Safety Trial of Live Attenuated Influenza (H7N3) Vaccine
Condition: Influenza; Avian Influenza
MeSH terms: Influenza, Human; Influenza in Birds
Study type: Interventional
Phase: Phase 1

Summary: 
      The study hypothesis is that two doses of cold-adapted, live monovalent
      A/17/mallard/Netherlands/00/95 (H7N3) influenza vaccine will be safe and immunogenic in
      healthy adults.
    

Detailed description: 
      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.

      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 final
      study visit. Interim histories (and diary cards) will again be reviewed and final blood and
      nasal wick specimens will be collected. Women will also undergo a final pregnancy screen.
      Subjects will complete the study at this time.

      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 7 days after each administration of study vaccine or
      placebo. ENT examination will also occur once per day on Days 7, 28, 35 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 7, 28 (prior to administration of dose two of study
      vaccine or placebo), 35 and 56, for testing by routine biochemical and hematological blood
      tests and by urinalysis by dipstick.

      For the evaluation of mucosal immunoglobulin A (IgA) antibody, nasal wick 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 hemagglutination inhibition [HAI], microneutralization and
      IgA and immunoglobulin G [IgG] EIA), 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 chicken embryos) and stability (by molecular sequencing of any isolated virus),
      nasal swab specimens will be taken on Days 1, 2, 3, 5, 7, 29, and 31. To assess priming and
      stimulation of cytotoxic T lymphocytes and other cytokine indicators, whole blood for
      isolation of peripheral blood mononuclear cells (PBMCs) will be collected on Days 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.
    

Intervention name(s): LAIV H7N3; placebo
Intervention type(s): Biological; Biological
Intervention description(s): 2 doses of vaccine; 2 doses of placebo
Other intervention name(s): A/17/mallard/Netherlands/00/95 (H7N3)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Influenza; Vaccine; Pandemic; H7N3