Safety, Immunogenicity, and Dose Ranging Study of Inactivated Zika Virus Vaccine in Healthy Participants

Study Overview
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Brief Summary
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The purpose of this study is to describe the safety, tolerability and immunogenicity of two doses of purified inactivated Zika virus vaccine (PIZV) given 28 days apart. Three different vaccine doses containing different protein concentrations (2, 5 or 10 microgram [mcg]) each, will be given as 2 dose schedule to flavivirus naive and primed healthy adults. Participants will be followed for 7 days post each dose for tolerability and up to 6 months post dose 2 for safety. Immunogenicity assessment will be performed at 28 days post each dose and 6 months post dose 2. In addition, the selected dose group and control group will be followed till 24 months post dose 2 for safety and persistence of immunity.

Detailed Description
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The vaccine being tested in this study is called PIZV or TAK-426 adjuvanted with aluminum hydroxide. The Zika virus vaccine is being tested to provide safety and immunogenicity data to enable the vaccine to be further developed clinically. The study will enroll approximately 240 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four groups-which will remain undisclosed to the study observer: Placebo PIZV: 2 microgram (mcg) Low Dose PIZV: 5 mcg Medium Dose PIZV: 10 mcg High Dose All participants will be administered either placebo or PIZV by intramuscular (IM) injection into the middle third of the deltoid muscle, preferably in the non-dominant arm on Days 1 (Visit 1) and 29 (Visit 4). This multi-center trial will be conducted in the United States and Puerto Rico. The overall time to participate in this study is up to 25 months. Participants will make multiple visits to the clinic on Days 1, 8, 29, 36, 57, 211, 393 and will be contacted by telephone on Day 133 (Visit 7) and Day 575 (Visit 9) and also visit the clinic on Day 757 (Visit 11) depending on the study arm, for a final follow-up assessment.

Official Title
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A Phase 1, Randomized, Observer-Blind, Placebo-Controlled, Safety, Immunogenicity, and Dose Ranging Study of Purified Inactivated Zika Virus Vaccine (PIZV) Candidate in Flavivirus Naïve and Primed Healthy Adults Aged 18 to 49 Years

Conditions
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Virus, Zika, Zika Virus Disease, Flavivirus Infections, Healthy Participants

Intervention / Treatment
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* Drug: Placebo
* Biological: PIZV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and eligibility screening tests (hematology, biochemistry and urinalysis) and clinical judgment of the investigator. Vital signs must be within normal limits (ie, below Grade 1 as specified in the Food and Drug Administration [FDA] Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers). Screening tests must be within normal limits or not be above Grade 1 as defined in the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers. Participants who can comply with trial procedures and are available for the duration of follow-up. All female participants must be willing to undergo serum beta human chorionic gonadotropin (B-hCG) pregnancy test and must test negative by urine pregnancy test prior to each study vaccination. Exclusion Criteria: Participants and participants' partners with confirmed Zika virus (ZIKV) infection by self-report. Traveling to flavivirus endemic countries or flavivirus endemic regions of the United States (US) or US territories*, within 4 weeks prior to screening or planned travel through to Visit 6 (applicable only to participants to be enrolled into the flavivirus naïve cohort). a. Centers for Disease Control and Prevention (CDC) website define the information about the flavivirus endemic countries and US regions and territories. Known hypersensitivity or allergy to any of the vaccine candidate components (including excipients of the investigational vaccine or placebo). Has any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (example, Guillain-Barré syndrome). Known or suspected impairment/alteration of immune function, including: