A Phase I Study Priming With an Inactivated A/H7N9 Influenza Virus Vaccine With or Without MF59 Adjuvant Followed by Live Attenuated A/H7N9 Influenza Virus Vaccine

The study will be conducted as a Phase I prospective, randomized study in healthy adult
subjects at a single center. Adult subjects age 18 to 47 years and meeting all enrollment
criteria will choose to participate as subjects who receive unadjuvanted or adjuvanted H7H9
pIIV vaccine followed by a live vaccine boost at 4 weeks (Group 1, n=24), 12 weeks (Group 2,
n=24), or 24 weeks (Group 3, n=24), or to be in an observational group (Group 4, n=16) which
will not be scheduled for a booster dose but may serve as a roll-over group for subjects who
withdraw prior to the second vaccination but agree to remain in follow-up. Within each group,
subjects will be randomized at a 1:1 ratio to receive a single dose of either unadjuvanted
H7N9 pIIV at 15 mcg (Subgroup A), or the same vaccine adjuvanted with the oil-in-water
emulsion, MF59, (Subgroup B) delivered intramuscularly. Finally, a fifth group (Group 5,
n=12) will receive two intramuscular doses of adjuvanted H7N9 pIIV separated by four weeks.
The total duration of study participation for all subjects will be approximately 13 months.
Recruitment, enrollment and administration of study product will be suspended when one of the
following occurs in the clinical or research laboratory at the clinical site: at least two
respiratory cultures or PCR assays are determined to be positive for influenza or at least
10% diagnostic tests (rapid tests, respiratory cultures or PCR assays) performed for
influenza as positive during two consecutive weeks in the clinical or research laboratory at
the clinical site. Recruitment, enrollment and administration of study product may be resumed
after 2 weeks without a signal that influenza is still circulating in the community, as
defined by the same measures that indicate the start of influenza season (i.e., less than 2
respiratory cultures or PCR assays are determined to positive for influenza or less than 10%
of diagnostic tests performed or influenza with positive results). The primary objectives of
this study are to (1) assess the safety of H7N9 pLAIV administered to individuals who have
previously received MF59-adjuvanted or unadjuvanted H7N9 pIIV, (2) evaluate the ability of a
single dose of unadjuvanted H7N9 pIIV to prime for enhanced immunogenicity (booster response)
to subsequent administration of antigenically-matched H7N9 pLAIV vaccine, and to (3) evaluate
the ability of a single dose of MF59-adjuvanted H7N9 pIIV to prime for enhanced
immunogenicity (booster response) to subsequent administration of antigenically-matched H7N9
pLAIV vaccine. The secondary objectives of this study are to (1) assess the safety of priming
with MF59-adjuvanted H7N9 pIIV or unadjuvanted H7N9 pIIV, (2) assess the immune response in
subjects vaccinated with a single dose of MF59-adjuvanted H7N9 pIIV or a single dose of
unadjuvanted H7N9 pIIV, and to (3) compare the booster effect seen after intervals of 4
weeks, 12 weeks, or 24 weeks within each priming group.

Inclusion Criteria:

1. Provide written informed consent prior to initiation of any study procedures,
including future use of specimens.

2. Are able to understand and comply with planned study procedures and be available for
all study visits.

3. Are males or non-pregnant, non-breastfeeding females, 18 to 47 years old, inclusive.

4. Are in good health, as determined by medical history, and targeted physical
examination to ensure any existing medical diagnoses or conditions (except those
exclusionary) are stable* **.

*Stable chronic medical condition - no change in prescription medication, dose, or
frequency of medication in the last 3 months (defined as 90 days) and health outcomes
of the specific disease are considered to be within acceptable limits in the last 6
months (defined as 180 days). Any 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 violation 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 violation 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. Note:
Topical, nasal, and inhaled medications (with the exception of steroids as outlined in
the Subject Exclusion Criteria), vitamins, and contraceptives are permitted.

5. Oral temperature is less than 100.4 degrees Fahrenheit.

6. Pulse is 55 to 100 bpm, inclusive.

7. Systolic blood pressure is 90 to 140 mmHg, inclusive.

8. Diastolic blood pressure is 55 to 90 mmHg, inclusive.

9. Women of childbearing potential* in sexual relationships with men must use an
acceptable method of contraception** from 30 days prior to pIIV administration until
90 days after last study vaccination.

*Not sterilized via tubal ligation, bilateral oophorectomy or hysterectomy and still
menstruating or < 1 year of the last menses if menopausal).

