<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/NCT01676402</url>
  </required_header>
  <id_info>
    <org_study_id>VRC 703</org_study_id>
    <secondary_id>VRC 703</secondary_id>
    <nct_id>NCT01676402</nct_id>
  </id_info>
  <brief_title>Seasonal Influenza HA DNA With Trivalent Inactivated Vaccine (TIV) Administered ID or IM in Healthy Adults 18-70 Years</brief_title>
  <official_title>Open-Label, Randomized Phase 1b Study of the Safety &amp; Immunogenicity of Investigational Seasonal Influenza DNA Vaccine Followed by TIV Administered Intradermally (ID) or Intramuscularly (IM) in Healthy Adults 18-70 Years</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Emmes Company, LLC</agency>
      <agency_class>Industry</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 is a Phase Ib study in healthy adults (18-70 years) to evaluate the safety,&#xD;
      tolerability, and immunogenicity of same season and sequential season vaccination schedules&#xD;
      consisting of the 2012/2013 seasonal influenza DNA vaccine (HA DNA) and licensed trivalent&#xD;
      influenza vaccine (TIV) administered intradermally (ID) or intramuscularly (IM). The&#xD;
      hypothesis is that evaluation of these investigational schedules will inform development of&#xD;
      novel influenza vaccine strategies that may offer improved and cross-protective immunity&#xD;
      against antigenically diverse influenza strains.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Vaccines are an effective way to prevent influenza infection. Each year the World Health&#xD;
      Organization (WHO) and the U.S FDA recommend the influenza strains to include in the seasonal&#xD;
      influenza vaccines. The licensed seasonal influenza vaccines are directed against 3 influenza&#xD;
      virus strains: an influenza A H1N1, an influenza A H3N2, and an influenza B. The currently&#xD;
      approved vaccines depend upon labor-intensive methods that limit manufacturing speed and&#xD;
      capacity. Influenza vaccines that can be more rapidly produced and that induce stronger,&#xD;
      broader and more persistent immune responses are a recognized public health need.&#xD;
&#xD;
      In this protocol we propose to use DNA vaccine antigen delivery to induce immune responses&#xD;
      against native hemagglutinin (HA) structures prior to boosting with licensed TIV ID or with&#xD;
      TIV IM.&#xD;
&#xD;
      The study will allow evaluation of the safety and immunogenicity of same season and&#xD;
      sequential season vaccination schedules. The same season regimens (2012/13 prime and boost&#xD;
      with a 14 week interval) consist of HA DNA prime with TIV ID boost -- or -- HA DNA prime with&#xD;
      TIV IM boost. The active comparator for these schedules are TIV ID or TIV IM alone because a&#xD;
      single dose of TIV is the standard for adult influenza vaccination within a single season.&#xD;
      The sequential season regimens (2012/13 prime and 2013/14 boost) consist of concurrent&#xD;
      administration (in different arms) of HA DNA and TIV ID prime with TIV ID boost -- or -- HA&#xD;
      DNA and TIV IM prime with TIV IM boost. The active comparator for these regimens will be TIV&#xD;
      ID followed by TIV ID boost -- or -- TIV IM followed by TIV IM boost, administered sequential&#xD;
      seasons consistent with as typical pattern of use for these licensed vaccines. Evaluation of&#xD;
      the investigational schedules and active comparator schedules will inform development of&#xD;
      novel influenza vaccine strategies that may offer improved and cross-protective immunity&#xD;
      against diverse influenza strains.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">April 2014</completion_date>
  <primary_completion_date type="Actual">April 2014</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of solicited adverse events after the first injection</measure>
    <time_frame>Day 0 to Day 7</time_frame>
    <description>Incidence is reported for solicited events for 7 days after the first injection. For all Groups the collection period for solicited adverse events following the first injection Day 0 to Day 7.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of solicited adverse events after the second injection</measure>
    <time_frame>Day of injection to 7 days after second injection</time_frame>
    <description>Incidence is reported for solicited events for 7 days after the second injection. The period of solicitation is defined by the actual day of second injection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of unsolicited adverse events of any severity 28 days after the first injection</measure>
    <time_frame>Day 0 to Day 28</time_frame>
