Clinical Trial: A Phase I Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of MVA-BN Yellow Fever Vaccine With and Without Montanide ISA-720 Adjuvant in 18-45 Year Old Healthy Volunteers

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase I, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of MVA-BN Yellow Fever Vaccine With and Without Montanide ISA

Brief Summary: This study is a multi-center, double-blind, placebo-controlled, Phase I study to evaluate the safety, reactogenicity, tolerability, and immunogenicity of MVA-BN-YF in Flavivirus-naïve healthy male and non-pregnant female adult subjects. There are six dose groups in this study. Subjects who have never received a licensed or investigational smallpox vaccine will be randomized to Groups 1-5 and vaccine administration and follow-up will be conducted in a double-blinded fashion. Subjects who have previously received two, 1 x 108 TCID50 doses of MVA-BN between 19 and 45 days apart by SC or IM routes will be enrolled in Group 6 and will be dosed open-label. Since this is a first in human, phase I study, a sentinel cohort will be utilized. The first two subjects (1st sentinel group) one at each clinical site will be randomized to Group 2 or 3 and vaccinated with MVA-BN-YF with or without ISA 720. Subjects and study personnel will be blinded as to whether ISA 720 was administered.

Detailed Summary: This study is a multi-center, double-blind, placebo-controlled, Phase I study to evaluate the safety, reactogenicity, tolerability, and immunogenicity of MVA-BN-YF in Flavivirus-naïve healthy male and non-pregnant female adult subjects. There are six dose groups in this study. Subjects who have never received a licensed or investigational smallpox vaccine will be randomized to Groups 1-5 and vaccine administration and follow-up will be conducted in a double-blinded fashion. Subjects who have previously received two, 1 x 108 TCID50 doses of MVA-BN between 19 and 45 days apart by SC or IM routes will be enrolled in Group 6 and will be dosed open-label. Since this is a first in human, phase I study, a sentinel cohort will be utilized. The first two subjects (1st sentinel group) one at each clinical site will be randomized to Group 2 or 3 and vaccinated with MVA-BN-YF with or without ISA 720. Subjects and study personnel will be blinded as to whether ISA 720 was administered. Subjects will be monitored for safety for one day, and if no pre-defined halting rule is met (Section 9.5.1) then two additional subjects (2nd sentinel group) one at each clinical site will be assigned to the group the previous subject was not assigned to. These subjects will be vaccinated and monitored as above. A total of 4 sentinel subjects will be vaccinated. Primary objectives are assessment of the safety, tolerability, and reactogenicity of MVA-BN-YF vaccine administered with or without ISA 720; comparison of the safety, tolerability, and reactogenicity of MVA-BN-YF vaccine administered with or without ISA 720 with YF-VAX and MVA-BN. Secondary objectives are: assessment of the immunogenicity against the MVA-BN backbone and Yellow Fever virus (YF) antigen insert of MVA-BN-YF with and without ISA 720 as assessed by kinetics of the immune responses, seroconversion rates, and peak Geometric Mean Titer (GMT); assessment of the impact of previous MVA-BN vaccination on peak immune responses to
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Current Primary Outcome:

  • Comparison of grade 3 local, systemic or laboratory toxicities through Day 8 after any vaccination [ Time Frame: Days 1-8 and 29-36 ]
  • Continuous Grade 2 or greater local reactogenicity through Day 8 after any vaccination. [ Time Frame: Days 1-8 and 29-36 ]
  • Number of related AESIs [ Time Frame: Days 1-394 ]
  • Number of related SAEs [ Time Frame: Days 1-394 ]
  • Number of serious adverse events and adverse events of special interest considered related to study vaccination reported at any time after the first vaccination through the end of the study overall and in each dose group. [ Time Frame: Days 1-394 ]
  • Number of withdrawals due to any reason between dose groups [ Time Frame: Days 1-394 ]
  • Occurrence of solicited injection site and systemic reactogenicity events from the time of each study vaccination through Day 8 after each study vaccination overall and in each dose group. [ Time Frame: Days 1-8 and 29-36 ]
  • The number of subjects overall and in each dose group with new onset of a chronic medical condition at any time after the first vaccination. [ Time Frame: Days 1-394 ]
  • The number of subjects overall and in each dose group with unsolicited vaccine-related AEs from time of first vaccination through 28 days after the last vaccination. [ Time Frame: Days 1-57 ]
  • The number of vaccine-related laboratory AEs in each dose group from the time of first vaccination through 28 days after the last vaccination [ Time Fra

    Original Primary Outcome:

    • Comparison of grade 3 local, systemic or laboratory toxicities through Day 8 after any vaccination [ Time Frame: Days 1-8 and 29-36 ]
    • Number of related SAEs [ Time Frame: Days 1-211 ]
    • Number of related AESIs [ Time Frame: Days 1-211 ]
    • Occurrence of solicited injection site and systemic reactogenicity events from the time of each study vaccination through Day 8 after each study vaccination overall and in each dose group. [ Time Frame: Days 1-8 and 29-36 ]
    • Number of serious adverse events and adverse events of special interest considered related to study vaccination reported at any time after the first vaccination through the end of the study overall and in each dose group. [ Time Frame: Days 1-211 ]
    • The number of vaccine-related laboratory AEs in each dose group from the time of first vaccination through 28 days after the last vaccination [ Time Frame: Days 1-57 ]
    • The number of subjects overall and in each dose group with unsolicited vaccine-related AEs from time of first vaccination through 28 days after the last vaccination. [ Time Frame: Days 1-57 ]
    • The number of subjects overall and in each dose group with new onset of a chronic medical condition at any time after the first vaccination. [ Time Frame: Days 1-211 ]
    • Number of withdrawals due to any reason between dose groups [ Time Frame: Days 1-211 ]
    • Continuous Grade 2 or greater local reactogenicity through Day 8 after any vaccination. [ Time Frame: 

