Immunogenicity and Safety Study of Self-amplifying mRNA COVID-19 Vaccine Administered With Influenza Vaccines in Adults

A Phase 3, Multicenter, Observer-blind, Randomized, Controlled Study to Evaluate the Immunogenicity, Reactogenicity, and Safety of a Self-Amplifying RNA COVID-19 Vaccine (ARCT-2303), Administered Concomitantly With Quadrivalent Influenza Vaccines, in Adults

This is a multicenter, observer-blind, randomized, controlled phase 3 study to evaluate the immunogenicity, reactogenicity, and safety of an investigational self-amplifying RNA COVID-19 vaccine (ARCT-2303) administered concomitantly with quadrivalent influenza vaccines or standalone in adults who previously received authorized COVID-19 vaccine.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Biological: ARCT-2303; Biological: Influenza vaccine; Other: Placebo; Biological: Influenza vaccine, adjuvanted

Detailed Description

Approximately 1680 participants previously vaccinated with authorized COVID-19 vaccine will be enrolled in this study in two age cohorts (younger adults and older adults). Within each cohort, participants will be randomly assigned in a ratio of 1:1:1 to receive the ARCT-2303 vaccine concomitantly with a quadrivalent influenza vaccine, the ARCT-2303 vaccine and placebo, or the quadrivalent influenza vaccine and placebo. The assessment of immunogenicity will be performed 28 days after vaccination. To provide equal benefit from the participation in the study and complete seasonal vaccination against COVID-19 and influenza, a switchover vaccine dose (influenza, ARCT-2303 or placebo) will be administered 28 days after initial vaccination. All participants will be followed up for safety assessment until the end of the study.

A historical control group vaccinated on a similar schedule (ARCT-154 vaccine) from a previous study (ARCT-154-J01) will be used to compare with the immunogenicity of the ARCT-2303 vaccine.

Cohort A (younger adults; approximately 1200 participants):

• Group 1a (ARCT-2303/Influenza vaccine): participants will receive one dose of ARCT-2303 and one dose of Influenza vaccine (opposite arms) on Day 1, and one dose of placebo on Day 29.
• Group 2a (ARCT-2303): participants will receive one dose of ARCT-2303 and one dose of placebo (opposite arms) on Day 1, and one dose of Influenza vaccine on Day 29.
• Group 3a (Influenza vaccine): participants will receive one dose of Influenza vaccine and one dose of placebo (opposite arms) on Day 1, and one dose of ARCT-2303 on Day 29.

Cohort B (older adults; approximately 480 participants):

• Group 1b (ARCT-2303/Influenza vaccine): participants will receive one dose of ARCT-2303 and one dose of Influenza vaccine (opposite arms) on Day 1, and one dose of placebo on Day 29.
• Group 2b (ARCT-2303): participants will receive one dose of ARCT-2303 and one dose of placebo (opposite arms) on Day 1, and one dose of Influenza vaccine on Day 29.
• Group 3b (Influenza vaccine): participants will receive one dose of Influenza vaccine and one dose of placebo (opposite arms) on Day 1, and one dose of ARCT-2303 on Day 29.

• Study Type: Interventional
• Enrollment (Actual): 1514
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia
      • Paratus Clinical Canberra
  • New South Wales
    • Central Coast, New South Wales, Australia
      • Paratus Clinical Central Coast
    • Miranda, New South Wales, Australia
      • Sutherland Shire Clinical Research - Walski
    • Sydney, New South Wales, Australia
      • Australian Clinical Research Network (ACRN)
    • Sydney, New South Wales, Australia
      • Austrials - St. Leonards
    • Sydney, New South Wales, Australia
      • Emeritus Research Sydney
    • Sydney, New South Wales, Australia
      • Griffith University Clinical Trials Unit
    • Sydney, New South Wales, Australia
      • Northern Beaches Clinical Research - Walski
    • Sydney, New South Wales, Australia
      • Paratus Clinical Blacktown
    • Wollongong, New South Wales, Australia
      • Wollongong Clinical Research
  • Queensland
    • Brisbane, Queensland, Australia
      • Nucleus Network Brisbane (Q-Pharm)
    • Brisbane, Queensland, Australia
      • Paratus Clinical Brisbane
    • Brisbane, Queensland, Australia
      • USC Southbank
    • Morayfield, Queensland, Australia
      • USC Morayfield
    • Sunshine Coast, Queensland, Australia
      • USC Sippy Down
  • South Australia
    • Adelaide, South Australia, Australia
      • CMAX
  • Victoria
    • Melbourne, Victoria, Australia
      • Nucleus Network
    • Melbourne, Victoria, Australia
      • Austrials -Sunshine
    • Melbourne, Victoria, Australia
      • Emeritus Research Melbourne
    • Melbourne, Victoria, Australia
      • The Peter Doherty Institute for infection and immunity
    • Melbourne, Victoria, Australia
      • Veritus Research
  • Western Australia
    • Perth, Western Australia, Australia
      • Clinitrials - Mount Site
• Costa Rica
  • San José, Costa Rica
    • Clínica San Agustín
  • San José, Costa Rica
    • IICIMED
• Honduras
  • Comayagua, Honduras
    • Organización y centro de investigación clínica Ochoa (OCINCO)
  • San Pedro Sula, Honduras
    • Deposito de Medicamentos de Investigación Cousin Agustín (DEMEDICA)
  • Tegucigalpa, Honduras
    • Inversiones en Investigación Médica S.A (INVERIME)
• Philippines
  • City of Muntinlupa, Philippines
    • Tropical Disease Foundation - Putatan Health Center
  • Quezon City, Philippines
    • Far Eastern University - Nicanor R. M Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1, Individuals are male, female, or transgender adults ≥18 years of age.