Chronic use of oral steroids (equivalent to 20 milligram per day [mg/day] prednisone greater than or equal to [>=] 12 weeks / >= 2 milligram per kilogram [mg/kg] body weight / day prednisone >= 2 weeks) within 60 days prior to Day 1 (use of inhaled, intranasal, or topical corticosteroids is allowed). Receipt of parenteral steroids (equivalent to 20 mg/day prednisone >= 12 weeks / >= 2 mg/kg body weight / day prednisone >= 2 weeks) within 60 days prior to Day 1. Receipt of immunostimulants within 60 days prior to Day 1. Receipt of parenteral, epidural or intra-articular immunoglobulin preparation, blood products, and/or plasma derived products within 3 months prior to Day 1 or planned during the full length of the trial. In addition, participants must be advised not to donate blood during the study period. Known Human Immunodeficiency Virus (HIV) infection or HIV-related disease. Genetic immunodeficiency. Has known current or chronic hepatitis B and/or hepatitis C infections. Has abnormalities of spleen or thymic function. Has a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time. Individuals participating in any clinical trial with another investigational product, including ZIKV vaccine clinical trial within 30 days prior to first trial visit or intent to participate in another clinical trial at any time during the conduct of this trial. Individuals who received any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of investigational vaccine/placebo administration. Female participants who are pregnant or breastfeeding, or are planning to become pregnant. Any positive or indeterminate pregnancy test. If female participant of childbearing potential, sexually active, and who has not used any of the acceptable contraceptive methods for at least 2 months prior to trial entry: Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: menopausal for at least 2 years without any other alternative medical cause (as confirmed by a healthcare professional), status after bilateral tubal ligation for at least 1 year, status after bilateral oophorectomy, or status after hysterectomy. Acceptable birth control methods are defined as one or more of the following: Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring). Barrier (condom with spermicide or diaphragm with spermicide) each and every time during intercourse. Intrauterine device. Monogamous relationship with vasectomized partner. Partner must have been vasectomized for at least six months prior to the participants' trial entry. If female participant of childbearing potential and sexually active, refusal to use an acceptable contraceptive method from trial entry through 2 months after the last dose of investigational vaccine/placebo. In addition female participants of childbearing potential must be advised not to donate ova during this period. To avoid sexual transmission of ZIKV from natural exposure: Refusal to use latex condoms correctly and consistently by sexually active participants even if other contraceptive measures are used from signing the informed consent form (ICF) through the end of the trial. Male participants must be advised not to donate sperm during this period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Flavivirus-naïve Cohort: Placebo<br>Placebo injection, intramuscular (IM), once on Day 1 (first dose) and Day 29 (second dose). | Drug: Placebo<br>* Placebo (normal saline (0.9% NaCl) IM injection.<br>|
| Experimental: Flavivirus-naïve Cohort: PIZV 2 mcg (Low Dose)<br>PIZV 0.5 mL, 2 mcg antigen, IM injection, once on Day 1 (first dose) and Day 29 (second dose). | Biological: PIZV<br>* Purified inactivated Zika virus vaccine with aluminum hydroxide adjuvant IM injection.<br>* Other names: TAK-426;|
| Experimental: Flavivirus-naïve Cohort: PIZV 5 mcg (Medium Dose)<br>PIZV 0.5 mL, 5 mcg antigen, IM injection, once on Day 1 (first dose) and Day 29 (second dose). | Biological: PIZV<br>* Purified inactivated Zika virus vaccine with aluminum hydroxide adjuvant IM injection.<br>* Other names: TAK-426;|
| Experimental: Flavivirus-naïve Cohort: PIZV 10 mcg (High Dose)<br>PIZV 0.5 mL, 10 mcg antigen, IM injection, once on Day 1 (first dose) and Day 29 (second dose). | Biological: PIZV<br>* Purified inactivated Zika virus vaccine with aluminum hydroxide adjuvant IM injection.<br>* Other names: TAK-426;|
