Seasonal Influenza HA DNA (VRC) With Trivalent Inactivated Vaccine (TIV) Administered ID or IM in Healthy Adults Ages 18-70 Years (VRC 703)

• Incidence of solicited adverse events after the first injection [ Time Frame: Day 0 to Day 7 ] [ Designated as safety issue: Yes ]
  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.
  
  
• Incidence of solicited adverse events after the second injection [ Time Frame: Day of injection to 7 days after second injection ] [ Designated as safety issue: Yes ]
  Incidence is reported for solicited events for 7 days after the second injection. For Groups 1 and 2 the second injection occurs on Day 98, so the collection period for solicited adverse events is Day 98 to Day 105. For Groups 3 - 6 the second injection occurs on Day 308, so the collection period for solicited adverse events Day 308 to day 315.
  
  
• Incidence of unsolicited adverse events of any severity 28 days after the first injection [ Time Frame: Day 0 to Day 28 ] [ Designated as safety issue: Yes ]
  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.
  
  
• 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 ] [ Designated as safety issue: Yes ]
  For Groups 1 and 2 the second injection occurs on Day 98, so the reporting period for unsolicited adverse events is Day 98 to Day 126. For Groups 3 - 6 the second injection occurs on Day 308, so the reporting period for unsolicited adverse events Day 308 to Day 336.
  
  
• 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 ] [ Designated as safety issue: Yes ]
  For Groups 1 and 2 the second injection occurs on Day 98 (SAE and new chronic medical condition reporting period Day 0- Day 266), and for Groups 3-6 the second injection occurs on Day 308 (SAE and new chronic medical condition reporting period Day 0- Day 476).
  
  
• Number of subjects with influenza or influenza-like illnesses [ Time Frame: Day 0 to 24 weeks after second injection ] [ Designated as safety issue: Yes ]
  For Groups 1 and 2 the second injection occurs on Day 98 (influenza or ILI reporting period Day 0-Day 266), and for Groups 3-6 the second injection occurs on Day 308 (influenza or ILI reporting period Day 0-Day 476).
  
  
• Mean change from baseline in safety laboratory measures [ Time Frame: Day 21 ] [ Designated as safety issue: Yes ]
  At Day 21 (window Day 21-28) blood will be drawn prior to receiving the second injection to measure hemoglobin, hematocrit, RBC, WBC, MCV, platelets
  
  
• Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2) [ Time Frame: Day 119 ] [ Designated as safety issue: No ]

  Seroconversion is defined a pre-vaccination strain-specific HAI titer <1:10 and a post-vaccination 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.

  
  
• Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4) [ Time Frame: Day 21 ] [ Designated as safety issue: No ]
  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.
  
  
• Geometric Mean HAI Titer for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2) [ Time Frame: Day 119 ] [ Designated as safety issue: No ]
  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.
  
  
• 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 ] [ Designated as safety issue: No ]
  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.
  
  

• Seroconversion for each of the 2012/13 and 2013/14 influenza vaccine strains [ Time Frame: 3 weeks after each study injection ] [ Designated as safety issue: No ]
  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.
  
  
• Geometric Mean HAI Titer for each of the 2012/13 and 2013/14 influenza vaccine strains [ Time Frame: 3 weeks after each study injection ] [ Designated as safety issue: No ]
  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.
  
  
• 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 ] [ Designated as safety issue: No ]
  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.
  
  
• 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 ] [ Designated as safety issue: No ]
  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.
  
  

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 with a 44 week interval) 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, also at a 44 week interval, because this is a vaccination pattern consistent with sequential season vaccinations. 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.