2. Healthy participants or participants with pre-existing stable medical conditions.

3. Participant or legally authorized representatives must freely provide documented informed consent prior to study procedures being performed.

4. Individuals must have been previously vaccinated with COVID-19 vaccines.

5. Individuals of childbearing potential must be willing to adhere to contraceptive requirements.

Exclusion Criteria:

1. Individuals with acute medical illness or febrile illness.
2. Individuals with a positive SARS-CoV-2 rapid antigen test at Screening.
3. Individuals with a history of COVID-19 or virologically confirmed SARS-CoV-2 infection within the past 5 months or history of COVID-19 with ongoing sequelae.
4. Individuals with a known history of severe hypersensitivity reactions, including anaphylaxis, or other significant adverse reactions to any components of mRNA vaccine, or influenza vaccine, including egg protein.
5. Individuals who have a positive pregnancy test at the Screening visit or who intend to become pregnant or breastfeed during the study.
6. Individuals with a history of myocarditis, pericarditis, myopericarditis or cardiomyopathy.
7. Individuals with a history of Guillain-Barré syndrome, encephalomyelitis, or transverse myelitis.
8. Individuals with a history of congenital or acquired immunodeficiency.
9. Individuals who have received immunomodulatory, immunostimulatory, or immunosuppressant drugs within 3 months of Screening; or individuals requiring systemic corticosteroids exceeding 10 mg/day of prednisone equivalent for ≥10 days within 30 days of Screening.
10. Individuals who have received immunoglobulins and/or any blood or blood products within the 3 months before the first vaccine administration or plan to receive such products at any time during the study.
11. Individuals with a documented history of HIV infection, or who are currently known to have active tuberculosis.
12. Individuals receiving treatment with another investigational drug, biological agent, or device.
13. Individuals who have received any investigational COVID-19 vaccines.
14. Individuals who received any influenza vaccine within 6 months prior to enrollment or plan to receive an influenza vaccine during the study period.
15. Individuals who have received any other licensed vaccines within 14 days prior to enrollment in this study or who are planning to receive any vaccine up to 14 days after the study vaccination.
16. Individuals who are investigator site staff members, employees of the Sponsor or the Clinical Research Organization directly involved in the conduct of the study, or site staff members otherwise supervised by the investigator or immediate family members of any of the previously mentioned individuals.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1a (ARCT-2303/Influenza vaccine); Participants will receive one 0.5-mL IM (intramuscular) dose of ARCT-2303 and one 0.5-mL IM dose of influenza vaccine on Day 1 followed by a 0.5-mL IM dose of placebo on Day 29.	Biological: ARCT-2303; Self-Amplifying RNA COVID-19 vaccine (Omicron XBB.1.5); Biological: Influenza vaccine; Licensed cell-based influenza vaccine; Other: Placebo; 0.9% saline
Experimental: Group 2a (ARCT-2303); Participants will receive one 0.5-mL IM dose of ARCT-2303 and one 0.5-mL IM dose of placebo on Day 1 followed by a 0.5-mL IM dose of influenza vaccine on Day 29.	Biological: ARCT-2303; Self-Amplifying RNA COVID-19 vaccine (Omicron XBB.1.5); Biological: Influenza vaccine; Licensed cell-based influenza vaccine; Other: Placebo; 0.9% saline
Active Comparator: Group 3a (Influenza vaccine); Participants will receive one 0.5-mL IM dose of influenza vaccine and one 0.5-mL IM dose of placebo on Day 1 followed by a 0.5-mL IM dose of ARCT-2303 on Day 29.	Biological: ARCT-2303; Self-Amplifying RNA COVID-19 vaccine (Omicron XBB.1.5); Biological: Influenza vaccine; Licensed cell-based influenza vaccine; Other: Placebo; 0.9% saline
Experimental: Group 1b (ARCT-2303/ Influenza vaccine); Participants will receive one 0.5-mL IM dose of ARCT-2303 and one 0.5-mL IM dose of influenza vaccine on Day 1 followed by a 0.5-mL IM dose of placebo on Day 29.	Biological: ARCT-2303; Self-Amplifying RNA COVID-19 vaccine (Omicron XBB.1.5); Other: Placebo; 0.9% saline; Biological: Influenza vaccine, adjuvanted; Licensed influenza vaccine, adjuvanted
Experimental: Group 2b (ARCT-2303); Participants will receive one 0.5-mL IM dose of ARCT-2303 and one 0.5-mL IM dose of placebo on Day 1 followed by a 0.5-mL IM dose of influenza vaccine on Day 29.	Biological: ARCT-2303; Self-Amplifying RNA COVID-19 vaccine (Omicron XBB.1.5); Other: Placebo; 0.9% saline; Biological: Influenza vaccine, adjuvanted; Licensed influenza vaccine, adjuvanted
Active Comparator: Group 3b (Influenza vaccine); Participants will receive one 0.5-mL IM dose of influenza vaccine and one 0.5-mL IM dose of placebo on Day 1 followed by a 0.5-mL IM dose of ARCT-2303 on Day 29.	Biological: ARCT-2303; Self-Amplifying RNA COVID-19 vaccine (Omicron XBB.1.5); Other: Placebo; 0.9% saline; Biological: Influenza vaccine, adjuvanted; Licensed influenza vaccine, adjuvanted

