Reactogenicity, Safety and Immunogenicity of a Live Monovalent A/17/Mallard/Netherlands/00/95 (H7N3) Influenza Vaccine

This is a phase I, double-blind, individually-randomized (3:1, vaccine:placebo), controlled trial with two groups, LAIV H7N3 and matched placebo. Healthy male and female adults 18 through 49 years of age will be invited to participate. For feasibility reasons and in order for an independent Safety Monitoring Committee (SMC) to review safety data in a small group of subjects initially, the total cohort of 40 subjects will be enrolled in two sub-cohorts: one cohort of 12 subjects, randomized at 3:1 (9 vaccine and 3 placebo), followed two weeks later by a second cohort of 28 subjects randomized at 3:1 (21 vaccine and 7 placebo). After all 12 volunteers of the first sub-cohort have been observed for the first isolation period (Day 1 to Day 7), an interim safety review will be performed by the SMC. The SMC will review all adverse events (AEs), including clinical laboratory evaluations (pre- and post-vaccination) and shedding data, for all subjects and will advise if the volunteers of the first sub-cohort may receive dose two of study vaccine or placebo and if the additional 28 volunteers of the second sub-cohort may be enrolled into the study. As for the first sub-cohort, the SMC will also review all safety data for the second sub-cohort and for the entire participant population of the trial. For each sub-cohort, the procedures and timelines are here summarized.

On the day of first screening, about 7 days (between 4 and 14 days) prior to administration of dose one of study vaccine or placebo, subjects will be screened for eligibility through medical history review, physical examination, testing for serologic evidence of chronic viral infection [human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV), with proper pre- and post-test counseling], routine biochemical and hematological blood tests and urinalysis by dipstick.

Subject screening for eligibility will continue and be completed on the second screening day (S2). This second screening day will occur the same day as scheduled admission to the isolation unit and administration of study vaccine or placebo (Day 0). Women will undergo pregnancy tests using urine samples. All subjects will undergo an ear, nose and throat (ENT) examination. Fully eligible subjects will be admitted to the isolation unit. At that time, nasal swab, nasal wick, and blood specimens will be collected for virologic and immunological testing prior to administration of study vaccine or placebo. Blood and urine specimens will be again collected for routine biochemical and hematological blood tests and urinalysis by dipstick; these results will serve to define baseline status for subject prior to receipt of study vaccine or placebo but will not be used for screening purposes. Subjects will be unaware of which allocation, LAIV H7N3 or matched placebo, is received; study vaccine and placebo will be masked. Subjects will be carefully monitored for adverse reactions while in the isolation unit.

All subjects will remain in the isolation unit for at least 7 days after receipt of study vaccine or placebo. Nasal swabs will be collected daily while subjects are in isolation to test for presence of influenza virus shed in the nasal passage. Any subject exhibiting conjunctivitis will also have a conjunctival swab collected on the day of appearance of the sign. Any subject exhibiting influenza A virus shedding, as determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) positivity on a nasal swab specimen, in the 2 days prior to each planned discharge day after each dose (Days 6 or 7 or Days 34 or 35) will be kept in the isolation until PCR-diagnosis results confirm that no influenza virus is present in a tested clinical specimen for at least two consecutive days. Any subject still exhibiting evidence of influenza virus shedding in a nasal swab on Days 6 or 7 or Days 34 or 35 post-administration with each dose might be placed on influenza antiviral (oseltamivir) treatment at the standard dose for treatment of 75 milligrams (mg) twice a day for a course of 5 days.

After discharge from the isolation unit, subjects will complete diary cards for AEs and use of concomitant medications. Subjects will return to the isolation unit at four weeks (Day 28) after administration of dose one of study vaccine or placebo. At that time, similar procedures will be used for admittance to the isolation unit, for receipt of dose two of study vaccine or placebo and for isolation and follow-up, with the additional procedure of review of interim histories (and diary cards) since first discharge after dose one.