| Placebo Comparator: Flavivirus-primed Cohort: Placebo<br>Placebo injection, IM, once on Day 1 (first dose) and Day 29 (second dose). | Drug: Placebo<br>* Placebo (normal saline (0.9% NaCl) IM injection.<br>|
| Experimental: Flavivirus-primed Cohort: PIZV 2 mcg (Low Dose)<br>PIZV 0.5 mL, 2 mcg antigen, IM injection, once on Day 1 (first dose) and Day 29 (second dose). | Biological: PIZV<br>* Purified inactivated Zika virus vaccine with aluminum hydroxide adjuvant IM injection.<br>* Other names: TAK-426;|
| Experimental: Flavivirus-primed Cohort: PIZV 5 mcg (Medium Dose)<br>PIZV 0.5 mL, 5 mcg antigen, IM injection, once on Day 1 (first dose) and Day 29 (second dose). | Biological: PIZV<br>* Purified inactivated Zika virus vaccine with aluminum hydroxide adjuvant IM injection.<br>* Other names: TAK-426;|
| Experimental: Flavivirus-primed Cohort: PIZV 10 mcg (High dose)<br>PIZV 0.5 mL, 10 mcg antigen, IM injection, once on Day 1 (first dose) and Day 29 (second dose). | Biological: PIZV<br>* Purified inactivated Zika virus vaccine with aluminum hydroxide adjuvant IM injection.<br>* Other names: TAK-426;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Solicited Local Injection Site Reactions by Severity Within 7 Days After Dose 1 of PIZV or Placebo | Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after first vaccination and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), erythema (<25 mm, mild: >=25 to- <=50 mm, moderate: >50 to <=100 mm, severe: >100 mm), and swelling and induration (<25 mm, mild: >=25 to <=-50 mm, moderate: >50 to <=100 mm, severe: >100 mm). Only categories for which there was at least 1 participant are reported. | Within 7 days after Dose 1 (Day 8) | 
| Percentage of Participants With Solicited Local Injection Site Reactions by Severity Within 7 Days After Dose 2 of PIZV or Placebo | Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after first vaccination and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), erythema (<25 mm, mild: >=25 to <=50 mm, moderate: >50 to <=100 mm, severe: >100 mm), and swelling and induration (<25 mm, mild: >=25 to <=50 mm, moderate: >50 to <=100 mm, severe: >100 mm). Only categories for which there was at least 1 participant are reported. | Within 7 days after Dose 2 (Day 36) | 
| Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity Within 7 Days After Dose 1 of PIZV or Placebo | Solicited systemic AEs included fever, headache, fatigue, malaise, arthralgia, and myalgia that occurred within 7 days of first vaccination. Solicited systemic AEs (headache, fatigue, malaise, arthralgia, and myalgia) was graded from 0 to 3 by severity; where 0=None, 1=Mild: No interference with daily activity, 2=Moderate: Interference with daily activity, 3=Severe: Prevents daily activity; A systemic AE of fever (defined as ≥38°C or ≥100.4°F) was graded from 1 to 4 by severity; where 1=Mild: 38.0-38.4°C, 2=Moderate: 38.5-38.9°C, 3=Severe: 39.0-40°C, and 4=Potentially life threatening:>40°C. Only categories for which there was at least 1 participant are reported. | Within 7 days after Dose 1 (Day 8) | 
| Percentage of Participants With Solicited Systemic AEs by Severity Within 7 Days After Dose 2 of PIZV or Placebo | Solicited systemic AEs included fever, headache, fatigue, malaise, arthralgia, and myalgia that occurred within 7 days of first vaccination. Solicited systemic AEs (headache, fatigue, malaise, arthralgia, and myalgia) was graded from 0 to 3 by severity; where 0=None, 1=Mild: No interference with daily activity, 2=Moderate: Interference with daily activity, 3=Severe: Prevents daily activity; A systemic AE of fever (defined as ≥38°C or ≥100.4°F) was graded from 1 to 4 by severity; where 1=Mild: 38.0-38.4°C, 2=Moderate: 38.5-38.9°C, 3=Severe: 39.0-40°C, and 4=Potentially life threatening:>40°C. Only categories for which there was at least 1 participant are reported. | Within 7 days after Dose 2 (Day 36) | 
| Percentage of Participants Who Experienced at Least One Non-serious Unsolicited AE Within 28 Days After Dose 1 of PIZV or Placebo | An AE was defined as any untoward medical occurrence in participants administered a trial vaccine; it does not necessarily have to have a causal relationship with trial vaccine administration. | Within 28 days after Dose 1 (Day 29) | 