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Groups 2a and 2b and ARCT-154-J01 Historical Control: Geometric Mean Titers (GMT) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Neutralizing Antibody Titers Against Omicron XBB.1.5 Subvariant at Day 29		Day 29
Groups 2a and 2b and ARCT-154-J01 Historical Control: Number of Participants With Seroconversion to SARS-CoV-2 Neutralizing Antibody Against Omicron XBB.1.5 Subvariant at Day 29	Seroconversion was defined as either a pre-vaccination titer below the lower limit of quantitation (LLOQ) and a postvaccination titer ≥4xLLOQ; or a pre-vaccination titer ≥LLOQ and a ≥4-fold increase in post-vaccination titer.	Day 29
Groups 1a and 3a: Adjusted Hemagglutination Inhibition (HI) GMTs Against Influenza Vaccine Strains at Day 29	Influenza vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Day 29
Groups 1a and 2a: Adjusted GMTs of SARS-CoV-2 Neutralizing Antibody Against Omicron XBB.1.5 Subvariant at Day 29		Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Groups 1a and 2a: GMT of SARS-CoV-2 Neutralizing Antibodies Against Omicron XBB.1.5 Subvariant at Days 1, 29 and 181		Group 1a: Days 1 and 29; Group 2a: Days 1, 29, and 181
Groups 1a and 2a: Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Neutralizing Antibodies Against Omicron XBB.1.5 Subvariant at Days 29 and 181	GMFR is reported as a ratio to Day 1.	Group 1a: Day 29; Group 2a: Days 29 and 181
Groups 1a and 2a: Number of Participants With Seroconversion of SARS-CoV-2 Neutralizing Antibodies Against Omicron XBB.1.5 Subvariant at Day 29	Seroconversion was defined as either a pre-vaccination titer below the LLOQ and a postvaccination titer ≥4xLLOQ; or a pre-vaccination titer ≥LLOQ and a ≥4-fold increase in post-vaccination titer.	Day 29
Groups 1a and 2a: Number of Participants With SARS-CoV-2 Neutralizing Antibody Against Omicron XBB.1.5 Subvariant Titer ≥ LLOQ at Days 1 and 29		Days 1 and 29
Groups 1a and 3a: GMTs of HI Assay Titers Against Influenza Vaccine Strains at Days 1 and 29	Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Days 1 and 29
Groups 1a and 3a: GMFR of HI Assay Titers Against Influenza Vaccine Strains at Day 29	Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata. GMFR is reported as a ratio to Day 1.	Day 29
Groups 1a and 3a: Number of Participants With Seroconversion of HI Assay Titers Against Influenza Vaccine Strains at Day 29	Seroconversion was defined as either a pre-vaccination titer below the LLOQ and a postvaccination titer ≥4xLLOQ; or a pre-vaccination titer ≥LLOQ and a ≥4-fold increase in post-vaccination titer. Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Day 29
Groups 1a and 3a: Number of Participants With HI Titer ≥1:40 at Days 1 and 29	Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Days 1 and 29
Groups 1b and 2b: GMTs of SARS-CoV-2 Neutralizing Antibodies Against Omicron XBB.1.5 Subvariant at Days 1, 29 and 181		Group 1b: Days 1 and 29, Group 2b: Days 1, 29 and 181
Groups 1b and 2b: GMFRs of SARS-CoV-2 Neutralizing Antibodies Against Omicron XBB.1.5 Subvariant at Days 29 and 181	GMFR is reported as a ratio to Day 1.	Group 1b: Day 29 and Group 2b: Days 29 and 181
Groups 1b and 2b: Number of Participants With Seroconversion of SARS-CoV-2 Neutralizing Antibodies Against Omicron XBB.1.5 Subvariant at Day 29	Seroconversion was defined as either a pre-vaccination titer below the LLOQ and a postvaccination titer ≥4xLLOQ; or a pre-vaccination titer ≥LLOQ and a ≥4-fold increase in post-vaccination titer.	Day 29
Groups 1b and 2b: Number of Participants With SARS-CoV-2 Neutralizing Antibody Against Omicron XBB.1.5 Subvariant Titer ≥ LLOQ at Days 1 and 29		Days 1 and 29
Groups 1b and 3b: GMTs of HI Assay Titers Against Influenza Vaccine Strains at Days 1 and 29	Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Days 1 and 29