      Current Secondary Outcome:

      • Comparison of GMT (as measured by PRNT or ELISA) to MVA-BN at study D211 between subjects who received MVA-BN and one and two doses of MVA-BN-YF with or without ISA 720 (dose groups 1-4). [ Time Frame: Day 211 ]
      • Comparison of GMT (as measured by PRNT) to YF at study D211 between subjects who received YF-VAX and one and two doses of MVA-BN-YF with or without ISA 720 (dose groups 2-6). [ Time Frame: Day 211 ]
      • Comparison of GMT (as measured by PRNT) to YF at study D211 in subjects who received MVA-BN-YF between subjects previously vaccinated with MVA-BN (dose group 6) compared to subjects with no previous MVA-BN vaccination (dose groups 2-4). [ Time Frame: Day 211 ]
      • Comparison of peak GMT (as measured by PRNT or ELISA) to MVA-BN between dose groups who received MVA-BN (after two doses) and MVA-BN-YF with or without ISA 720 (dose groups 1-4). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • Comparison of peak GMT (as measured by PRNT) to YF after each vaccination between dose groups who received YF-VAX or MVA-BN-YF with or without ISA-720 (dose groups 2-6). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • Comparison of peak GMT (as measured by PRNT) to YF after first vaccination with MVA-BN-YF in subjects previously vaccinated with MVA-BN (dose group 6) compared to subjects with no previous MVA-BN vaccination (dose groups 2-4). [ Time Frame: Days 29, 36, 43, 50, 57, 211, 301 ]
      • Comparison of peak GMT (as measured by PRNT) to YF at any time point between dose groups who received YF-VAX or MVA-BN-YF with or without ISA-720 (dose groups 2-6). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • Peak GMT (as measured by PRNT or ELISA) to MVA in dose groups 1-4 and 6. [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • Peak GMT (as measured by PRNT) to YF in dose groups 2-6 [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • Per visit GMT (as measured by PRNT) to YF in dose groups 2-6 for each post-vaccination visit [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • Per-visit GMT (as measured by PRNT or ELISA) to MVA in dose groups 1-4 and 6 for each post-vaccination visit. [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • The proportion of subjects in dose groups 1-4 seroconverting to MVA-BN for each post-vaccination visit (where seroconversion is defined as PRNT50 =/ >2 or ELISA titer =/ >50 or at least a 2-fold rise in ELISA antibody responses compared with baseline [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]
      • The proportion of subjects in dose groups 2-6 seroconverting to YF for each post-vaccination visit (where seroconversion is defined as PRNT50 titer =/ >20 or at least a 4-fold increase in neutralizing antibody responses to YF compared with baseline [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211, 301 ]


      Original Secondary Outcome:

      • Per-visit GMT (as measured by PRNT or ELISA) to MVA in dose groups 1-4 and 6 for each post-vaccination visit. [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • The proportion of subjects in dose groups 1-4 seroconverting to MVA-BN for each post-vaccination visit (where seroconversion is defined as PRNT50 =/ >2 or ELISA titer =/ >50 or at least a 2-fold rise in ELISA antibody responses compared with baseline [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Peak GMT (as measured by PRNT) to YF in dose groups 2-6 [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Peak GMT (as measured by PRNT or ELISA) to MVA in dose groups 1-4 and 6. [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Comparison of peak GMT (as measured by PRNT) to YF after first vaccination with MVA-BN-YF in subjects previously vaccinated with MVA-BN (dose group 6) compared to subjects with no previous MVA-BN vaccination (dose groups 2-4). [ Time Frame: Days 29, 36, 43, 50, 57, 211 ]
      • Comparison of peak GMT (as measured by PRNT) to YF at any time point between dose groups who received YF-VAX or MVA-BN-YF with or without ISA-720 (dose groups 2-6). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Comparison of GMT (as measured by PRNT) to YF at study D211 in subjects who received MVA-BN-YF between subjects previously vaccinated with MVA-BN (dose group 6) compared to subjects with no previous MVA-BN vaccination (dose groups 2-4). [ Time Frame: Day 211 ]
      • The proportion of subjects in dose groups 2-6 seroconverting to YF for each post-vaccination visit (where seroconversion is defined as PRNT50 titer =/ >20 or at least a 4-fold increase in neutralizing antibody responses to YF compared with baseline [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Comparison of peak GMT (as measured by PRNT) to YF after each vaccination between dose groups who received YF-VAX or MVA-BN-YF with or without ISA-720 (dose groups 2-6). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Comparison of peak GMT (as measured by PRNT or ELISA) to MVA-BN between dose groups who received MVA-BN (after two doses) and MVA-BN-YF with or without ISA 720 (dose groups 1-4). [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]
      • Comparison of GMT (as measured by PRNT) to YF at study D211 between subjects who received YF-VAX and one and two doses of MVA-BN-YF with or without ISA 720 (dose groups 2-6). [ Time Frame: Day 211 ]
      • Comparison of GMT (as measured by PRNT or ELISA) to MVA-BN at study D211 between subjects who received MVA-BN and one and two doses of MVA-BN-YF with or without ISA 720 (dose groups 1-4). [ Time Frame: Day 211 ]
      • Per visit GMT (as measured by PRNT) to YF in dose groups 2-6 for each post-vaccination visit [ Time Frame: Days 1, 15, 22, 29, 36, 43, 50, 57, 211 ]


      Information By: National Institute of Allergy and Infectious Diseases (NIAID)

      Dates:
      Date Received: April 14, 2016
      Date Started: July 5, 2016
      Date Completion: December 29, 2017
      Last Updated: January 26, 2017
      Last Verified: July 12, 2016