Phase I, Randomized, Double-blinded, Placebo-Controlled Dose De-escalation Study to Evaluate Safety and Immunogenicity of Alum Adjuvanted Zika Virus Purified Inactivated Vaccine (ZPIV) in Adults in a Flavivirus Endemic Area
Condition: Zika Virus Infection
MeSH terms: Zika Virus Infection
Study type: Interventional
Phase: Phase 1

Summary: 
      This study is randomized, double-blinded, placebo-controlled, Phase 1, dose de-escalation
      study to evaluate the safety, reactogenicity, and immunogenicity of Alum Adjuvanted Zika
      Virus Purified Inactivated Vaccine (ZPIV) administered to healthy male and non-pregnant
      female adult subjects. This study will enroll 90 healthy male and non-pregnant female
      subjects between the ages of 21 and 49 and will be conducted at Ponce Medical School
      Foundation, Inc.-CAIMED in Ponce, Puerto Rico. The duration of each subject's participation
      is approximately 26 months from recruitment through the last study visit. The entire study is
      expected to take approximately 49 months to complete. Two dose levels will be evaluated. Each
      subject will receive either placebo or 5 mcg (Group 1) or 2.5 mcg (Group 2) of ZPIV
      administered by intramuscular (IM) injection on Days 1 and 29. Solicited local and systemic
      reactogenicity data will be collected from all subjects through Day 8 after each vaccination.
      All subjects will be monitored for occurrence of unsolicited adverse events until 28 days
      after the second vaccination. The study will consist of a screening period of up to 28 days,
      a vaccination period in which subjects will receive a prime dose of vaccine on Day 1 followed
      by a boost on Day 29, and a follow-up period of 24 months post boost vaccination. Primary
      objectives are: 1) Assess the safety and reactogenicity of a homologous prime boost regimen
      of ZPIV given at two different dose levels. 2) Compare the safety and reactogenicity of ZPIV
      after each vaccination, between dosage groups, and by pre-vaccination flavivirus immune
      status.
    

Detailed description: 
      This study is a single-center, randomized, double-blinded, placebo-controlled, Phase 1, dose
      de-escalation study to evaluate the safety, reactogenicity, and immunogenicity of a purified
      inactivated, alum-adjuvanted ZIKV vaccine (ZPIV) administered in a homologous prime-boost
      regimen to healthy male and non-pregnant female adult subjects living in a flavivirus-endemic
      area. This study will enroll 90 subjects between the ages of 21 and 49 and will be conducted
      at Ponce Medical School Foundation, Inc.-CAIMED in Ponce, Puerto Rico. The entire duration of
      each subject's participation is approximately 26 months including recruitment and collection
      of data on the safety and reactogenicity of the study vaccine and collection of samples for
      the assessment of immunogenicity. This study is expected to take approximately 49 months to
      complete. Two dose levels will be evaluated. Each subject will receive either placebo or 5
      mcg (Group 1) or 2.5 mcg (Group 2) of ZPIV administered by intramuscular (IM) injection on
      Days 1 and 29. The study will consist of a screening period of up to 28 days, a vaccination
      period in which subjects will receive a prime dose of vaccine on Day 1 followed by a
      homologous boost on Day 29, and a follow-up period of 24 months post boost vaccination. The
      study will begin with enrollment of 2 sentinel subjects in Group 1 who will receive 5 mcg
      ZPIV open label. One sentinel subject will be vaccinated, followed for one day for safety and
      reactogenicity, and if no halting rules are met per determination of the PI and co-PI, then
      the second sentinel subject will receive 5 mcg ZPIV open-label. Both sentinels will be
      followed for safety through Day 8 and if no predefined halting rules are met and no safety
      concerns are identified, then enrollment of the Group 1 non-sentinel subjects will proceed in
      double-blind fashion. The same procedure will be used for administration of the boost
      vaccination to the Group 1 sentinels: 1 sentinel (can be either) will receive 5 mcg ZPIV
      open-label, be followed for one day for safety and reactogenicity, and if no halting rules
      are met, then the 2nd sentinel will receive the boost vaccine. Both sentinels will be
      followed until Day 8 after 2nd vaccination for safety and reactogenicity and if no halting
      rules are met, then boost vaccination of the Group 1 non-sentinel subjects can proceed.
      Enrollment of the 2.5 mcg ZPIV group (Group 2) can begin after or at the same time
      non-sentinel subjects in Group 1 receive the 1st dose of vaccine. As of December 18, 2017,
      the majority of non-sentinel subjects in Group 1 have already received the 1st dose and have
      been followed until Day 8 for safety and reactogenicity, and no halting rules have been met
      or safety concerns identified. As this is a dose de-escalation study, concurrent enrollment
      of some remaining non-sentinel subjects in Groups 1 is permitted after enrollment of Group 2
      subjects has begun; also, no sentinel subjects will be used in Group 2. All subjects in Group
      2 will receive study product or placebo in double-blind fashion. The original study design
      planned to enroll 40 ZPIV recipients and 5 placebo recipients in each Group. However, due a
      natural disaster (hurricane Maria), 11 subjects enrolled in Group 1 had loss of samples at
      key timepoints. To rebalance the number of evaluable subjects between Groups, Group 1
      enrollment will be increased by 5 subjects and Group 2 enrollment will be decreased by 5
      subjects, for a total enrollment of 50 subjects in Group 1 and 40 in Group 2. Treatment
      assignments for both groups will be assigned according to the originally planned 8:1 ratio of
      ZPIV: placebo. Without compromising the blind of the study, we can anticipate approximately
      35 evaluable ZPIV recipients and approximately 5 evaluable placebo recipients in each group.
      All subjects will receive a homologous boost of ZPIV or placebo 28 days post-prime if no
      halting rules precluding second vaccination are met (Section 9). All subjects will be
      monitored for occurrence of unsolicited AEs until 28 days after the second vaccination SAEs,
      AESIs, and history of new medical conditions with onset after the first vaccination will be
      collected for the duration of the study. Blood for evaluation of antibodies to ZIKV by ELISA
      and neutralizing antibody assays will be collected at Visit 00, prior to each vaccination,
      and at multiple timepoints afterward. Primary objectives are: 1) Assess the safety and
      reactogenicity of a homologous prime boost regimen of ZPIV given at two different dose levels
      in a dose de-escalation format in healthy adult subjects who live in Puerto Rico, a
      flavivirus endemic area. 2) Compare the safety and reactogenicity profile of ZPIV after each
      vaccination, between dosage groups, and by pre-vaccination flavivirus immune status.
      Secondary Objectives are: 1) Assess the humoral immune response to a homologous prime-boost
      regimen of ZPIV after each dose of vaccine as determined by kinetics of the immune responses,
      seroconversion rates, and Geometric Mean Titers (GMT) overall, and compare results between
      dosage groups and by pre-vaccination flavivirus immune status. 2) Assess the durability of
      the humoral immune response to ZPIV at 6, 12, 18, and 24 months after the second vaccine
      administration overall, and compare results between dosage groups and by pre-vaccination
      flavivirus immune status.
    

Intervention name(s): Placebo; Zika Virus Purified Inactivated Vaccine (ZPIV)
Intervention type(s): Other; Biological
Intervention description(s): Placebo; Zika Virus Purified Inactivated Vaccine with aluminum hydroxide adjuvant.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Flavivirus; Inactivated; Phase I; Vaccine; ZIKA; ZPIV