Groups 1b and 3b: GMFRs of of HI Assay Titers Against Influenza Vaccine Strains at Day 29	Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata. GMFR is reported as a ratio to Day 1.	Day 29
Groups 1b and 3b: Number of Participants With Seroconversion of HI Assay Titers Against Influenza Vaccine Strains at Day 29	Seroconversion was defined as either a pre-vaccination titer below the LLOQ and a postvaccination titer ≥4xLLOQ; or a pre-vaccination titer ≥LLOQ and a ≥4-fold increase in post-vaccination titer. Vaccine strains were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Day 29
Groups 1b and 3b: Number of Participants With HI Titer ≥1:40 at Days 1 and 29	Vaccine strains analyzed for this outcome measure were A/H1N1, A/H3N2, B/Victoria, and B/Yamagata.	Days 1 and 29
Number of Participants With Local and Systemic Adverse Events (AEs)	Systemic AEs: fatigue, headache, myalgia, arthralgia, nausea, dizziness, chills, and fever. Solicited local (injection site) AEs: injection site pain, erythema, and swelling. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Day 8 and Day 36 (up to 7 days after each study vaccination)
Number of Participants With Unsolicited AEs	An unsolicited AE was an AE that was not listed as 'solicited' and was defined as any spontaneously occurring AE (serious and non-serious). Potential unsolicited AEs may have been medically attended (defined as symptoms or illnesses requiring hospitalization, or emergency room visit, or visit to/by a healthcare provider) or were of concern to the participants. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Up to Day 29 (Up to 28 days after first study vaccination) and up to Day 57 (28 days after second study vaccination)
Number of Participants With Serious Adverse Events (SAEs), AEs Leading to Early Termination From Study, Medically Attended Adverse Event (MAAEs), and Adverse Event of Special Interest (AESIs)	SAEs were defined as any event that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly or birth defect, or was an important medical event. A MAAE was an AE that led to an unscheduled visit (including a telemedicine visit) to a healthcare practitioner. AESIs were defined as AEs potentially associated with Coronavirus Disease 2019 (COVID-19) and COVID-19 vaccines. Number of participants with AEs leading to early termination included AEs leading to death. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Day 1 up to Day 181

Collaborators and Investigators

• Sponsor: Arcturus Therapeutics, Inc.
• Collaborators: Novotech (Australia) Pty Limited; Seqirus
• Investigators: Study Director: Clinical Program Director, Arcturus Therapeutics

Publications and helpful links

General Publications

• Giles ML, Tabora C, Baccarini C, Barrientos L, Vargas JC, Montellano ME, Nguyen P, Deshmukh S, Neville M, Hohenboken M, van Boxmeer J, Jin H, Bugarini R, Liu X, Walson JL, Verhoeven C, Smolenov I. 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. EClinicalMedicine. 2025 Aug 20;87:103428. doi: 10.1016/j.eclinm.2025.103428. eCollection 2025 Sep.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2024
• Primary Completion (Actual): October 9, 2024
• Study Completion (Actual): November 21, 2024

Study Registration Dates

• First Submitted: February 23, 2024
• First Submitted That Met QC Criteria: February 23, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Actual): December 12, 2025
• Last Update Submitted That Met QC Criteria: November 26, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Biological Products; Complex Mixtures; Vaccines; Viral Vaccines; Influenza Vaccines
• Other Study ID Numbers: ARCT-2303-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No