ARCT-2303-01 and received fees for study participation.

Figures

Fig. 1
Fig. 1
Study flow chart for the two age cohorts. Abbreviations: aQIV, adjuvanted quadrivalent influenza vaccine; PPS, per protocol set; QIV, quadrivalent influenza vaccine.
Fig. 2
Fig. 2
Geometric mean titre (GMT) ratios for the five primary antigens tests with 95% CI bars. Upper panels show the GMT ratio for neutralising antibodies against the Omicron XBB.1.5.6 antigen when ARCT-2303 was administered concomitantly vs separately from the quadrivalent influenza vaccine (QIV). Lower panel shows the GMT ratios for the four influenza antigens when QIV was administered concomitantly vs separately from ARCT-2303.
Fig. 3
Fig. 3
Persistence of the immune response to the vaccine antigen: neutralising antibodies against XBB.1.5.6 are shown for young and older adults who received ARCT-2303 (n = 93 per group) and against Wuhan-Hu-1 ancestral strain in all adults in the historical study after receiving ARCT-154 (n = 385). Respective GMFR are shown below the figure, and proportions of each group who still had a titre at 6 months equal to the peak titres measured 1-month post-vaccination are shown as percentages. Abbreviations: GMFR, geometric mean fold rise; GMT, geometric mean titer.
Fig. 4
Fig. 4
Geometric mean titres (GMTs) with 95% CI bars of neutralising antibodies against the indicated SARS-CoV-2 variant at Days 1, 29, and 181 following vaccination with ARCT-2303 (n = 35, n = 93 for XBB 1.5.6), with GMFR from Day 1 and 95% CI (all unadjusted) shown below. Abbreviations: GMFR, geometric mean fold rise; GMT, geometric mean titer; CI, confidence interval.
Fig. 5
Fig. 5
a. Solicited local reactions occurring within 7 days after ARCT-2303 or influenza vaccines in the young and older adult study cohorts. The local reactions at the injection site for ARCT-2303, (a)QIV, and placebo from co-administered and the standalone groups were pooled, as frequencies were similar between the treatment groups. Abbreviations: aQIV, adjuvanted quadrivalent influenza vaccine; QIV, quadrivalent influenza vaccine. b. Solicited systemic adverse events occurring in the 7 days after ARCT-2303 or influenza vaccines in the young and older adult study cohorts.
See this image and copyright information in PMC

References

    1. Murdoch L., Quan K., Baber J.A., et al. Safety and immunogenicity of the BNT162b2 vaccine coadministered with seasonal inactivated influenza vaccine in adults. Infect Dis Ther. 2023;12(9):2241–2258. - PMC - PubMed
    1. Naficy A., Kuxhausen A., Seifert A., et al. No immunological interference or concerns about safety when seasonal quadrivalent influenza vaccine is co-administered with a COVID-19 mRNA-1273 booster vaccine in adults: a randomized trial. Hum Vaccin Immunother. 2024;20(1) - PMC - PubMed
    1. Toback S., Galiza E., Cosgrove C., et al. Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022;10(2):167–179. - PMC - PubMed
    1. Moderna announces positive Phase III data for Covid-19/Influenza mRNA vaccine. 2024. https://www.clinicaltrialsarena.com/analyst-comment/moderna-positive-pha... Available at:
    1. Novavax initiates Phase 3 trial for COVID-19-influenza combination and stand-alone influenza. 2024. https://ir.novavax.com/press-releases/2024-12-10-Novavax-Initiates-Phase... Available at:

Associated data

LinkOut - more resources