<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01674205</url>
  </required_header>
  <id_info>
    <org_study_id>URMC 12-001</org_study_id>
    <nct_id>NCT01674205</nct_id>
  </id_info>
  <brief_title>Study of Immune Responses in Healthy Adults Receiving Live Influenza Virus Vaccines</brief_title>
  <official_title>Exploratory Evaluation of Host Biomarkers That Predict the Vaccine Virus Replication and Immunogenicity of Seasonal and Pandemic Formulations of Live Attenuated Influenza A Virus Vaccines Based on the A/Ann Arbor/6/60 ca Master Donor Virus (MDV)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Rochester</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Institute of Allergy and Infectious Diseases (NIAID)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study seeks to understand the host factors that affect the replication and immune&#xD;
      response of seasonal and candidate pandemic live attenuated influenza vaccine (LAIV) in&#xD;
      humans and to develop biomarkers that can predict the viral shedding and immune response to&#xD;
      LAIVs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Influenza A viruses are widely distributed in nature and exist as many different subtypes.&#xD;
      Pandemics of influenza can occur, and vaccine development is focused on those subtypes that&#xD;
      are predicted to represent the greatest pandemic threat to the human population. This study&#xD;
      seeks to understand the host factors that affect the replication and immune response of&#xD;
      seasonal and candidate pandemic LAIVs in humans and to develop biomarkers that can predict&#xD;
      the viral shedding and immune response to LAIVs.&#xD;
&#xD;
      Three vaccines will be evaluated: the licensed seasonal LAIV, with a focus on the H3N2&#xD;
      component; the H9N2 G9/AA ca vaccine, which is among the most immunogenic of the candidate&#xD;
      pandemic LAIVs evaluated to date; and the H2N3 MO 2066/AA ca vaccine, which is among the&#xD;
      least immunogenic of the candidate pandemic LAIVs evaluated to date. The seasonal LAIV will&#xD;
      be evaluated in an outpatient setting, while the other two vaccines will be evaluated in an&#xD;
      inpatient setting. In each setting, some participants will receive a placebo vaccine.&#xD;
&#xD;
      Study participants will be assigned to one of four groups. Participants who are seronegative&#xD;
      to both H9N2 G9/AA ca and H2N3 MO 2006/AA ca viruses will be randomly assigned to receive one&#xD;
      of those vaccines (Group 1: H9N2 G9/AA ca; Group 2: H2N3 MO 2006/AA ca) or placebo (Group 4)&#xD;
      and will remain in an inpatient isolation facility. Participants who are seronegative to the&#xD;
      H3 component of seasonal LAIV will be randomly assigned to receive either seasonal vaccine&#xD;
      (Group 3) or placebo (Group 4) and will be followed as outpatients.&#xD;
&#xD;
      All participants will remain in the study for 56 days. Participants in the inpatient arms&#xD;
      will be admitted on Day -2, will receive study vaccine on Day 0, and will undergo a basic&#xD;
      history, physical examination, and nasal wash each day until discharge. On some study days,&#xD;
      inpatient participants will undergo a blood collection and/or a nasal swab; at the screening&#xD;
      visit and on Day -1 or Day -2, participants will give a urine sample.&#xD;
&#xD;
      Participants in the outpatient arms will receive study vaccine on Day 0 and will have study&#xD;
      visits on Days 1, 2, 3, 4, 5, 6, 7, 14, 28, and 56. On Days 1 through 7, participants will&#xD;
      undergo a basic history, physical examination, and nasal wash. On some visits, participants&#xD;
      may undergo a blood collection and/or a nasal swab; at the screening visit and on Day -1,&#xD;
      participants will give a urine sample. Unused blood or nasal wash samples will be stored and&#xD;
      may be used in future research studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">June 2013</completion_date>
  <primary_completion_date type="Actual">June 2013</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the curve (AUC) of nasal virus shedding after vaccine dose as assessed by liquid titration of nasal secretions on Madin Darby Canine Kidney (MDCK) cells</measure>
    <time_frame>Measured through Day 9</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Development of serum antibody as assessed by either HAI or microneutralization (MN) assays</measure>