| Percentage of Participants Who Experienced at Least One Non-serious Unsolicited AE Within 28 Days After Dose 2 of PIZV or Placebo | An AE was defined as any untoward medical occurrence in a clinical investigation participants administered a trial vaccine; it does not necessarily have to have a causal relationship with trial vaccine administration. | Within 28 days after Dose 2 (Day 57) | 
| Percentage of Participants Who Experienced at Least One Serious Adverse Event (SAE) Within 28 Days After Dose 1 of PIZV or Placebo | A SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. | Within 28 days after Dose 1 (Day 29) | 
| Percentage of Participants Who Experienced at Least One SAE Within 28 Days After Dose 2 of PIZV or Placebo | A SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. | Within 28 days after Dose 2 (Day 57) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibody for Zika Virus (ZIKV) 28 Days After Dose 2 of PIZV or Placebo | GMTs of neutralizing antibodies for ZIKV were measured by the Zika plaque reduction neutralization test (PRNT) test, by assessing the quantity of neutralizing antibodies that bind ZIKV in the assay. The assay results were reported as titers (reciprocal value of the dilution of the serum from the vaccinated individual that inhibits for 50% the plaque formation). | 28 days after Dose 2 (Day 57) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced at Least One SAE During the Study | A SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. | From day of first vaccination (Day 1) up to end of the study (Day 757) | 
| GMTs of Neutralizing Antibody for ZIKV 28 Days After Dose 1 and 6 Months After Dose 2 | GMTs of neutralizing antibodies for ZIKV were measured by Zika PRNT test, by assessing the quantity of neutralizing antibodies that bind ZIKV in the assay. The assay results were reported as titers (reciprocal value of the dilution of the serum from the vaccinated individual that inhibits for 50% the plaque formation). | 28 days after Dose 1 (Day 29); 6 months after Dose 2 (Day 211) | 
| GMTs of Neutralizing Antibody for ZIKV 12 Months and 24 Months After Dose 2 in Applicable Groups | GMTs of neutralizing antibodies for ZIKV were measured by Zika PRNT test, by assessing the quantity of neutralizing antibodies that bind ZIKV in the assay. The assay results were reported as titers (reciprocal value of the dilution of the serum from the vaccinated individual that inhibits for 50% the plaque formation). As prespecified in the protocol, only data for applicable groups (Placebo and PIZV 10 mcg who were followed beyond Day 211) were analyzed and reported at Days 393 and 757 for Flavivirus-naïve Cohort and Flavivirus-primed Cohort. | 12 months after Dose 2 (Day 393); 24 months after Dose 2 (Day 757) | 
| Percentage of Participants Seropositive for Neutralizing Antibodies Against PIZV 28 Days After Dose 1, 28 Days After Dose 2, and 6 Months After Dose 2 | Seropositive participants were defined as participants with detectable serum antibodies (tested positive at or above limit of detection, LOD) as measured by the neutralization assay. | 28 days after Dose 1 (Day 29); 28 days after Dose 2 (Day 57); 6 months after Dose 2 (Day 211) | 
| Percentage of Participants Seropositive for PIZV 12 Months and 24 Months After Dose 2 in Applicable Groups | Seropositive participants were defined as participants with detectable serum antibodies (tested positive at or above limit of detection, LOD) as measured by the neutralization assay. As prespecified in the protocol, only data for applicable groups (Placebo and PIZV 10 mcg who were followed beyond Day 211) were analyzed and reported at Days 393 and 757 for Flavivirus-naïve Cohort and Flavivirus-primed Cohort. | 12 months after Dose 2 (Day 393); 24 months after Dose 2 (Day 757) | 
| Percentage of Participants Seroconverted for PIZV 28 Days Post Dose 1 and 28 Days Post Dose 2 | Seroconverted participants were defined as participants at Baseline with detectable post-vaccination serum antibodies (test results are at or above LOD) and seropositive participants at Baseline with a four-fold increase in post-vaccination antibodies from Baseline, as measured by the neutralization assay. | 28 days after Dose 1 (Day 29); 28 days after Dose 2 (Day 57) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy