Study of Immune Responses in Healthy Adults Receiving Live Influenza Virus Vaccines
Study of Immune Responses in Healthy Adults Receiving Live Influenza Virus Vaccines
This study seeks to understand the host factors that affect the replication and immune
 response of seasonal and candidate pandemic live attenuated influenza vaccine (LAIV) in
 humans and to develop biomarkers that can predict the viral shedding and immune response to
 LAIVs.
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