    <time_frame>Measured through Day 56</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Development of a significant increase in nasal secretion hemagglutinin (HA)-specific antibody assessed by enzyme-linked immunosorbent assay (ELISA)</measure>
    <time_frame>Measured through Day 56</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Detection of influenza-specific immunoglobulin G (IgG) or immunoglobulin A (IgA) secreting B cells assessed by antibody secreting cells (ASC) assay</measure>
    <time_frame>Measured at Day 7</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Development of greater than 200 influenza-specific interferon-gamma-secreting cells per million lymphocytes as assessed by enzyme-linked immunospot assay (ELISPOT)</measure>
    <time_frame>Measured at Day 28</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Influenza, Human</condition>
  <arm_group>
    <arm_group_label>Group 1 (Inpatient, H2N3 MO 2006/AA ca)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive one dose of vaccine on Day 0, with 0.2 mL being delivered by Accuspray device (0.1 mL per nostril).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2 (Inpatient, H9N2 G9/AA ca)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive one dose of vaccine on Day 0, with 0.5 mL being delivered as nose drops (0.25 mL per nostril) using a sterile, needle-less tuberculin syringe.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 3 (Outpatient, seasonal LAIV [FluMist®])</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2012-2013 trivalent seasonal live attenuated influenza vaccine (FluMist®)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 4 (Both inpatient and outpatient, placebo)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive either the L-15 placebo delivered by nose drops or the FluMist® placebo delivered as a nasal spray.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>A/swine/Missouri/4296424/2006 (H2N3) x A/Ann Arbor/6/60 ca (H2N3 MO 2006/AA ca)</intervention_name>
    <arm_group_label>Group 1 (Inpatient, H2N3 MO 2006/AA ca)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>A/chicken/Hong Kong/G9/97 (H9N2) x A/Ann Arbor/6/60 ca (H9N2 G9/AA ca)</intervention_name>
    <arm_group_label>Group 2 (Inpatient, H9N2 G9/AA ca)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>2012-2013 trivalent seasonal live attenuated influenza vaccine (FluMist®)</intervention_name>
    <arm_group_label>Group 3 (Outpatient, seasonal LAIV [FluMist®])</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Vaccine placebo (Leibovitz-15 [L-15])</intervention_name>
    <arm_group_label>Group 4 (Both inpatient and outpatient, placebo)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Vaccine placebo (FluMist®)</intervention_name>
    <arm_group_label>Group 4 (Both inpatient and outpatient, placebo)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  General good health, without significant medical illness, physical examination&#xD;
             findings, or significant laboratory abnormalities as determined by the investigator&#xD;
&#xD;
          -  Agree to storage of blood specimens for future research&#xD;
&#xD;
          -  Available for the duration of the trial. For the inpatient component of the study,&#xD;
             participants must be willing and able to remain within the Isolation Unit for the&#xD;
             specified duration of confinement. For the outpatient component of the study,&#xD;
             participants must be willing and able to make daily outpatient follow-up visits as&#xD;
             specified by the protocol.&#xD;
&#xD;
          -  Willingness to participate in the study as evidenced by signing the informed consent&#xD;
             document&#xD;
&#xD;
          -  Female participants must agree to use effective birth control methods for the duration&#xD;
             of the study (for example, pharmacologic contraceptives including oral, parenteral,&#xD;
             and transcutaneous delivery; condoms with spermicide; diaphragm with spermicide;&#xD;
             intrauterine device; abstinence from heterosexual intercourse; or surgical&#xD;
             sterilization). All female participants will be considered being of child-bearing&#xD;
             potential except those who have undergone hysterectomy and those in whom menopause&#xD;
             occurred at least 1 year prior to the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy as determined by a positive human choriogonadotropin (beta-HCG) test&#xD;