    <description>Incidence is reported for unsolicited events for 28 days after the first injection. For all Groups the reporting period for unsolicited adverse events following the first injection Day 0 to Day 28.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of unsolicited adverse events of any severity for 28 days after the second injection</measure>
    <time_frame>Day of injection to 28 days after injection</time_frame>
    <description>The 28 day period following second injection is defined by the actual day of second injection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of serious adverse events or new chronic medical conditions through 24 weeks after the 2nd injection</measure>
    <time_frame>Day 0 to 24 weeks after second injection</time_frame>
    <description>The day of second injection varies by group; the duration of time from Day 0 through 24 weeks after second injection is defined by the actual day of second injection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of subjects with influenza or influenza-like illnesses (ILI)</measure>
    <time_frame>Day 0 to 24 weeks after second injection</time_frame>
    <description>The day of second injection varies by group; the duration of time from Day 0 through 24 weeks after second injection is defined by the actual day of second injection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean change from baseline in safety laboratory measures</measure>
    <time_frame>Day 21</time_frame>
    <description>At Day 21 (window Day 21-28) blood will be drawn to measure hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC), mean corpuscular volume (MCV), platelets</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2)</measure>
    <time_frame>Day 119</time_frame>
    <description>Seroconversion is defined a pre-vaccination strain-specific HAI titer &lt;1:10 and a post-vaccination hemagglutination inhibition (HAI) titer ≥1:40 or a pre-vaccination.&#xD;
Blood is collected at baseline (Day 0) and at 3 weeks following completion of the 2012/2013 vaccination regimen (3 weeks after 2012/13 TIV ID or TIV IM boost for Group 1 and Group 2, Day 119) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4)</measure>
    <time_frame>Day 21</time_frame>
    <description>Blood is collected at baseline (Day 0) and at 3 weeks following completion of the 2012/2013 prime injection (3 weeks after 2012/13 TIV ID or TIV IM prime Group 3 and Group 4, Day 21) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Geometric Mean HAI Titer for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2)</measure>
    <time_frame>Day 119</time_frame>
    <description>Blood is collected 3 weeks following completion of the 2012/2013 vaccination regimen 3 weeks after 2012/13 TIV ID or TIV IM boost for (Group 1 and Group 2, Day 119) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Geometric Mean HAI titer for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4)</measure>
    <time_frame>3 weeks after completion of the HA DNA prime, Day 21</time_frame>
    <description>Blood is collected 3 weeks following completion of the 2012/2013 prime injection (3 weeks after 2012/13 TIV ID or TIV IM prime Group 3 and Group 4, Day 21) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Seroconversion for each of the 2012/13 and 2013/14 influenza vaccine strains</measure>
    <time_frame>3 weeks after each study injection</time_frame>
    <description>For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 and 2013/2014 influenza vaccines. Seroconversion is defined a pre-vaccination strain-specific HAI titer &lt;1:10 and a post-vaccination HAI titer ≥1:40 or a pre-vaccination.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric Mean HAI Titer for each of the 2012/13 and 2013/14 influenza vaccine strains</measure>
    <time_frame>3 weeks after each study injection</time_frame>
    <description>For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 and 2013/2014 influenza vaccines.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of subjects with four-fold rise from baseline for each of the 2012/13 and 2013/14 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies</measure>
    <time_frame>3 weeks after each study injection</time_frame>
    <description>For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing 2012/2013 and 2013/2014 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric Mean neutralization titer of 2012/13 and 2013/14 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies</measure>
    <time_frame>3 weeks after each study injection</time_frame>
    <description>For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing 2012/2013 and 2013/2014 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">316</enrollment>
  <condition>Influenza</condition>
  <arm_group>
