<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/NCT01730144</url>
  </required_header>
  <id_info>
    <org_study_id>130020</org_study_id>
    <secondary_id>13-I-0020</secondary_id>
    <nct_id>NCT01730144</nct_id>
  </id_info>
  <brief_title>Studying Cell Immune Responses to a Live Flu Vaccine in Healthy Adults</brief_title>
  <official_title>Elucidation of the Mucosal Immune Responses to Live Attenuated Influenza Vaccine In Healthy Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - One form of the influenza vaccine is a nasal spray. It uses a live but weakened flu virus.&#xD;
      Researchers want to better under how the live vaccine interacts with the body s immune&#xD;
      system. They will test the nasal spray flu vaccine (called FluMist) against a saline (salt&#xD;
      water) nasal spray. They will then look at blood and nasal cell samples to see how the&#xD;
      vaccine affects these cells immune response.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To look at immune changes in nasal and blood cells in people who receive live flu vaccine.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Healthy volunteers between 18 and 49 years of age.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will have five outpatient visits for this study. Each visit will last up to&#xD;
           2 hours.&#xD;
&#xD;
        -  At the first visit, participants will have a physical exam and medical history. They&#xD;
           will give blood and urine samples. Nasal cell samples will also be collected.&#xD;
&#xD;
        -  A week later, participants will have either the nasal spray flu vaccine or a saline&#xD;
           spray. They will know which spray they will receive. Blood samples will be collected.&#xD;
&#xD;
        -  Two days after the vaccination, they will have another physical exam. Blood and nasal&#xD;
           cell samples will be collected.&#xD;
&#xD;
        -  At the final two visits (1 week and 1 month after the vaccination), more blood samples&#xD;
           will be collected.&#xD;
&#xD;
        -  Those who had the saline spray will be able to have the actual vaccine spray at the last&#xD;
           study visit.&#xD;
&#xD;
        -  The ratio of participants who receive vaccine to those who receive saline will be 4:1.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Two types of influenza vaccines are currently licensed in the US, trivalent inactivated&#xD;
      vaccine (TIV), administered by intramuscular injection, and LAIV, administered by nasal&#xD;
      spray. Both vaccines are safe and effective in their approved age groups. Neutralizing&#xD;
      antibody in the serum has been found to be a correlate of protection for TIV, but the immune&#xD;
      correlates of protection for LAIV are not known. Defining the origin and nature of&#xD;
      transcriptional responses to LAIV in URT in infected and bystander epithelial and lymphocyte&#xD;
      cells in healthy adults will be a highly informative first step in a systems approach toward&#xD;
      understanding the molecular basis of viral replication restriction and the regulation of the&#xD;
      local mucosal immune responses following LAIV administration.&#xD;
&#xD;
      This natural history study will use a systems biology approach to identify LAIV replication&#xD;
      niches among a variety of URT cell types and characterize the host immune response to LAIV.&#xD;
      Healthy volunteers aged 18-49 years will be prescreened for low (&lt;1:10) serum HAI titer&#xD;
      against the component influenza vaccine virus strains (influenza A H1N1 and H3N2, and&#xD;
      influenza B) of the licensed seasonal LAIV. Ten HAIlow or -negative individuals will be&#xD;
      vaccinated intranasally with LAIV (n=8) or will receive saline intranasally (n=2). One week&#xD;
      prior to and 2 days after vaccine administration, an NP specimen will be collected using&#xD;
      flocked NP swabs. A blood sample will be collected at the time of NP swabbing and on Days 7&#xD;
      and 28 after vaccination. Total subject participation time from enrollment/baseline to the&#xD;
      final study visit will be 5 weeks.&#xD;
&#xD;