**Includes, but is not limited to, abstinence from intercourse with a male partner,
monogamous relationship with a vasectomized partner, male condoms with the use of
applied spermicide, intrauterine devices, and licensed hormonal methods, with use of a
highly effective method of contraception for a minimum of 30 days prior to study
product exposure and agree to practice highly effective contraception for the duration
of study product exposure, including 3 months (defined as 90 days) after the last
study vaccination. A highly effective method of contraception is defined as one which
results in a low failure rate (i.e., less than 1% per year) when used consistently and
correctly.

10. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 24 hours prior to study vaccination.

Exclusion Criteria:

1. Have an acute illness within 72 hours prior to study vaccination.

2. Any medical disease or condition that, in the opinion of the investigator, is a
contraindication to study participation*.

*Includes medical disease or condition that would place the subject at an unacceptable
risk of injury, render them unable to meet the requirements of the protocol, or may
interfere with the evaluation of responses or their successful completion of the
study.

3. Have history of any significant acute or chronic medical conditions* or need for
chronic medications that, in the opinion of the investigator, will interfere with
immunogenicity or affect safety.

*Chronic medical condition - a medical condition persisting 3 months (defined as 90
days) or longer

4. Have immunosuppression or are taking systemic immunosuppressants as a result of an
underlying illness or treatment.

5. Diagnosis of asthma or reactive airway disease within the past 2 years.

6. History of surgical splenectomy.

7. Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 36 months prior
to vaccination.

8. Have known active neoplastic disease or a history of any hematologic malignancy.

9. Have known hepatitis B or hepatitis C infection.

10. Have known hypersensitivity or allergy to eggs, egg or chicken protein, squalene-based
adjuvants, or other components of the study vaccine.

11. Known allergy or intolerance to oseltamivir.

12. Have a history of severe reactions following previous immunization with licensed or
unlicensed influenza virus vaccines.

13. Have a history of Guillain-Barré Syndrome.

14. Have a history of neuralgia, paresthesia, neuritis, convulsions, or encephalomyelitis
within 90 days prior to study vaccination.

15. Have a history of autoimmune disease*.

*Including, but not limited to, neuroinflammatory diseases, vasculitis, clotting
disorders, dermatitis, arthritis, thyroiditis, or muscle, liver, or kidney disease.

16. Have a history of alcohol or drug abuse within 5 years prior to study vaccination.

17. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other
psychiatric diagnosis that may interfere with subject compliance or safety
evaluations.

18. 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.

19. Have taken oral or parenteral corticosteroids of any dose within 30 days prior to
study vaccination.

20. Chronic use (defined as daily use for > 7days within the 30 days prior to study
vaccination) of any inhaled medication, including inhaled corticosteroids.

21. Received any licensed live vaccine within 30 days prior to pIIV vaccination. This is
inclusive of licensed seasonal influenza vaccines.

22. Received any licensed inactivated vaccine within 14 days prior to pIIV vaccination.
This is inclusive of licensed seasonal influenza vaccines.

23. Planned receipt of any vaccine from the first study vaccination through the follow-up
visit at approximately 56 days after the second study vaccination. This is inclusive
of licensed seasonal influenza vaccines

24. Received immunoglobulin or other blood products (with exception of Rho D
immunoglobulin) within 90 days prior to study vaccination.

25. Received an experimental agent* within 30 days prior to pIIV administration or planned
receipt of an experimental agent to within 90 days after pLAIV administration.

*Includes vaccine, drug, biologic, device, blood product, or medication.

26. Plans to enroll in another clinical trial* that could interfere with safety assessment
of the investigational product at any time during the study period.

*Includes trials that have a study intervention such as a drug, biologic, or device

27. Prior participation in a clinical trial of influenza A/H7 vaccine* or have a history
of A/H7 actual or potential exposure or infection prior to the first study
vaccination.

*Documented receipt of placebo in such a trial is not exclusionary

28. Plan to travel outside the U.S. (continental U.S., Hawaii and Alaska) in the time
between the first study vaccination and 56 days after the second study vaccination.

29. Positive screening pregnancy test or other evidence of pregnancy.

30. Female subjects who are breastfeeding or plan to breastfeed at any given time from the
first study vaccination until 30 days after their last study vaccination.

31. Seropositive to the H7N9 influenza A virus (serum HAI titer > 1:8) during the
screening period prior to the first study vaccination.

32. Positive urine drug screen for opiates and cocaine at the time of check-in for the
period of confinement.

33. Positive ELISA and confirmatory Western blot tests for human immunodeficiency virus-1
(HIV-1) during the screening period prior to vaccination.

34. Current smoker unwilling to stop smoking for the period of confinement. A nicotine
patch during the period of confinement may be offered.