Effect of Age and Prior Immunity on Response to H1N1 Vaccines in Children

The study will be conducted as a randomized, prospective, open-label evaluation of the
clinical tolerability, vaccine virus shedding, and serum and mucosal antibody response to
vaccination with either live monovalent novel H1N1 influenza vaccine (LAIV) or monovalent
inactivated novel H1N1 influenza vaccine (IIV) in healthy children between the ages of 4 and
9 years. Children will be screened for antibody to A/Brisbane/57/07 (H1N1) and
A/California/07/09 (H1N1) prior to randomization. Children with evidence of prior exposure
to the 2009 pandemic H1N1 virus will be excluded. Those with antibodies to A/Brisbane/57/07
(H1N1) will be stratified by preexisting antibody. Vaccine will be administered on days 0
and 28.

Safety of vaccination will be assessed using symptoms collected by parents for 7 days after
each dose of vaccine. Serum will be obtained prior to and on day 28 following each dose of
vaccine and assessed for antibody by HAI, ELISA, B-cell ELISPOT and neutralization
techniques. Nasal secretions will be obtained by nasal aspiration prior to and on day 28
after each dose and assessed for HA-specific IgA antibody by ELISA. Nasal swabs will be
obtained on days 2, 4, and 7 after each dose of live vaccine and assessed for the presence
and magnitude of vaccine virus shedding of the live attenuated vaccine by rtRT-PCR and
TCID50 on MDCK cells.

Inclusion Criteria:

- Aged between 4 and 9 years, inclusive.

- Pre-vaccination serum HAI titer to A/California/07/09 of 8 or less

- No prior history of laboratory documented infection with novel H1N1 virus or
immunization with novel H1N1 vaccine.

- in good health, as determined by: vital signs (heart rate <140 bpm; blood pressure:
systolic ≥ 90 mm Hg and ≤140 mm Hg; diastolic ≤ 90 mm Hg; oral temperature <100.0ºF);
medical history; and targeted physical examination, when necessary, based on medical
history. Stable medical condition is defined as: no recent increase in prescription
medication, dose, or frequency of medication in the last 3 months and health outcomes
of the specific disease are considered to be within acceptable limits in the last 6
months.

- subject/parents are able to understand and comply with the planned study procedures,
including being available for all study visits.

- subject/parents have provided informed consent prior to any study procedures. (An
assent will be obtained for all children 6 years and older)

Exclusion Criteria:

- a previous history of vaccination against novel H1N1 virus or a laboratory documented
history of previous novel H1N1 infection.

- History of egg allergy or allergy to other components of vaccine.

- History of wheezing.

- immunosuppressed as a result of an underlying illness or treatment with
immunosuppressive or cytotoxic drugs, or use of anticancer chemotherapy or radiation
therapy.

- has an active neoplastic disease.

- has long-term (greater than 2 weeks) use of oral or parenteral steroids, or high-dose
inhaled steroids (>800 mg/day of beclomethasone dipropionate or equivalent) within
the preceding 6 months (nasal and topical steroids are allowed).

- received immunoglobulin or another blood product within the 3 months prior to
enrollment in this study.

- has received an inactivated vaccine within the 2 weeks or a live vaccine within the 4
weeks prior to enrollment in this study or plans to receive another vaccine within
the next 28 days (or 56 days for vaccine naïve recipients).

- has an acute or chronic medical condition that, in the opinion of the investigator,
would render vaccination unsafe or would interfere with the evaluation of responses.
These conditions include chronic conditions recognized as risk factors for influenza
complications or as contraindications for live vaccination, including chronic cardiac
(exclusive of hypertension) or pulmonary conditions (including asthma), diabetes
mellitus, or renal impairment.

- has an acute illness or an oral temperature greater than 99.9 degrees F (37.7 degrees
C) within 3 days prior to enrollment or vaccination. Subjects who had an acute
illness that was treated symptoms resolved are eligible to enroll as long as
treatment is completed and symptoms resolve > 3 days prior to enrollment.

- is currently participating or plans to participate in a study that involves an
experimental agent (vaccine, drug, biologic, device, blood product, or medication) or
has received an experimental agent within 1 month prior to enrollment in this study,
or expects to receive another experimental agent during participation in this study,
or intends to donate blood during the study period.

- has any condition that would, in the opinion of the site investigator, place the
subject at an unacceptable risk of injury or render the subject unable to meet the
requirements of the protocol.

- has a known human immunodeficiency virus, hepatitis B, or hepatitis C infection.

- has a previous history of Guillain-Barré syndrome within 6 weeks of receipt of
influenza vaccination.

- has any condition that the principal investigator (PI) believes may interfere with
successful completion of the study.