      We propose to recover cells from NP swab samples and sort individual cells of different&#xD;
      subsets based on specific surface phenotypic markers. We will then utilize&#xD;
      microfluidics-based real-time reverse transcriptase polymerase chain reaction (rRT-PCR) to&#xD;
      quantify transcripts from bulk and single cells. These transcripts will include&#xD;
      strand-specific influenza RNA for determining virus replication, genes for assigning cells to&#xD;
      specific epithelial or lymphocyte subpopulations, selected genes in the IFN signaling&#xD;
      pathways to determine innate immune responses, and genes involved in activation and effector&#xD;
      functions of different immune cell subsets. Results will be analyzed with several&#xD;
      bioinformatics tools, with an emphasis on the differential signaling responses between&#xD;
      various cells types. The mucosal transcriptional data will be correlated with B and T cell&#xD;
      immunity markers and traditional serology (HAI and neutralization assays) before and after&#xD;
      vaccination to identify key factors affecting the immune response to LAIV.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 17, 2012</start_date>
  <completion_date type="Actual">July 12, 2019</completion_date>
  <primary_completion_date type="Actual">April 17, 2013</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Significant differences in transcription of selected genes in nasal mucosal epithelial and immune cells isolated from recipients of LAIV compared to pre-vaccination levels in the same cell populations isolated.</measure>
    <time_frame>One week prior to and 2 days after vaccine administration and on Days 7 and 28 after vaccination.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>1) Development of serum antibody assessed by either HAI or microneutralization (MN) assays.2) Development of 200 influenza-specific interferon-gamma (IFN- &gt;=)-secreting cells per million lymphocytes as assessed by enzymelinked immunospo...</measure>
    <time_frame>One week prior to and 2 days after vaccine administration, and on Days 7 and 28 after vaccination.</time_frame>
  </secondary_outcome>
  <enrollment type="Actual">10</enrollment>
  <condition>Normal Physiology</condition>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Adult males and females between 18 and 49 years of age.&#xD;
&#xD;
          -  Females of child-bearing potential must have a negative serum beta-human&#xD;
             choriogonadotropin (HCG) on Day -7 and agree to use an effective birth control method&#xD;
             for the duration of the study (for example, pharmacologic contraceptives including&#xD;
             oral, parenteral, and transcutaneous delivery; condoms with spermicide; diaphragm with&#xD;
             spermicide; intrauterine device; abstinence from heterosexual intercourse, surgical&#xD;
             sterilization). All female subjects 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;
          -  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, NP swab, and RNA specimens for future research.&#xD;
&#xD;
          -  Available for the duration of the study. Subjects must be willing and able to make&#xD;
             follow-up visits as specified by the protocol.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Any contraindiciations for adults for the receipt of LAIV:&#xD;
&#xD;
             --Hypersensitivity to eggs, egg proteins, gentamicin, gelatin, or arginine,or&#xD;
             life-threatening reactions to previous influenza vaccination.&#xD;
&#xD;
          -  Currently breast-feeding.&#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 one of the protocol investigators will&#xD;
             be exclusionary at baseline, prior to vaccination.&#xD;
&#xD;
          -  Evidence of upper respiratory tract illness (URI) including fever, sore throat, and&#xD;
             rhinorrhea. Enrollment of subjects with evidence of URI on Study Day -7 will be&#xD;
             temporarily deferred.&#xD;
&#xD;
          -  Deviated nasal septum or nasal obstruction.&#xD;
&#xD;
          -  Body Mass Index greater than 35.&#xD;
&#xD;
