Safety and Immunogenicity Study of Self-Amplifying RNA Pandemic Influenza Vaccine in Adults

A Phase 1, First-in-human, Randomized, Observer-blind, Parallel Design, Controlled, Dose Level and Schedule-finding Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of a Self-Amplifying mRNA Pandemic Influenza Vaccine (ARCT-2304) When Administered to Healthy Adults

The goal of this clinical trial is to evaluate the safety and immune responses of three different dose levels a self-amplifying RNA pandemic influenza vaccine (ARCT-2304) in adults. The key objectives of the study are:

• To evaluate safety and reactogenicity of different dose levels of the ARCT-2304 vaccine
• To describe the Immune responses of different dose levels of the ARCT-2304 vaccine as measured by hemagglutination inhibition (HAI) and neuraminidase enzyme-linked lectin (ELLA) antibody responses

Researchers will compare the results with licensed influenza vaccines to select the most optimal dose level and schedule for vaccine administration in terms of safety and immunogenicity for further development of the vaccine.

Participants will receive 2 doses of the ARCT-2304 vaccine or 1 dose of licensed influenza vaccine and 1 dose of placebo.

They will be asked:

• to complete a daily diary for 7 days after each vaccination, answering questions how they have been feeling on that day.
• to provide blood samples at each visit in the clinic
• to comply with all study visits and procedures (e.g., be available for planned telephone contacts and unscheduled clinic visits, if required)

Phase 1, first-in-human, randomized, controlled, observer blind, dose level and schedule-finding study, to evaluate the safety, reactogenicity, and immunogenicity of a self-amplifying mRNA pandemic influenza (H5N1) vaccine (ARCT-2304) when administered as a 2-dose vaccination series to healthy adults in comparison with an inactivated influenza vaccine.

Study drug (ARCT-2304 or control) will be administered as a 2-dose vaccination series as an intramuscular (IM) injection. The study comprises two parts.

In Part 1, 120 participants (young adults) will be randomized to one of the three dose levels of the ARCT-2304 vaccine or control vaccine. Participants will be further randomized to one of the two different vaccination schedules.

In Part 2, 80 participants (older adults) will be randomized to one of the three dose levels of the ARCT-2304 vaccine or control vaccine. Participants will be further randomized to one of the two different vaccination schedules.

Investigational Vaccine: ARCT-2304

Control Vaccines: licensed influenza vaccines

Main Inclusion Criteria:

• Individuals are male or female adults 18-80 years of age.
• Healthy participants or participants with pre-existing stable medical conditions.
• Individuals of childbearing potential must be willing to adhere to contraceptive requirements.

Main Exclusion Criteria:

• Individuals with acute medical conditions or febrile illness, including body temperature ≥100.4°F (≥38.0°C measured by any method) within 3 days prior to randomization.
• Individuals with a known history of severe hypersensitivity reactions, including anaphylaxis, or other significant adverse reactions to any mRNA vaccine, influenza vaccine, or excipients.
• Individuals with a history of myocarditis, pericarditis, myopericarditis, or cardiomyopathy.
• Individuals who received any influenza vaccine within 3 months prior to first vaccine administration or plan to receive an influenza vaccine during the study period.
• Individuals who have received mRNA vaccination within 60 days before the first vaccine administration.
• Individuals who have received or plan to receive an A/H5N1 influenza vaccine and/or individuals who had substantial exposure to or direct contact with poultry, wild birds, live cattle, or raw milk.