&#xD;
          -  Currently breastfeeding&#xD;
&#xD;
          -  Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic,&#xD;
             rheumatologic, autoimmune, or renal disease by history, physical examination, and/or&#xD;
             laboratory studies including urine testing. Clinically significant alanine&#xD;
             aminotransferase (ALT) levels, as determined by the Principal Investigator, will be&#xD;
             exclusionary at baseline, prior to vaccination.&#xD;
&#xD;
          -  Behavioral or cognitive impairment or psychiatric disease that in the opinion of the&#xD;
             investigator affects the ability of the subject to understand and cooperate with the&#xD;
             study protocol&#xD;
&#xD;
          -  Previous enrollment in an H2 or H9 influenza vaccine trial or in any study of an avian&#xD;
             influenza vaccine&#xD;
&#xD;
          -  For the inpatient arm, seropositive to the H2N3 influenza A virus or the H9N2&#xD;
             influenza A virus (serum HAI titer &gt;1:8). For the outpatient arm, seropositive to the&#xD;
             H3N2 component of seasonal LAIV (serum hemagglutination inhibition [HAI] titer greater&#xD;
             than 1:8).&#xD;
&#xD;
          -  Positive urine drug toxicology test indicating narcotic use/dependency&#xD;
&#xD;
          -  Have medical, occupational, or family problems as a result of alcohol or illicit drug&#xD;
             use during the past 12 months&#xD;
&#xD;
          -  Other condition that in the opinion of the investigator would jeopardize the safety or&#xD;
             rights of a participant participating in the trial or would render the subject unable&#xD;
             to comply with the protocol&#xD;
&#xD;
          -  History of anaphylaxis&#xD;
&#xD;
          -  Allergy to oseltamivir as determined by subject report&#xD;
&#xD;
          -  Current diagnosis of asthma or reactive airway disease (within the past 2 years)&#xD;
&#xD;
          -  History of Guillain-Barré Syndrome&#xD;
&#xD;
          -  Positive ELISA and confirmatory Western blot tests for human immunodeficiency virus-1&#xD;
             (HIV-1)&#xD;
&#xD;
          -  Positive ELISA and confirmatory test (e.g., recombinant immunoblot assay) for&#xD;
             hepatitis C virus (HCV)&#xD;
&#xD;
          -  Positive hepatitis B virus surface antigen (HBsAg) by ELISA&#xD;
&#xD;
          -  Known immunodeficiency syndrome&#xD;
&#xD;
          -  Use of corticosteroids (excluding topical preparations) or immunosuppressive drugs&#xD;
             within 30 days prior to vaccination&#xD;
&#xD;
          -  Receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to&#xD;
             study vaccination&#xD;
&#xD;
          -  History of a surgical splenectomy&#xD;
&#xD;
          -  Receipt of blood or blood-derived products (including immunoglobulin) within 6 months&#xD;
             prior to study vaccination&#xD;
&#xD;
          -  Current smoker unwilling to stop smoking for the duration of the study&#xD;
&#xD;
               -  A current smoker includes anyone stating he/she currently smokes any amount of a&#xD;
                  tobacco product&#xD;
&#xD;
               -  The decision to exclude a potential participant is determined by medical history&#xD;
                  and a clinician's clinical judgment based on the physical examination&#xD;
&#xD;
               -  After admission to the unit, nicotine patches will be provided to current smokers&#xD;
                  who request them for the inpatient portion of the study&#xD;
&#xD;
          -  Travel to the Southern Hemisphere within 14 days prior to study vaccination&#xD;
&#xD;
          -  Travel on a cruise ship within 14 days prior to study vaccination&#xD;
&#xD;
          -  Receipt of another investigational vaccine or drug within 30 days prior to study&#xD;
             vaccination&#xD;
&#xD;
          -  Allergy to eggs or egg products&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>42 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Treanor, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Rochester Medical Center: Facility for Evaluation of Flu Vaccines</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Karron RA, Callahan K, Luke C, Thumar B, McAuliffe J, Schappell E, Joseph T, Coelingh K, Jin H, Kemble G, Murphy BR, Subbarao K. A live attenuated H9N2 influenza vaccine is well tolerated and immunogenic in healthy adults. J Infect Dis. 2009 Mar 1;199(5):711-6. doi: 10.1086/596558.</citation>