          -  NIH employee involved in direct patient care, consistent with the NIH CC policy that&#xD;
             employees should avoid patient care for 5 days following receipt of LAIV. In addition,&#xD;
             NIH employees must not be under the supervision of the study principal or associate&#xD;
             investigators.&#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;
          -  Seropositive to the influenza A component viruses of seasonal LAIV (serum HAI titer of&#xD;
             greater than or equal to 1:10).&#xD;
&#xD;
          -  Has had medical, occupational, or family problems as a result of alcohol or illicit&#xD;
             drug 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 subject participating in the study or would render the subject unable to&#xD;
             comply with the protocol.&#xD;
&#xD;
          -  History of anaphylaxis.&#xD;
&#xD;
          -  Current diagnosis of asthma or reactive airway disease (within the past 2 years).&#xD;
&#xD;
          -  History of Guillain-Barr(SqrRoot)(Copyright) Syndrome.&#xD;
&#xD;
          -  Positive enzyme-linked immunosorbent assay (ELISA) and confirmatory Western blot tests&#xD;
             for human immunodeficiency virus-1 (HIV-1).&#xD;
&#xD;
          -  Positive ELISA and confirmatory test (e.g., recombinant immunoblotassay) for hepatitis&#xD;
             C virus (HCV).&#xD;
&#xD;
          -  Positive hepatitis B virus surface antigen (HBsAg) by ELISA.&#xD;
&#xD;
          -  Known immunodeficiency syndrome.&#xD;
&#xD;
          -  Use of oral, injected, or inhaled corticosteroids (excluding topical preparations) or&#xD;
             immunosuppressive drugs within 30 days prior to enrollment in the study.&#xD;
&#xD;
          -  Use of any herbal supplement 30 days prior to study enrollment.&#xD;
&#xD;
          -  Receipt of 2012-2013 influenza vaccine (TIV or LAIV).&#xD;
&#xD;
          -  Receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to&#xD;
             enrollment in the study.&#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.&#xD;
&#xD;
          -  Travel to the Southern Hemisphere 30 days prior to study enrollment or anticipated&#xD;
             travel to the Southern Hemisphere during the study.&#xD;
&#xD;
          -  Travel on a cruise ship 30 days prior to study enrollment or anticipated travel on a&#xD;
             cruise ship during the study.&#xD;
&#xD;
          -  Receipt of another investigational vaccine or drug within 30 days prior to enrollment&#xD;
             in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tara N Palmore, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Sen A, Rothenberg ME, Mukherjee G, Feng N, Kalisky T, Nair N, Johnstone IM, Clarke MF, Greenberg HB. Innate immune response to homologous rotavirus infection in the small intestinal villous epithelium at single-cell resolution. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20667-72. doi: 10.1073/pnas.1212188109. Epub 2012 Nov 27.</citation>
    <PMID>23188796</PMID>
  </reference>
  <reference>
    <citation>Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, Pulendran B. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol. 2011 Jul 10;12(8):786-95. doi: 10.1038/ni.2067.</citation>
    <PMID>21743478</PMID>
  </reference>
  <reference>
    <citation>Zhu W, Higgs BW, Morehouse C, Streicher K, Ambrose CS, Woo J, Kemble GW, Jallal B, Yao Y. A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children. Vaccine. 2010 Apr 1;28(16):2865-76. doi: 10.1016/j.vaccine.2010.01.060. Epub 2010 Feb 12.</citation>
    <PMID>20153794</PMID>
  </reference>
  <verification_date>July 12, 2019</verification_date>
  <study_first_submitted>November 17, 2012</study_first_submitted>
  <study_first_submitted_qc>November 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2012</study_first_posted>
  <last_update_submitted>October 17, 2019</last_update_submitted>
  <last_update_submitted_qc>October 17, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Nasal Spray Vaccine</keyword>
  <keyword>Nasal Cells</keyword>
  <!-- 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/NCT01730144
org study id: 130020
secondary id: 13-I-0020
nct id: NCT01730144
lead sponsor: 
Background:

