Assess Safety and Immunogenicity of A/H5 Inactivated Monovalent Influenza Vaccines at Different Antigen Dose Levels Adjuvanted With AS03 or MF59

Randomized, Double-Blind, Phase 2 Study to Assess Safety and Immunogenicity of A/H5 Inactivated Monovalent Influenza Vaccines at Different Antigen Dose Levels Adjuvanted With AS03® or MF59®

This BARDA-sponsored, randomized, double-blind, phase 2 study is designed to assess safety and immunogenicity of A/H5 inactivated monovalent influenza vaccines at different antigen dose levels adjuvanted with AS03 or MF59.

This is a randomized, double-blind, phase 2 study to assess safety and immunogenicity of egg-based H5N8 and H5N1 influenza vaccines at different antigen dose levels (3.75, 7.5, and 15 μg) adjuvanted with AS03A full dose, AS03A half dose (H5N8 only), or MF59. AS03A is the adjuvant AS03®. Healthy adult male and female (non-pregnant) participants, aged 18 years and older, will be screened for baseline health status to ensure trial eligibility. Participants meeting all the inclusion and none of the exclusion criteria will be randomized to receive vaccine doses according to treatment groups defined by antigen (H5N1 or H5N8), antigen dose level (3.75, 7.5, and 15 μg), and adjuvant (AS03A full dose, AS03A half dose, or MF59). Two doses of adjuvanted vaccine separated by 21 days will be administered to approximately 1380 participants, including 780 participants 18 through 64 years old who will be randomized equally to 1 of 13 treatment groups (A, B, C, D, E, F, G, H, I, J, K, M, and N), and 600 participants ≥65 years old who will be randomized equally to 1 of 10 treatment groups (B, C, E, F, H, I, K, L, N, and O).

Safety assessments will be based on solicited Adverse Events (AEs) (local and systemic reactogenicity symptoms) with onset within 8 days following each vaccination, inclusive of the vaccination day (Day 1 through Day 8 and Day 22 through Day 29); unsolicited Treatment Emergent Adverse Events (TEAEs) with onset within 22 days following each vaccination, inclusive of the vaccination day (Day 1 through Day 22 and Day 22 through Day 43); and treatment-emergent Serious Adverse Events (SAEs), Potential Immune-Mediated Diseases (pIMDs), and Medically Attended Adverse Events (MAAEs) occurring during study participation (through Day 203). Immunogenicity assessments will include titer, seroprotection rate, and seroconversion rate based on serum Hemagglutination Inhibition (HAI) antibodies, and titer and seroconversion rate based on serum microneutralization (MN) antibodies. Study vaccines will be prepared and administered by unblinded personnel. All other trial assessments will be performed only by blinded personnel.

Inclusion Criteria:

1. Male or non-pregnant female, 18 years of age or older at the time of screening and informed consent.

2. Willing and able to provide written informed consent prior to initiation of study procedures.

3. Agrees to have specimens collected during this trial specifically for the purpose of future research stored for future research use.

4. In relatively stable health, as determined by medical history and physical examination.

   a. Any chronic medical diagnoses or conditions should be stable and well managed, with no significant changes expected during the study period, and in the opinion of the site investigator, will not impact the ability to assess safety and/or immunogenicity per the study design.

5. If a female of childbearing potential who is sexually active, agrees to use an adequate method of birth control from Screening through 4 weeks following the last study vaccination and has used an adequate birth control method for at least 2 months prior to Screening.

   a. Female of childbearing potential is defined as post onset menarche and pre-menopausal person capable of becoming pregnant. This does not include females who meet any of the following conditions:

   i. menopausal >2 years

   ii. tubal ligation >1 year

   iii. bilateral salpingo-oophorectomy

   iv. hysterectomy.

   b. Adequate contraception is defined as a contraceptive method with a failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label, for example: oral contraceptives, either combined or progestogen alone; injectable progestogen; implants of etonogestrel or levonorgestrel; estrogenic vaginal ring; percutaneous contraceptive patches; intrauterine device or intrauterine system; the female participant has exclusively female sexual partners; male partner is sterile or otherwise unable to produce sperm (information on the person's sterility can come from the site personnel's review of the participant's medical records or interview with the participant regarding her medical history); male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository); or male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository).

6. Available for all study visits, willing to participate in all study procedures, and not planning to relocate from the area for the duration of the study.

Exclusion Criteria:

1. Has an acute illness, as determined by the site investigator, within 72 hours prior to vaccination.

   a. An acute illness that is nearly resolved, with only minor residual symptoms remaining, is allowable if, in the opinion of the site investigator, the residual symptoms will not interfere with the ability of study staff to assess safety parameters as required by the protocol.

2. Has a history of severe reaction to any influenza vaccine.

3. Has a known allergy to squalene-based adjuvants.

4. Female of childbearing potential who has a positive urine pregnancy test or who is currently breastfeeding.

5. Has a body mass index >35 kg/m2 .

6. Has known human immunodeficiency virus, hepatitis B, or hepatitis C infection (based on medical history).

7. Has a history of any pIMDs (list provided in Protocol Appendix 3), neuralgia, paresthesia, neuritis, convulsions, or encephalomyelitis within 90 days prior to Screening, or a family history of Guillain-Barré syndrome.

8. Has narcolepsy or a first degree relative with narcolepsy.

9. Has a history of alcohol or drug abuse within 5 years prior to Screening.

10. Has any diagnosis, current or past, of schizophrenia, bipolar disease, or any other psychiatric diagnosis that may, in the opinion of the site investigator, interfere with participant compliance or safety evaluations.

11. Is immunosuppressed due to an underlying disease or medication, use of anticancer chemotherapy (cytotoxic), or radiation therapy.

12. With the exception of basal or squamous cell skin cancer, has known active neoplastic disease, including hematologic malignancy.

13. Has long-term use (≥14 consecutive days) of glucocorticoids including oral or parenteral prednisone or prednisone equivalent (>20 mg total dose per day) or high-dose inhaled steroids (>800 µg/day of beclomethasone dipropionate or equivalent) within 1 month prior to screening in this study. However, participants on low-dose inhaled steroids (≤800 µg/day of beclomethasone dipropionate or equivalent) or topical steroids are not excluded.

14. Has received immunoglobulin or other blood product (with the exception of Rho[D] immune globulin) within the 90 days prior to screening in this study.

15. Has received any (licensed or under Emergency Use Authorization [EUA]) live vaccines within 4 weeks or inactivated, messenger RNA (mRNA), or recombinant protein vaccines within 2 weeks prior to screening, or plans to receive such vaccines (including seasonal influenza and COVID-19 vaccines) from screening through 22 days following the second dose of the study vaccine, inclusive of the vaccination day (Screening Visit through Day 43).

16. Is participating or plans to participate in another interventional clinical trial (either active or follow-up phase) during the study period.

17. Has participated in an A(H5) influenza vaccine study in the past or has a history of A(H5) influenza infection prior to vaccination in this study. This includes, but is not limited to, influenza sub-types A(H5N1), A(H5N8), and A(H5N6).

18. Has any laboratory test result or clinical findings (including vital signs) that singly or in combination are likely to unfavorably alter the risks of participant participation or to confound study safety or immunogenicity results, in the opinion of the site investigator. Additionally, the following are exclusionary:

    1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN), or
    2. Bilirubin >1.5 times the ULN unless isolated Gilbert's syndrome.

19. Has any disease or medical condition that, in the opinion of the site investigator, might confound interpretation of safety or immunogenicity.