    <arm_group_label>Group 1: HA DNA + TIV ID</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) at Day 0 and licensed 2012/13 TIV ID at Week 14±2 wks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2: HA DNA + TIV IM</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) at Day 0 and licensed 2012/13 TIV IM at Week 14±2 wks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 3: TIV ID + TIV ID</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>licensed 2012/13 TIV ID at Day 0 and licensed 2013/14 TIV ID at Week 44±2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 4: TIV IM + TIV IM</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2012/13 licensed TIV IM at Day 0 and licensed 2013/14 TIV IM at Week 44±2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 5: (HA DNA and TIV ID) + TIV ID</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) and licensed 2012/13 TIV ID at Day 0 followed by licensed 2013/14 TIV ID at Week 44±2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 6: (HA DNA and TIV IM) + TIV IM</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) and licensed 2012/13 TIV IM at Day 0 followed by licensed 2013/14 TIV IM at Week 44±2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Seasonal Influenza DNA vaccine</intervention_name>
    <description>VRC-FLUDNA063-00-VP is composed of 3 closed-circular DNA plasmids that encode for the hemagglutinin (HA) from the following 3 strains: A/California/04/2009 (H1); A/Victoria/361/2011 (H3), and B/Wisconsin/2010. DNA vaccine vials will be supplied at 4 mg/mL in single use vials. The 4 mg dosage is administered as a 1 mL volume.</description>
    <arm_group_label>Group 1: HA DNA + TIV ID</arm_group_label>
    <arm_group_label>Group 2: HA DNA + TIV IM</arm_group_label>
    <arm_group_label>Group 5: (HA DNA and TIV ID) + TIV ID</arm_group_label>
    <arm_group_label>Group 6: (HA DNA and TIV IM) + TIV IM</arm_group_label>
    <other_name>VRC-FLUDNA063-00-VP</other_name>
    <other_name>HA DNA Vaccine</other_name>
    <other_name>Seasonal influenza trivalent DNA vaccine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TIV</intervention_name>
    <description>2012/13, 2013/14 Seasonal Influenza Trivalent Inactivated Vaccine (TIV)</description>
    <arm_group_label>Group 1: HA DNA + TIV ID</arm_group_label>
    <arm_group_label>Group 2: HA DNA + TIV IM</arm_group_label>
    <arm_group_label>Group 3: TIV ID + TIV ID</arm_group_label>
    <arm_group_label>Group 4: TIV IM + TIV IM</arm_group_label>
    <arm_group_label>Group 5: (HA DNA and TIV ID) + TIV ID</arm_group_label>
    <arm_group_label>Group 6: (HA DNA and TIV IM) + TIV IM</arm_group_label>
    <other_name>2012/13 Seasonal Influenza TIV (Fluzone)</other_name>
    <other_name>2013/14 Seasonal Influenza TIV (Fluzone)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        A subject must meet all of the following criteria:&#xD;
&#xD;
          -  Healthy adults, 18 to 70 years old; volunteers who will be older than 64 during the&#xD;
             2013/2014 influenza season will not be enrolled after 11/16/2012.&#xD;
&#xD;
          -  Available for clinical follow-up&#xD;
&#xD;
          -  Able and willing to complete the informed consent process&#xD;
&#xD;
          -  Willing to donate blood for sample storage to be used for future research&#xD;
&#xD;
          -  Physical examination and laboratory results without clinically significant findings&#xD;
             and a Body Mass Index (BMI) ≤40 within the 70 days prior to enrollment&#xD;
&#xD;
          -  Has not yet received the current year (2012/13) influenza vaccine prior to enrollment&#xD;
             and agrees to receive seasonal influenza vaccines during study participation only from&#xD;
             the study site&#xD;
&#xD;
        Laboratory Criteria within 70 days prior to enrollment:&#xD;
&#xD;
          -  Hemoglobin within institutional normal limits&#xD;
&#xD;
          -  White blood cells either within institutional normal range or accompanied by site&#xD;
             physician approval as consistent with healthy adult status&#xD;
&#xD;
          -  Platelets = 125,000 - 500,000/mm3&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Serum creatinine ≤ 1 x ULN based on site institutional normal range&#xD;
&#xD;
        Criteria applicable to women of childbearing potential:&#xD;
&#xD;
          -  Negative human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day&#xD;
             of enrollment&#xD;
&#xD;
          -  Agree to use an effective means of birth control from 21 days prior to enrollment&#xD;
             through 3 weeks after the second study vaccination&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        A subject will be excluded if one or more of the following conditions apply:&#xD;
&#xD;
        Women Specific:&#xD;
&#xD;
          -  Breast-feeding or planning to become pregnant while participating in the study&#xD;
&#xD;
        Subject has received any of the following substances:&#xD;
&#xD;
          -  More than 10 days of systemic immunosuppressive medications or cytotoxic medications&#xD;
             within the 12 weeks prior to enrollment or any within the 14 days prior to enrollment&#xD;
&#xD;
          -  Blood products within 16 weeks prior to enrollment&#xD;
&#xD;
          -  Immunoglobulin within 8 weeks prior to enrollment&#xD;
&#xD;
          -  Investigational research agents within 28 days (4 weeks) prior to enrollment or&#xD;
             planning to receive investigational products while on the study.&#xD;
&#xD;
          -  Allergy treatment with antigen injections, unless on maintenance schedule and allergy&#xD;
             shots could be staggered with the study vaccinations, within 14 days (2 weeks) prior&#xD;
             to enrollment&#xD;
&#xD;
          -  Current anti-tuberculosis (TB) prophylaxis or therapy&#xD;
&#xD;
        Subject has a history of any of the following clinically significant conditions:&#xD;
&#xD;
          -  Contraindication to receiving an FDA-approved seasonal influenza vaccination&#xD;
&#xD;
          -  Serious reactions to vaccines that preclude receipt of study vaccinations, as&#xD;
             determined by the site investigator&#xD;
&#xD;
          -  Hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic forms of&#xD;
             angioedema&#xD;
&#xD;
          -  Asthma that is severe, unstable or required emergent care, urgent care,&#xD;
             hospitalization or intubation during the previous two years or that is expected to&#xD;
             require the use of oral, intravenous or high dose inhaled corticosteroids&#xD;
&#xD;
          -  Diabetes mellitus type I&#xD;
&#xD;
          -  Thyroid disease that is not well-controlled&#xD;
&#xD;
          -  Generalized idiopathic urticaria within the 1 year prior to enrollment&#xD;
&#xD;
          -  Hypertension that is not well controlled&#xD;
&#xD;
          -  Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or&#xD;
             platelet disorder requiring special precautions), or significant bruising or bleeding&#xD;
             difficulties with IM injections or blood draws, or use of blood thinners such as&#xD;
             Coumadin or Plavix®&#xD;
&#xD;
          -  Malignancy that is active or treated malignancy for which there is not reasonable&#xD;
             assurance of sustained cure or malignancy that is likely to recur during the period of&#xD;
             the study&#xD;
&#xD;
          -  Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol&#xD;
             withdrawal more than 3 years ago, or 3) seizures for which no treatment has been&#xD;
             required within the 3 years prior to enrollment&#xD;
&#xD;
          -  Asplenia, functional asplenia or any condition resulting in the absence or removal of&#xD;
             the spleen&#xD;
&#xD;
          -  Guillain-Barré Syndrome&#xD;
&#xD;
          -  Psychiatric condition that precludes compliance with the protocol; past or present&#xD;
             psychoses; disorder requiring lithium; or within 5 years prior to enrollment, a&#xD;
             history of suicide plan or attempt&#xD;
&#xD;
          -  Any medical, psychiatric, or other condition that, in the judgment of the&#xD;
             investigator, is a contraindication to protocol participation or impairs ability to&#xD;
             give informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Barney S Graham, M.D., Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>Chief, Clinical Trials Core Vaccine Research Center, NIAID, NIH</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Julie Ledgerwood, DO</last_name>
    <role>Study Chair</role>
    <affiliation>Deputy Chief, Clinical Trials Core Vaccine Research Center, NIAID, NIH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University School of Medicine</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospitals &amp; Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Louis University - Doisy Research Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Ledgerwood JE, Wei CJ, Hu Z, Gordon IJ, Enama ME, Hendel CS, McTamney PM, Pearce MB, Yassine HM, Boyington JC, Bailer R, Tumpey TM, Koup RA, Mascola JR, Nabel GJ, Graham BS; VRC 306 Study Team. DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials. Lancet Infect Dis. 2011 Dec;11(12):916-24. doi: 10.1016/S1473-3099(11)70240-7. Epub 2011 Oct 3.</citation>
    <PMID>21975270</PMID>
  </reference>
  <reference>
    <citation>Ledgerwood JE, Graham BS. DNA vaccines: a safe and efficient platform technology for responding to emerging infectious diseases. Hum Vaccin. 2009 Sep;5(9):623-6. doi: 10.4161/hv.8627. No abstract available.</citation>
    <PMID>19779298</PMID>
  </reference>
  <results_reference>
    <citation>Carter C, Houser KV, Yamshchikov GV, Bellamy AR, May J, Enama ME, Sarwar U, Larkin B, Bailer RT, Koup R, Chen GL, Patel SM, Winokur P, Belshe R, Dekker CL, Graham BS, Ledgerwood JE; VRC 703 study team. Safety and immunogenicity of investigational seasonal influenza hemagglutinin DNA vaccine followed by trivalent inactivated vaccine administered intradermally or intramuscularly in healthy adults: An open-label randomized phase 1 clinical trial. PLoS One. 2019 Sep 18;14(9):e0222178. doi: 10.1371/journal.pone.0222178. eCollection 2019.</citation>
    <PMID>31532789</PMID>
  </results_reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>August 13, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <last_update_submitted>August 22, 2022</last_update_submitted>
  <last_update_submitted_qc>August 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Influenza A (H1)</keyword>
  <keyword>Influenza A (H3)</keyword>
  <keyword>Influenza B</keyword>
  <keyword>DNA Vaccine</keyword>
  <keyword>Trivalent Inactivated Vaccine (TIV)</keyword>
  <keyword>Healthy Adults</keyword>
  <keyword>Intradermal (ID)</keyword>
  <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/NCT01676402
org study id: VRC 703
secondary id: VRC 703
nct id: NCT01676402
lead sponsor: 
collaborator: 
has dmc: No
This is a Phase Ib study in healthy adults (18-70 years) to evaluate the safety,
      tolerability, and immunogenicity of same season and sequential season vaccination schedules
      consisting of the 2012/2013 seasonal influenza DNA vaccine (HA DNA) and licensed trivalent
      influenza vaccine (TIV) administered intradermally (ID) or intramuscularly (IM). The
      hypothesis is that evaluation of these investigational schedules will inform development of
      novel influenza vaccine strategies that may offer improved and cross-protective immunity
      against antigenically diverse influenza strains.
Vaccines are an effective way to prevent influenza infection. Each year the World Health
      Organization (WHO) and the U.S FDA recommend the influenza strains to include in the seasonal
      influenza vaccines. The licensed seasonal influenza vaccines are directed against 3 influenza
      virus strains: an influenza A H1N1, an influenza A H3N2, and an influenza B. The currently
      approved vaccines depend upon labor-intensive methods that limit manufacturing speed and
      capacity. Influenza vaccines that can be more rapidly produced and that induce stronger,
      broader and more persistent immune responses are a recognized public health need.

      In this protocol we propose to use DNA vaccine antigen delivery to induce immune responses
      against native hemagglutinin (HA) structures prior to boosting with licensed TIV ID or with
      TIV IM.

      The study will allow evaluation of the safety and immunogenicity of same season and
      sequential season vaccination schedules. The same season regimens (2012/13 prime and boost
      with a 14 week interval) consist of HA DNA prime with TIV ID boost -- or -- HA DNA prime with
      TIV IM boost. The active comparator for these schedules are TIV ID or TIV IM alone because a
      single dose of TIV is the standard for adult influenza vaccination within a single season.
      The sequential season regimens (2012/13 prime and 2013/14 boost) consist of concurrent
      administration (in different arms) of HA DNA and TIV ID prime with TIV ID boost -- or -- HA
      DNA and TIV IM prime with TIV IM boost. The active comparator for these regimens will be TIV
      ID followed by TIV ID boost -- or -- TIV IM followed by TIV IM boost, administered sequential
      seasons consistent with as typical pattern of use for these licensed vaccines. Evaluation of
      the investigational schedules and active comparator schedules will inform development of
      novel influenza vaccine strategies that may offer improved and cross-protective immunity
      against diverse influenza strains.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Incidence of solicited adverse events after the first injection
time frame: Day 0 to Day 7
description: Incidence is reported for solicited events for 7 days after the first injection. For all Groups the collection period for solicited adverse events following the first injection Day 0 to Day 7.
measure: Incidence of solicited adverse events after the second injection
time frame: Day of injection to 7 days after second injection
description: Incidence is reported for solicited events for 7 days after the second injection. The period of solicitation is defined by the actual day of second injection.
measure: Incidence of unsolicited adverse events of any severity 28 days after the first injection
time frame: Day 0 to Day 28
description: Incidence is reported for unsolicited events for 28 days after the first injection. For all Groups the reporting period for unsolicited adverse events following the first injection Day 0 to Day 28.
measure: Incidence of unsolicited adverse events of any severity for 28 days after the second injection
time frame: Day of injection to 28 days after injection
description: The 28 day period following second injection is defined by the actual day of second injection.
measure: Incidence of serious adverse events or new chronic medical conditions through 24 weeks after the 2nd injection
time frame: Day 0 to 24 weeks after second injection
description: The day of second injection varies by group; the duration of time from Day 0 through 24 weeks after second injection is defined by the actual day of second injection.
measure: Number of subjects with influenza or influenza-like illnesses (ILI)
time frame: Day 0 to 24 weeks after second injection
description: The day of second injection varies by group; the duration of time from Day 0 through 24 weeks after second injection is defined by the actual day of second injection.
measure: Mean change from baseline in safety laboratory measures
time frame: Day 21
description: At Day 21 (window Day 21-28) blood will be drawn to measure hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC), mean corpuscular volume (MCV), platelets
measure: Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2)
time frame: Day 119
description: Seroconversion is defined a pre-vaccination strain-specific HAI titer <1:10 and a post-vaccination hemagglutination inhibition (HAI) titer ≥1:40 or a pre-vaccination.
Blood is collected at baseline (Day 0) and at 3 weeks following completion of the 2012/2013 vaccination regimen (3 weeks after 2012/13 TIV ID or TIV IM boost for Group 1 and Group 2, Day 119) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.
measure: Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4)
time frame: Day 21
description: Blood is collected at baseline (Day 0) and at 3 weeks following completion of the 2012/2013 prime injection (3 weeks after 2012/13 TIV ID or TIV IM prime Group 3 and Group 4, Day 21) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.
measure: Geometric Mean HAI Titer for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2)
time frame: Day 119
description: Blood is collected 3 weeks following completion of the 2012/2013 vaccination regimen 3 weeks after 2012/13 TIV ID or TIV IM boost for (Group 1 and Group 2, Day 119) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.
measure: Geometric Mean HAI titer for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4)
time frame: 3 weeks after completion of the HA DNA prime, Day 21
description: Blood is collected 3 weeks following completion of the 2012/2013 prime injection (3 weeks after 2012/13 TIV ID or TIV IM prime Group 3 and Group 4, Day 21) for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 influenza vaccines.
measure: Seroconversion for each of the 2012/13 and 2013/14 influenza vaccine strains
time frame: 3 weeks after each study injection
description: For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 and 2013/2014 influenza vaccines. Seroconversion is defined a pre-vaccination strain-specific HAI titer <1:10 and a post-vaccination HAI titer ≥1:40 or a pre-vaccination.
measure: Geometric Mean HAI Titer for each of the 2012/13 and 2013/14 influenza vaccine strains
time frame: 3 weeks after each study injection
description: For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing in an HAI assay for each of the influenza strains influenza in the 2012/2013 and 2013/2014 influenza vaccines.
measure: Proportion of subjects with four-fold rise from baseline for each of the 2012/13 and 2013/14 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies
time frame: 3 weeks after each study injection
description: For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing 2012/2013 and 2013/2014 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies.
measure: Geometric Mean neutralization titer of 2012/13 and 2013/14 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies
time frame: 3 weeks after each study injection
description: For all study groups, blood is collected from all subjects at baseline and at 3 weeks following each study injection for testing 2012/2013 and 2013/2014 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies.
