Safety/Efficacy Study of Seqirus A/H7N9 IIV With or Without MF59(R) Adjuvant to Prevent Avian Influenza

This is a randomized, double-blinded, Phase II study in healthy males and non-pregnant females, 18-64 years of age. This clinical trial is designed to assess the safety, reactogenicity, and immunogenicity of a pre-pandemic 2017 monovalent inactivated influenza A/H7N9 virus vaccine (2017 H7N9 IIV) manufactured by Seqirus Inc (Seqirus) administered at different dosages (3.75 microgram mcg, 7.5 mcg and 15 mcg of hemagglutinin (HA) per dose) given with MF59(R) adjuvant manufactured by Seqirus Inc., or without adjuvant (15 mcg of HA per dose). Phosphate buffered saline (PBS) diluent manufactured by Patheon Manufacturing Services LLC will be used to achieve certain targeted doses. Approximately 371 subjects who are in good health and meet all eligibility criteria will be randomized into one of 4 study groups. The study will be conducted at up to 7 Vaccine and Treatment Unit (VTEU) sites and will last approximately 17 months, with subject participation duration of approximately 13 months. The Primary Objectives of the study are: 1) To assess the safety and reactogenicity following receipt of two doses of 2017 H7N9 IIV administered intramuscularly (IM) at different dosages approximately 21 days apart given with or without MF59(R) adjuvant; 2) To assess the serum hemagglutinin inhibition (HAI) and neutralizing (Neut) antibody responses approximately 21 days following receipt of two doses of 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without MF59(R) adjuvant.

This is a randomized, double-blinded, Phase II study in healthy males and non-pregnant females, 18-64 years of age. This clinical trial is designed to assess the safety, reactogenicity, and immunogenicity of a pre-pandemic 2017 monovalent inactivated influenza A/H7N9 virus vaccine (2017 H7N9 IIV) manufactured by Seqirus Inc (Seqirus) administered at different dosages (3.75 mcg, 7.5 mcg and 15 mcg of hemagglutinin (HA) per dose) given with MF59(R) adjuvant manufactured by Seqirus Inc., or without adjuvant (15 mcg of HA per dose). Phosphate buffered saline (PBS) diluent manufactured by Patheon Manufacturing Services LLC will be used to achieve certain targeted doses. Approximately 371 subjects who are in good health and meet all eligibility criteria will be randomized into one of 4 study groups. The study will be conducted at up to 7 Vaccine and Treatment Unit (VTEU) sites and will last approximately 17 months, with subject participation duration of approximately 13 months. The Primary Objectives of the study are: 1) To assess the safety and reactogenicity following receipt of two doses of 2017 H7N9 IIV administered intramuscularly (IM) at different dosages approximately 21 days apart given with or without MF59(R) adjuvant; 2) To assess the serum hemagglutinin inhibition (HAI) and Neutralizing (Neut) antibody responses approximately 21 days following receipt of two doses of 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without MF59(R) adjuvant.

The secondary Objectives are: 1) To assess all unsolicited non-serious Adverse Events (AEs) following receipt of two doses of a 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without MF59(R) adjuvant; 2) To assess medically-attended adverse events (MAAEs) including new-onset chronic medical conditions (NOCMCs), potentially immune-mediated medical conditions (PIMMCs), and all Serious Adverse Events (SAEs) following receipt of two doses of a 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without MF59(R) adjuvant; 3) To assess the serum HAI and Neut antibody responses approximately 7 and 21 days following receipt of a single dose, and approximately 7 days following receipt of two doses of 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without MF59(R) adjuvant.

Eligibility Criteria:
Inclusion Criteria:

1. Provide written informed consent prior to initiation of any study procedures.
2. Are able to understand and comply with planned study procedures and be available for all study visits.
3. Are males or non-pregnant females, 18-64 years of age, inclusive.
4. Are in good health\*. \*As determined by physical examination and medical history to evaluate acute or currently ongoing chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, Emergency Room, or urgent care for condition and no adverse symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrollment. Any prescription change that is due to 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. Any change in prescription medication due to improvement of a disease outcome, as determined by the site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and study vaccination are acceptable provided there was no deterioration in the subject's chronic medical condition that necessitated a medication change, and there is no additional risk to the subject or interference with the evaluation of responses to study vaccination. \[Topical, nasal, and inhaled medications (with the exception of inhaled corticosteroids), herbals, vitamins, and supplements are permitted\].
5. Oral temperature is less than 100.0 degree Fahrenheit.
6. Pulse is 47 to 100 beats per minute, inclusive.
7. Systolic blood pressure is 85 to 150 millimeters of Mercury, inclusive.
8. Diastolic blood pressure is 55 to 95 millimeters of Mercury, inclusive.
9. Women of childbearing potential\* must agree to practice an acceptable contraception method\*\* from 30 days before first study vaccination until 60 days after last study vaccination.

