Experimental AD4-H5-VTN Vaccine in Healthy Volunteers
Condition: H5N1 Influenza
MeSH terms: Influenza, Human; Influenza in Birds
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Phase 1 randomized, single center, dose-escalation study designed to evaluate the
      safety and immunogenicity of live, replication competent recombinant Adenovirus type
      4-H5N1Influenza Vietnam 1194 Hemagglutinin (HA) (Ad4-H5-Vtn). Determining the optimal route
      and dose for this recombinant platform will greatly accelerate investigations of this vector
      as an influenza vaccine and an HIV vaccine platform.

      Intranasal and tonsillar administration of the vaccine will be separately assessed. The oral
      enteric-coated capsule will also be assessed in 10 outpatients using similar blood sampling
      for comparison. The Ad4-H5-Vtn orally administered as enteric-coated capsules has already
      been evaluated in an ascending dose Phase 1 study, in dosages as high as 10(11) viral
      particles (vp).

      The primary goal of this study is to evaluate safety of ascending dosages of the Ad4-H5-Vtn
      vaccine following intranasal and tonsillar administration. A dosage or dosages will be
      selected to further evaluate the humoral, cellular, and mucosal immune responses against both
      the vector and the inserted gene. The Ad4-H5-Vtn will be initiated at 10(3) vp. Once safety
      is established at the initial dose, a second round of testing will begin at the next ten-fold
      higher dose. The Ad4-H5-Vtn vaccine will be assessed in three participants at each dosage
      level. The maximum viral dose administered by the tonsillar route will be 10(8) vp.

      In addition to clinical and laboratory monitoring of safety, the principal assessments will
      be shedding of the Ad4-H5-Vtn virus in rectal, cervicovaginal, throat, and nasal swabs, and
      assessment of the antibody (mucosal and systemic) response to the HA and to the Ad4 virus.
      When safety has been confirmed in all three participants at a given dosage level, the next
      higher dose group is enrolled. If one grade 3 or greater toxicity (or pre-specified Grade 2
      toxicity, see Section 3.4) attributable to the vaccine is observed, the group will be
      expanded at that dose. If a second attributable grade 3 or greater toxicity (or pre-specified
      Grade 2 toxicity, see Section 3.4) is observed, the dose will be reduced one level and the
      group will be expanded. Up to 25 Ad4-seronegative individuals will be enrolled at the maximum
      tolerated dose to fully evaluate safety and immunogenicity in the protocol.

      All participants will be followed for 28 days following immunization, and again at 8 and 26
      weeks to evaluate any long-term toxicity and persistence of immunity. Tonsillar Participants
      will receive a booster dose of vaccine [SK1]at the 26-week visit and be seen for follow-up
      visits at Weeks 30 and 34. Household and intimate contacts will also be enrolled and
      monitored for Adenovirus and HAI antibodies.
    

Detailed description: 
      This is a Phase 1 randomized, single center, dose-escalation study designed to evaluate the
      safety and immunogenicity of live, replication competent recombinant Adenovirus type
      4-H5N1Influenza Vietnam 1194 Hemagglutinin (HA) (Ad4-H5-Vtn). Determining the optimal route
      and dose for this recombinant platform will greatly accelerate investigations of this vector
      as an influenza vaccine and an HIV vaccine platform.

      Tonsillar administration of the vaccine will be separately assessed. The oral enteric-coated
      capsule will also be assessed in 10 outpatients using similar blood sampling for comparison.
      The Ad4-H5-Vtn orally administered as enteric-coated capsules has already been evaluated in
      an ascending dose Phase 1 study, in dosages as high as 10(11) viral particles (vp).

      The primary goal of this study is to evaluate safety of ascending dosages of the Ad4-H5-Vtn
      vaccine following intranasal and tonsillar administration. A dosage or dosages will be
      selected to further evaluate the humoral, cellular, and mucosal immune responses against both
      the vector and the inserted gene. The Ad4-H5-Vtn will be initiated at 10(3) vp. Once safety
      is established at the initial dose, a second round of testing will begin at the next ten-fold
      higher dose. The Ad4-H5-Vtn vaccine will be assessed in three participants at each dosage
      level. The maximum viral dose administered by the tonsillar route will be 10(8) vp.

      In addition to clinical and laboratory monitoring of safety, the principal assessments will
      be shedding of the Ad4-H5-Vtn virus in rectal, cervicovaginal, throat, and nasal swabs, and
      assessment of the antibody (mucosal and systemic) response to the HA and to the Ad4 virus.
      When safety has been confirmed in all three participants at a given dosage level, the next
      higher dose group is enrolled. If one grade 3 or greater toxicity (or pre-specified Grade 2
      toxicity, see Section 3.4) attributable to the vaccine is observed, the group will be
      expanded at that dose. If a second attributable grade 3 or greater toxicity (or pre-specified
      Grade 2 toxicity, see Section 3.4) is observed, the dose will be reduced one level and the
      group will be expanded. Up to 25 Ad4-seronegative individuals will be enrolled at the maximum
      tolerated dose to fully evaluate safety and immunogenicity in the protocol.

      All participants will be followed for 28 days following immunization, and again at 8 and 26
      weeks to evaluate any long-term toxicity and persistence of immunity. All subjects will be
      offered to receive a booster vaccination with a recombinant hemagglutinin influenza H5
      vaccine after the 26-week visit and be seen for follow-up visits 4 and 8 weeks following
      booster immunization, with an additional telephone follow-up 6 months after boosting.
      Household and intimate contacts will also be enrolled and monitored for Adenovirus and HAI
      antibodies following Ad4-H5-Vtn administration only; household and intimate contacts will not
      be enrolled or monitored during the boost portion of the study.

      We will conduct an expansion H5N1 boost phase of this study, in which all vaccinees from the
      initial phase of the study will be offered re-enrollment to receive a booster vaccination
      with an FDA-approved H5N1 inactivated monovalent influenza vaccine. We will offer enrollment
      in the expansion phase to all participants who received the Ad4-H5-Vtn vaccine in the initial
      phase, regardless of whether they also received the recombinant hemagglutinin influenza H5
      vaccine boost. We will also enroll individuals who have never received an H5 influenza
      vaccine as controls. Participants will receive a single vaccination with the H5N1 vaccine and
      be seen for follow-up visits 4 and 8 weeks later for immunogenicity evaluations.
    

Intervention name(s): Ad4-H5-VTN vaccination-tonsillar route; Ad4-H5-vaccination-oral route
Intervention type(s): Biological; Biological
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Influenza Vaccine; H5N1 Influenza; Normal Volunteer; Adenovirus; Live Virus Vaccine; Healthy Volunteer; HV