    <PMID>19210163</PMID>
  </reference>
  <reference>
    <citation>Belshe RB. Current status of live attenuated influenza virus vaccine in the US. Virus Res. 2004 Jul;103(1-2):177-85. doi: 10.1016/j.virusres.2004.02.031.</citation>
    <PMID>15163507</PMID>
  </reference>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>August 23, 2012</study_first_submitted>
  <study_first_submitted_qc>August 23, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 28, 2012</study_first_posted>
  <last_update_submitted>December 14, 2015</last_update_submitted>
  <last_update_submitted_qc>December 14, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 15, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Influenza, Human</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01674205
org study id: URMC 12-001
nct id: NCT01674205
lead sponsor: 
collaborator: 
has dmc: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Triple (Participant, Care Provider, Investigator)
measure: Area under the curve (AUC) of nasal virus shedding after vaccine dose as assessed by liquid titration of nasal secretions on Madin Darby Canine Kidney (MDCK) cells
time frame: Measured through Day 9
measure: Development of serum antibody as assessed by either HAI or microneutralization (MN) assays
time frame: Measured through Day 56
measure: Development of a significant increase in nasal secretion hemagglutinin (HA)-specific antibody assessed by enzyme-linked immunosorbent assay (ELISA)
time frame: Measured through Day 56
measure: Detection of influenza-specific immunoglobulin G (IgG) or immunoglobulin A (IgA) secreting B cells assessed by antibody secreting cells (ASC) assay
time frame: Measured at Day 7
measure: Development of greater than 200 influenza-specific interferon-gamma-secreting cells per million lymphocytes as assessed by enzyme-linked immunospot assay (ELISPOT)
time frame: Measured at Day 28
arm group label: Group 1 (Inpatient, H2N3 MO 2006/AA ca)
arm group type: Experimental
description: Participants will receive one dose of vaccine on Day 0, with 0.2 mL being delivered by Accuspray device (0.1 mL per nostril).
arm group label: Group 2 (Inpatient, H9N2 G9/AA ca)
arm group type: Experimental
description: Participants will receive one dose of vaccine on Day 0, with 0.5 mL being delivered as nose drops (0.25 mL per nostril) using a sterile, needle-less tuberculin syringe.
arm group label: Group 3 (Outpatient, seasonal LAIV [FluMist®])
arm group type: Experimental
description: 2012-2013 trivalent seasonal live attenuated influenza vaccine (FluMist®)
arm group label: Group 4 (Both inpatient and outpatient, placebo)
arm group type: Placebo Comparator
description: Participants will receive either the L-15 placebo delivered by nose drops or the FluMist® placebo delivered as a nasal spray.
intervention type: Biological
intervention name: A/swine/Missouri/4296424/2006 (H2N3) x A/Ann Arbor/6/60 ca (H2N3 MO 2006/AA ca)
arm group label: Group 1 (Inpatient, H2N3 MO 2006/AA ca)
intervention type: Biological
intervention name: A/chicken/Hong Kong/G9/97 (H9N2) x A/Ann Arbor/6/60 ca (H9N2 G9/AA ca)
arm group label: Group 2 (Inpatient, H9N2 G9/AA ca)
intervention type: Biological
intervention name: 2012-2013 trivalent seasonal live attenuated influenza vaccine (FluMist®)
arm group label: Group 3 (Outpatient, seasonal LAIV [FluMist®])
intervention type: Biological
intervention name: Vaccine placebo (Leibovitz-15 [L-15])
arm group label: Group 4 (Both inpatient and outpatient, placebo)
intervention type: Biological
intervention name: Vaccine placebo (FluMist®)
arm group label: Group 4 (Both inpatient and outpatient, placebo)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 42 Years
healthy volunteers: Accepts Healthy Volunteers
last name: John Treanor, MD
role: Principal Investigator
affiliation: University of Rochester
facility: 
country: United States
citation: Karron RA, Callahan K, Luke C, Thumar B, McAuliffe J, Schappell E, Joseph T, Coelingh K, Jin H, Kemble G, Murphy BR, Subbarao K. A live attenuated H9N2 influenza vaccine is well tolerated and immunogenic in healthy adults. J Infect Dis. 2009 Mar 1;199(5):711-6. doi: 10.1086/596558.
PMID: 19210163
citation: Belshe RB. Current status of live attenuated influenza virus vaccine in the US. Virus Res. 2004 Jul;103(1-2):177-85. doi: 10.1016/j.virusres.2004.02.031.
PMID: 15163507
responsible party type: Sponsor
mesh term: Influenza, Human
mesh term: Vaccines