Reactogenicity, Safety and Immunogenicity of a LAIV А/17/Hong Kong/2017/75108 H7N9 Influenza Vaccine

This is a phase I, double-blind, individually-randomized (3:1, vaccine:placebo), controlled trial with two groups, LAIV H7N9 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 portion of subjects initially, the total cohort of 40 subjects will be enrolled in two cohorts: one cohort of 20 subjects, randomized at 3:1 (15 vaccine and 5 placebo), followed two weeks later by a second identically composed cohort of 20 subjects randomized at 3:1 (15 vaccine and 5 placebo). After all volunteers of the first cohort have been observed for the first isolation period (Day 0 to Day 6) after receipt of dose one, an interim safety review will be performed by a SMC. The SMC will review all AEs and shedding data, for all subjects and will advise if the volunteers of the first cohort may receive dose two of study vaccine or placebo and if the additional 20 volunteers of the second cohort may be enrolled into the study. For each cohort, the procedures and timelines are here summarized.

On the day of first screening (S1), 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)], routine biochemical and hematological blood tests and routine urinalysis.

For screening for serologic evidence of chronic viral infections, appropriate pre- and post-test counseling must be provided.

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 and examination by neurologist. Fully eligible subjects will be admitted to the isolation unit. At that time, nasal swabs, nasal wick, saliva 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 urinanalysis; 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 and investigators conducting assessments of safety will be unaware of which allocation, LAIV H7N9 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 6 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 RT-PCR positivity on a nasal swabs specimen, in the 2 days prior to each planned discharge day after each dose (Days 5 or 6 or Days 33 or 34) will be kept in the isolation until PCR-diagnosis results confirm that no influenza virus is present in a tested clinical specimens for at least two consecutive days.

Any subject still exhibiting evidence of influenza virus shedding in a nasal swabs on Days 5 or 6 or Days 33 or 34 post-administration with each dose will be placed on approved 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.

After second discharge from the isolation unit, subjects will again complete diary cards for AEs and use of concomitant medications. Subjects will then return to the study center at four weeks (Day 56) after administration of dose two of study vaccine or placebo for their study visit. Interim histories (and diary cards) will again be reviewed and blood and nasal wick specimens will be collected. Women will also undergo a final pregnancy screen.

For assessment of safety, subjects will be observed for two hours after each administration of study vaccine or placebo. Twice daily (early morning and late afternoon) examination will be also used to assess reactions for 6 days after each administration of study vaccine or placebo. ENT examination and examination by neurologist will also occur once per day on Days 6, 28, 34 and 56. Subjects will complete diary cards for unsolicited AEs from the day of each discharge until return to the isolation unit for dose two (at Day 28) or until return to the study center for the final study visit at four weeks post dose two (at Day 56). To assess safety, blood and urine specimens will also be collected on days 3, 6, 28 (prior to administration of dose two of study vaccine or placebo), days 31, 34 and 56 for testing by routine biochemical and hematological blood tests and urinanalysis respectively. On the 0th, 3rd and 31st days of the study, instrumental examinations will be carried out (ECG, echocardiogram, and spirometry with the assessment of respiratory function). In order to assess late adverse events, volunteers will remain under observation for 6 months after the second vaccination (28th day of the study) with monthly monitoring of their health condition by telephone.

For the evaluation of mucosal IgA antibody, nasal wick and saliva specimens will be collected on Day 0 (prior to administration of dose one of study vaccine or placebo), on Day 28 (prior to administration of dose two of study vaccine or placebo) and on Day 56. For the evaluation of serum antibodies (by HAI, microneutralization and IgA and IgG ELISA), serum specimens will be collected on Day 0 (prior to administration of dose one of study vaccine or placebo), on Day 28 (prior to administration of dose two of study vaccine or placebo) and on Day 56. To study virus infectivity (by isolation in embryonated chicken eggs) and viral genetic stability (by molecular sequencing of any isolated virus), nasal swab specimens will be taken on Days 1, 2, 3, 5, 6, 29, 30 and 31. To assess priming and stimulation of cytotoxic T lymphocytes and other cytokine indicators, whole blood for isolation of PBMCs will be collected on Days 0 (prior to administration of dose one of study vaccine or placebo), on Day 6 (prior to discharge from isolation unit), on Day 28 (prior to administration of dose two of study vaccine or placebo), and on Day 56.

The primary study hypothesis is that two doses of cold-adapted, live monovalent (H7N9) influenza vaccine will be safe in healthy adults.

Observed proportions of subjects exhibiting reactions, adverse events and clinical chemistry anomalies, as well as proportions of subjects seroconverting or seropositive for influenza antibodies using various methods, will be estimated with 95% confidence intervals. Geometric mean titers (GMTs) will be estimated with 95% confidence intervals. The study will be primarily evaluated based on the exact two-sided 95% confidence interval of the percentage of vaccine recipients experiencing vaccine-related serious adverse events within 28 days of any dose.