arm group label: Group 1: HA DNA + TIV ID
arm group type: Experimental
description: 2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) at Day 0 and licensed 2012/13 TIV ID at Week 14±2 wks
arm group label: Group 2: HA DNA + TIV IM
arm group type: Experimental
description: 2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) at Day 0 and licensed 2012/13 TIV IM at Week 14±2 wks
arm group label: Group 3: TIV ID + TIV ID
arm group type: Experimental
description: licensed 2012/13 TIV ID at Day 0 and licensed 2013/14 TIV ID at Week 44±2 weeks
arm group label: Group 4: TIV IM + TIV IM
arm group type: Experimental
description: 2012/13 licensed TIV IM at Day 0 and licensed 2013/14 TIV IM at Week 44±2 weeks
arm group label: Group 5: (HA DNA and TIV ID) + TIV ID
arm group type: Experimental
description: 2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) and licensed 2012/13 TIV ID at Day 0 followed by licensed 2013/14 TIV ID at Week 44±2 weeks
arm group label: Group 6: (HA DNA and TIV IM) + TIV IM
arm group type: Experimental
description: 2012/13 seasonal influenza DNA Vaccine (VRC-FLUDNA063-00-VP) and licensed 2012/13 TIV IM at Day 0 followed by licensed 2013/14 TIV IM at Week 44±2 weeks
intervention type: Biological
intervention name: Seasonal Influenza DNA vaccine
description: VRC-FLUDNA063-00-VP is composed of 3 closed-circular DNA plasmids that encode for the hemagglutinin (HA) from the following 3 strains: A/California/04/2009 (H1); A/Victoria/361/2011 (H3), and B/Wisconsin/2010. DNA vaccine vials will be supplied at 4 mg/mL in single use vials. The 4 mg dosage is administered as a 1 mL volume.
arm group label: Group 1: HA DNA + TIV ID
arm group label: Group 2: HA DNA + TIV IM
arm group label: Group 5: (HA DNA and TIV ID) + TIV ID
arm group label: Group 6: (HA DNA and TIV IM) + TIV IM
other name: VRC-FLUDNA063-00-VP
other name: HA DNA Vaccine
other name: Seasonal influenza trivalent DNA vaccine
intervention type: Biological
intervention name: TIV
description: 2012/13, 2013/14 Seasonal Influenza Trivalent Inactivated Vaccine (TIV)
arm group label: Group 1: HA DNA + TIV ID
arm group label: Group 2: HA DNA + TIV IM
arm group label: Group 3: TIV ID + TIV ID
arm group label: Group 4: TIV IM + TIV IM
arm group label: Group 5: (HA DNA and TIV ID) + TIV ID
arm group label: Group 6: (HA DNA and TIV IM) + TIV IM
other name: 2012/13 Seasonal Influenza TIV (Fluzone)
other name: 2013/14 Seasonal Influenza TIV (Fluzone)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Barney S Graham, M.D., Ph.D.
role: Study Director
affiliation: Chief, Clinical Trials Core Vaccine Research Center, NIAID, NIH
last name: Julie Ledgerwood, DO
role: Study Chair
affiliation: Deputy Chief, Clinical Trials Core Vaccine Research Center, NIAID, NIH
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Ledgerwood JE, Wei CJ, Hu Z, Gordon IJ, Enama ME, Hendel CS, McTamney PM, Pearce MB, Yassine HM, Boyington JC, Bailer R, Tumpey TM, Koup RA, Mascola JR, Nabel GJ, Graham BS; VRC 306 Study Team. DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials. Lancet Infect Dis. 2011 Dec;11(12):916-24. doi: 10.1016/S1473-3099(11)70240-7. Epub 2011 Oct 3.
PMID: 21975270
citation: Ledgerwood JE, Graham BS. DNA vaccines: a safe and efficient platform technology for responding to emerging infectious diseases. Hum Vaccin. 2009 Sep;5(9):623-6. doi: 10.4161/hv.8627. No abstract available.
PMID: 19779298
citation: Carter C, Houser KV, Yamshchikov GV, Bellamy AR, May J, Enama ME, Sarwar U, Larkin B, Bailer RT, Koup R, Chen GL, Patel SM, Winokur P, Belshe R, Dekker CL, Graham BS, Ledgerwood JE; VRC 703 study team. Safety and immunogenicity of investigational seasonal influenza hemagglutinin DNA vaccine followed by trivalent inactivated vaccine administered intradermally or intramuscularly in healthy adults: An open-label randomized phase 1 clinical trial. PLoS One. 2019 Sep 18;14(9):e0222178. doi: 10.1371/journal.pone.0222178. eCollection 2019.
PMID: 31532789
responsible party type: Sponsor
mesh term: Influenza, Human
mesh term: Vaccines