Study of Immune Responses in Healthy Adults Receiving Live Influenza Virus Vaccines

Influenza A viruses are widely distributed in nature and exist as many different subtypes.
Pandemics of influenza can occur, and vaccine development is focused on those subtypes that
are predicted to represent the greatest pandemic threat to the human population. This study
seeks to understand the host factors that affect the replication and immune response of
seasonal and candidate pandemic LAIVs in humans and to develop biomarkers that can predict
the viral shedding and immune response to LAIVs.

Three vaccines will be evaluated: the licensed seasonal LAIV, with a focus on the H3N2
component; the H9N2 G9/AA ca vaccine, which is among the most immunogenic of the candidate
pandemic LAIVs evaluated to date; and the H2N3 MO 2066/AA ca vaccine, which is among the
least immunogenic of the candidate pandemic LAIVs evaluated to date. The seasonal LAIV will
be evaluated in an outpatient setting, while the other two vaccines will be evaluated in an
inpatient setting. In each setting, some participants will receive a placebo vaccine.

Study participants will be assigned to one of four groups. Participants who are seronegative
to both H9N2 G9/AA ca and H2N3 MO 2006/AA ca viruses will be randomly assigned to receive
one of those vaccines (Group 1: H9N2 G9/AA ca; Group 2: H2N3 MO 2006/AA ca) or placebo
(Group 4) and will remain in an inpatient isolation facility. Participants who are
seronegative to the H3 component of seasonal LAIV will be randomly assigned to receive
either seasonal vaccine (Group 3) or placebo (Group 4) and will be followed as outpatients.

All participants will remain in the study for 56 days. Participants in the inpatient arms
will be admitted on Day -2, will receive study vaccine on Day 0, and will undergo a basic
history, physical examination, and nasal wash each day until discharge. On some study days,
inpatient participants will undergo a blood collection and/or a nasal swab; at the screening
visit and on Day -1 or Day -2, participants will give a urine sample.

Participants in the outpatient arms will receive study vaccine on Day 0 and will have study
visits on Days 1, 2, 3, 4, 5, 6, 7, 14, 28, and 56. On Days 1 through 7, participants will
undergo a basic history, physical examination, and nasal wash. On some visits, participants
may undergo a blood collection and/or a nasal swab; at the screening visit and on Day -1,
participants will give a urine sample. Unused blood or nasal wash samples will be stored and
may be used in future research studies.

Inclusion Criteria:

- General good health, without significant medical illness, physical examination
findings, or significant laboratory abnormalities as determined by the investigator

- Agree to storage of blood specimens for future research

- Available for the duration of the trial. For the inpatient component of the study,
participants must be willing and able to remain within the Isolation Unit for the
specified duration of confinement. For the outpatient component of the study,
participants must be willing and able to make daily outpatient follow-up visits as
specified by the protocol.

- Willingness to participate in the study as evidenced by signing the informed consent
document

- Female participants must agree to use effective birth control methods for the
duration of the study (for example, pharmacologic contraceptives including oral,
parenteral, and transcutaneous delivery; condoms with spermicide; diaphragm with
spermicide; intrauterine device; abstinence from heterosexual intercourse; or
surgical sterilization). All female participants will be considered being of
child-bearing potential except those who have undergone hysterectomy and those in
whom menopause occurred at least 1 year prior to the study.

Exclusion Criteria:

- Pregnancy as determined by a positive human choriogonadotropin (beta-HCG) test

- Currently breastfeeding

- Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,
rheumatologic, autoimmune, or renal disease by history, physical examination, and/or
laboratory studies including urine testing. Clinically significant alanine
aminotransferase (ALT) levels, as determined by the Principal Investigator, will be
exclusionary at baseline, prior to vaccination.

- Behavioral or cognitive impairment or psychiatric disease that in the opinion of the
investigator affects the ability of the subject to understand and cooperate with the
study protocol

- Previous enrollment in an H2 or H9 influenza vaccine trial or in any study of an
avian influenza vaccine

- For the inpatient arm, seropositive to the H2N3 influenza A virus or the H9N2
influenza A virus (serum HAI titer >1:8). For the outpatient arm, seropositive to the
H3N2 component of seasonal LAIV (serum hemagglutination inhibition [HAI] titer
greater than 1:8).

- Positive urine drug toxicology test indicating narcotic use/dependency

- Have medical, occupational, or family problems as a result of alcohol or illicit drug
use during the past 12 months

- Other condition that in the opinion of the investigator would jeopardize the safety
or rights of a participant participating in the trial or would render the subject
unable to comply with the protocol

- History of anaphylaxis

- Allergy to oseltamivir as determined by subject report

- Current diagnosis of asthma or reactive airway disease (within the past 2 years)

- History of Guillain-Barré Syndrome

- Positive ELISA and confirmatory Western blot tests for human immunodeficiency virus-1
(HIV-1)

- Positive ELISA and confirmatory test (e.g., recombinant immunoblot assay) for
hepatitis C virus (HCV)

- Positive hepatitis B virus surface antigen (HBsAg) by ELISA

- Known immunodeficiency syndrome

- Use of corticosteroids (excluding topical preparations) or immunosuppressive drugs
within 30 days prior to vaccination

- Receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to
study vaccination

- History of a surgical splenectomy

- Receipt of blood or blood-derived products (including immunoglobulin) within 6 months
prior to study vaccination

- Current smoker unwilling to stop smoking for the duration of the study

- A current smoker includes anyone stating he/she currently smokes any amount of a
tobacco product

- The decision to exclude a potential participant is determined by medical history
and a clinician's clinical judgment based on the physical examination

- After admission to the unit, nicotine patches will be provided to current
smokers who request them for the inpatient portion of the study

- Travel to the Southern Hemisphere within 14 days prior to study vaccination

- Travel on a cruise ship within 14 days prior to study vaccination

- Receipt of another investigational vaccine or drug within 30 days prior to study
vaccination

- Allergy to eggs or egg products