      - One form of the influenza vaccine is a nasal spray. It uses a live but weakened flu virus.
      Researchers want to better under how the live vaccine interacts with the body s immune
      system. They will test the nasal spray flu vaccine (called FluMist) against a saline (salt
      water) nasal spray. They will then look at blood and nasal cell samples to see how the
      vaccine affects these cells immune response.

      Objectives:

      - To look at immune changes in nasal and blood cells in people who receive live flu vaccine.

      Eligibility:

      - Healthy volunteers between 18 and 49 years of age.

      Design:

        -  Participants will have five outpatient visits for this study. Each visit will last up to
           2 hours.

        -  At the first visit, participants will have a physical exam and medical history. They
           will give blood and urine samples. Nasal cell samples will also be collected.

        -  A week later, participants will have either the nasal spray flu vaccine or a saline
           spray. They will know which spray they will receive. Blood samples will be collected.

        -  Two days after the vaccination, they will have another physical exam. Blood and nasal
           cell samples will be collected.

        -  At the final two visits (1 week and 1 month after the vaccination), more blood samples
           will be collected.

        -  Those who had the saline spray will be able to have the actual vaccine spray at the last
           study visit.

        -  The ratio of participants who receive vaccine to those who receive saline will be 4:1.
Two types of influenza vaccines are currently licensed in the US, trivalent inactivated
      vaccine (TIV), administered by intramuscular injection, and LAIV, administered by nasal
      spray. Both vaccines are safe and effective in their approved age groups. Neutralizing
      antibody in the serum has been found to be a correlate of protection for TIV, but the immune
      correlates of protection for LAIV are not known. Defining the origin and nature of
      transcriptional responses to LAIV in URT in infected and bystander epithelial and lymphocyte
      cells in healthy adults will be a highly informative first step in a systems approach toward
      understanding the molecular basis of viral replication restriction and the regulation of the
      local mucosal immune responses following LAIV administration.

      This natural history study will use a systems biology approach to identify LAIV replication
      niches among a variety of URT cell types and characterize the host immune response to LAIV.
      Healthy volunteers aged 18-49 years will be prescreened for low (<1:10) serum HAI titer
      against the component influenza vaccine virus strains (influenza A H1N1 and H3N2, and
      influenza B) of the licensed seasonal LAIV. Ten HAIlow or -negative individuals will be
      vaccinated intranasally with LAIV (n=8) or will receive saline intranasally (n=2). One week
      prior to and 2 days after vaccine administration, an NP specimen will be collected using
      flocked NP swabs. A blood sample will be collected at the time of NP swabbing and on Days 7
      and 28 after vaccination. Total subject participation time from enrollment/baseline to the
      final study visit will be 5 weeks.

      We propose to recover cells from NP swab samples and sort individual cells of different
      subsets based on specific surface phenotypic markers. We will then utilize
      microfluidics-based real-time reverse transcriptase polymerase chain reaction (rRT-PCR) to
      quantify transcripts from bulk and single cells. These transcripts will include
      strand-specific influenza RNA for determining virus replication, genes for assigning cells to
      specific epithelial or lymphocyte subpopulations, selected genes in the IFN signaling
      pathways to determine innate immune responses, and genes involved in activation and effector
      functions of different immune cell subsets. Results will be analyzed with several
      bioinformatics tools, with an emphasis on the differential signaling responses between
      various cells types. The mucosal transcriptional data will be correlated with B and T cell
      immunity markers and traditional serology (HAI and neutralization assays) before and after
      vaccination to identify key factors affecting the immune response to LAIV.
observational model: Other
time perspective: Prospective
measure: Significant differences in transcription of selected genes in nasal mucosal epithelial and immune cells isolated from recipients of LAIV compared to pre-vaccination levels in the same cell populations isolated.
time frame: One week prior to and 2 days after vaccine administration and on Days 7 and 28 after vaccination.
measure: 1) Development of serum antibody assessed by either HAI or microneutralization (MN) assays.2) Development of 200 influenza-specific interferon-gamma (IFN- >=)-secreting cells per million lymphocytes as assessed by enzymelinked immunospo...
time frame: One week prior to and 2 days after vaccine administration, and on Days 7 and 28 after vaccination.
criteria: 
gender: All
minimum age: 18 Years
maximum age: 49 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Tara N Palmore, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
facility: 
country: United States
citation: Sen A, Rothenberg ME, Mukherjee G, Feng N, Kalisky T, Nair N, Johnstone IM, Clarke MF, Greenberg HB. Innate immune response to homologous rotavirus infection in the small intestinal villous epithelium at single-cell resolution. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20667-72. doi: 10.1073/pnas.1212188109. Epub 2012 Nov 27.
PMID: 23188796
citation: Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, Pulendran B. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol. 2011 Jul 10;12(8):786-95. doi: 10.1038/ni.2067.
PMID: 21743478
citation: Zhu W, Higgs BW, Morehouse C, Streicher K, Ambrose CS, Woo J, Kemble GW, Jallal B, Yao Y. A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children. Vaccine. 2010 Apr 1;28(16):2865-76. doi: 10.1016/j.vaccine.2010.01.060. Epub 2010 Feb 12.
PMID: 20153794
responsible party type: Sponsor