Safety and Immunogenicity of Chimeric Hemagglutinin mRNA Vaccine Candidates

This is a Phase 1, randomized, controlled, dose-ranging clinical trial to assess the safety and immunogenicity of novel influenza A Group 1 and influenza A Group 2 mRNA chimeric hemagglutinin (HA) vaccine candidates given as intramuscular injections alone and in combination. A total of 60 healthy men and non-pregnant, non-breastfeeding women aged 18 through 59 years will be enrolled in one of 6 study arms. The 6 arms will consist of: 1) Sequential influenza A Group 1 mRNA chimeric hemagglutinin: cH8/1 (25 µg) followed by cH5/1 (25 µg), 2) Sequential influenza A Group 2 mRNA chimeric hemagglutinin: cH15/3 (25 µg) followed by cH4/3 (25 µg), 3) Sequential combined influenza A Group 1 and Group 2 mRNA chimeric hemagglutinin: cH8/1 + cH15/3 (25 µg) followed by cH5/1 + cH4/3 (25 µg), 4) A single dose of combined influenza A Group 1 and Group 2 mRNA chimeric hemagglutinin: cH8/1 + cH15/3 (50 µg) followed by placebo, 5) A single dose of combined influenza A Group 1 and Group 2 mRNA chimeric hemagglutinin: cH5/1 + cH4/3 (50 µg) followed by placebo, 6) Sequential combined influenza A Group 1 and Group 2 mRNA chimeric hemagglutinin: cH8/1 + cH15/3 (50 µg) followed by cH5/1 + cH4/3 (50 µg). The primary objectives are to evaluate safety and immunogenicity: 1) To assess the safety and reactogenicity of one or two doses of monovalent or bivalent Group 1 and 2 study products and 2) To describe the Group 1 and 2 anti-HA stalk IgG antibody responses of one or two doses of monovalent or bivalent Group 1 and 2 study products by ELISA.

Inclusion Criteria: 1. Provision of signed and dated informed consent form before the initiation of any study procedures. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Non-pregnant healthy adults, aged 18 to 59 years of age, inclusive, at the time of enrollment. 4. In good general health as evidenced by medical history or diagnosed with stable chronic medical or psychiatric diagnoses or conditions.\* \*As determined by medical history, medications use, and physical examination to evaluate ongoing chronic medical or psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would not affect the assessment of the safety of participants or the immunogenicity of study products. These medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, emergency room \[ER\] or urgent care for the condition \[excluding musculoskeletal conditions\], or invasive medical procedure and no adverse symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in chronic prescription medication or dose as a result of new symptoms or deterioration of the condition or disease being treated in the 30 days prior to enrollment. Any prescription change that is due to a change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Participants may be on chronic or as-needed (prn) medications if, in the opinion of the site PI or appropriate sub-investigator, they pose no additional risk to participant safety or assessment of reactogenicity and immunogenicity, and do not indicate a worsening or treatment of continued symptoms of medical diagnosis or condition. Note: Low-dose topical corticosteroids as outlined in the Exclusion Criteria as well as herbals, vitamins, and supplements are permitted. 5. Oral temperature is less than 100.4 degrees Fahrenheit\*. \*Inclusion requirement at enrollment and prior to study product administration. 6. Heart rate (HR) is 55 to 100 beats per minute, inclusive\*. \*Screening heart rate values in the normal range or with grade 1 abnormalities deemed not clinically significant by the site PI or designated clinician licensed to make medical diagnoses and listed on Form FDA 1572 are considered acceptable. 7. Systolic blood pressure is 90 to 140 mmHg, inclusive\*. \*Screening systolic blood pressure values in the normal range or with grade 1 abnormalities deemed not clinically significant by the site PI or designated clinician licensed to make medical diagnoses and listed on Form FDA 1572 are considered acceptable. 8. Diastolic blood pressure is 55 to 90 mmHg, inclusive\*. \*Screening diastolic blood pressure values in the normal range or with grade 1 abnormalities deemed not clinically significant by the site PI or designated clinician licensed to make medical diagnoses and listed on Form FDA 1572 are considered acceptable. 9. BMI between 18 kilograms/square meter (kg/m\^2) (inclusive) and \