   \*Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \< 1 year of the last menses if menopausal.

   \*\*Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the first study vaccination, barrier methods such as male or female condoms with spermicide or with the use of applied spermicide, intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to study vaccination.

Exclusion Criteria:

1. Have an acute illness\*, as determined by the site Principal Investigatoor or appropriate sub-investigator, within 72 hours prior to study vaccination.

   \*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site principal investigator or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
2. Have any medical disease or condition that, in the opinion of the site Principal Investigator or appropriate sub-investigator, is a contraindication to study participation\*.

   \*Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial.
3. Have immunosuppression as a result of an underlying illness or treatment, a recent history or current use of immunosuppressive or immunomodulating disease therapy.
4. Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study vaccination.
5. Have known active neoplastic disease or a history of any hematologic malignancy. Non-melanoma, treated, skin cancers are permitted.
6. Have known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
7. Have known hypersensitivity or allergy to eggs, egg or chicken protein, neomycin, kanamycin, formaldehyde, polysorbate 80, cetyltrimethylammonium bromide (CTAB), squalene-based adjuvants, or other components of the study vaccine.
8. Have a history of severe reactions following previous immunization with licensed or unlicensed influenza vaccines.
9. Have a history of Guillian-Barre Syndrome.
10. Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination.
11. Have a history of Potentially Immune Mediated Medical Conditions (PIMMCs)
12. Have a history of alcohol or drug abuse within 5 years prior to study vaccination.
13. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere with subject compliance or safety evaluations.
14. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination.
15. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 30 days prior to study vaccination.
16. Have taken high-dose inhaled corticosteroids\* within 30 days prior to each study vaccination.

    \*High-dose defined as per age as using inhaled high dose per reference chart https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf.
17. Received a licensed live vaccine within 30 days prior to the first study vaccination, or plan to receive a licensed live vaccine within 30 days before or after each study vaccination.
18. Received or plan to receive a licensed, inactivated, vaccine (excluding all flu vaccines) within 14 days before or after each study vaccination.
19. Received or plan to receive seasonal inactivated influenza virus (IIV) within 21 days before or after each study vaccination.
20. Received immunoglobulin or other blood products (with exception of Rho D immunoglobulin) within 90 days prior to each study vaccination.
21. Received an experimental agent\* within 30 days prior to the first study vaccination, or expect to receive an experimental agent\*\* during the 13-month trial-reporting period.

    \*Including vaccine, drug, biologic, device, blood product, or medication.

    \*\*Other than from participation in this trial.
22. Are participating or plan to participate in another clinical trial with an interventional agent\* that will be received during the 13-month trial-reporting period.

    \*Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication.
23. Received or plan to receive an influenza A / H7 vaccine\* or have a history of influenza A / H7 subtype infection.

    \*And assigned to a group receiving influenza A / H7 vaccine, does not apply to documented placebo recipients.
24. Have traveled to mainland China and had substantial\* direct contact with live or freshly slaughtered poultry or pigeons within the past five years.

    \*Substantial contact is defined as visited a poultry farm and/or a live poultry market.
25. Occupational exposure to or substantial direct physical contact\* with birds in the past year and through the 21 days after the second study vaccination.

    \*Exposure to free range chickens in the yard is exclusionary. Casual contact with birds at petting zoos or county or state fairs or having pet birds does not exclude subjects from study participation.
26. Female subjects who are breastfeeding at any given time from the first study vaccination until 30 days after the last study vaccination.
27. Plan to travel outside the US (continental US, Hawaii, and Alaska) from enrollment through 21 days after the second study vaccination.
28. Receipt of Multimeric-001 (M-001) vaccine.