Immunogenicity and Safety of Tetravalent Dengue Vaccine Candidate (TDV) in Flavivirus-Naïve and Dengue-Immune Adults

Study Overview
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Brief Summary
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The purpose of this study is to assess the neutralizing antibody response against each dengue serotype post-vaccination.

Detailed Description
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The vaccine being tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). TDV is being tested to protect people against dengue fever. This study will look at the immunogenicity and safety of TDV in flavivirus-naïve and dengue-immune adults. The study will enroll approximately 44 patients. Participants will be categorized into two groups based on results from serological testing performed by the trial center outside the scope of this trial (up to 70 days [10 weeks] prior to Day 1 [Month 0]): Group 1: Flavivirus-Naïve Participants Group 2: Dengue-Immune Participants All participants will receive subcutaneous injection of TDV on Day 1 (Month 0) and Day 90 (Month 3). This trial will be conducted in the United States. The overall time to participate in this study is 12 months. Participants will make multiple visits to the clinic, and 9 months after last dose of study drug for a follow-up assessment.

Official Title
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An Open-Label, Phase 2 Trial to Investigate the Humoral and Cell-Mediated Immune Responses and Safety of a Tetravalent Dengue Vaccine Candidate (TDV) Administered Subcutaneously in Flavivirus-Naïve and Dengue-Immune Healthy Adults

Conditions
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Dengue Fever

Intervention / Treatment
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* Biological: Takeda's Tetravalent Dengue Vaccine Candidate (TDV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Who are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the investigator. Group 1 only: immunologically naïve to dengue, Zika, Yellow Fever (YF), Japanese Encephalitis (JE), West Nile (WN) (based on negative results for detection of anti-DENV, anti-Zika, anti-YF, anti-JE, anti-WN antibodies) as documented by serological testing performed by the trial center outside the scope of this trial (up to 70 days [10 weeks] prior to Day 1 [Month 0]). Group 2 only: serology consistent with primary infection with either DENV-1 or DENV-3 (defined as detectable neutralizing antibodies against DENV-1 or DENV-3 only, or titers for DENV-1 or DENV-3 ≥4-times higher than titers for the 2 other dengue serotypes) as documented by serological testing performed by the trial center outside the scope of this trial (up to 70 days [10 weeks] prior to Day 1 [Month 0]). Exclusion Criteria: Has clinically active significant infection (as assessed by the investigator) or body temperature ≥38°C (100.4°F) within 3 days of the intended date of vaccination. Has history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (eg, Guillain-Barré syndrome). Known or suspected impairment/alteration of immune function including: Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥12 weeks and/or ≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (Month 0) (use of inhaled, intranasal, or topical corticosteroids is allowed). Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks and/or ≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (Month 0). Administration of immunoglobulins and/or any blood products within 3 months prior to Day 1 (Month 0) or planned administration during the trial. Receipt of immunostimulants within 60 days prior to Day 1 (Month 0). Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (Month 0). Known Human Immunodeficiency Virus (HIV) infection or HIV-related disease. Hepatitis C virus infection. Genetic immunodeficiency. Has planned vaccination (during the trial conduct) against any non-dengue flavivirus (eg, Zika, YF, JE, WN, tick-borne encephalitis, or Murray-Valley encephalitis). Planned travel (during the trial conduct) to any area endemic for dengue.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Takeda's Tetravalent Dengue Vaccine Candidate (TDV) 0.5 mL<br>TDV 0.5 mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in flavivirus-naïve participants (Group 1) and dengue-immune participants (Group 2). TDV comprised of 1 molecularly characterized, attenuated dengue virus strain and 3 chimeric dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing not less than 3.3, 2.7, 4.0, and 4.5 log10 plaque forming units (PFU) respectively. | Biological: Takeda's Tetravalent Dengue Vaccine Candidate (TDV)<br>* Tetravalent Dengue Vaccine (TDV) subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 15 | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by microneutralization test 50% (MNT50). | Day 15 | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 30 (Month 1) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 30 (Month 1) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 60 (Month 2) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 60 (Month 2) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 90 (Month 3) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 90 (Month 3) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 105 | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 105 | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 120 (Month 4) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 120 (Month 4) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 150 (Month 5) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 150 (Month 5) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 180 (Month 6) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 180 (Month 6) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 270 (Month 9) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 270 (Month 9) | 
| Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 360 (Month 12) | GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50. | Day 360 (Month 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Interferon-gamma (IFN-γ) Enzyme-linked Immunospot (ELISpot) Responses to Tetravalent Dengue Vaccine (TDV) | IFN-γ ELISpot response that is >3 times higher compared with baseline (no peptide) and ≥50 spots per 10^6 peripheral blood mononuclear cells (PBMC) is defined as cellular immune response. | Days 15, 30 (Month 1), 60 (Month 2), 90 (Month 3), 105, 120 (Month 4), 150 (Month 5), 180 (Month 6), 270 (Month 9), 360 (Month 12) | 
| Number of Spot Forming Cells [SFC]/10^6 Peripheral Blood Mononuclear Cells (PBMC) of IFN-γ ELISpot Responses to TDV | IFN-γ ELISpot response that is >3 times higher compared with baseline (no peptide) and ≥50 spots per 10^6 PBMC is defined as cellular immune response. | Days 15, 30 (Month 1), 60 (Month 2), 90 (Month 3), 105, 120 (Month 4), 150 (Month 5), 180 (Month 6), 270 (Month 9), 360 (Month 12) | 
| Phenotype Characterization of Cellular Immune Response to TDV Assessed by Intracellular Cytokine Staining (ICS) | Phenotype characterization of cellular immune response will be performed in a subset of participants with IFN- γ ELISPOT responses >500 SFC/10^6 cells and availability of sufficient cells. Markers will include cluster of differentiation (CD) 4, CD8, IFN-γ, tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2). | Days 15, 30 (Month 1), 60 (Month 2), 90 (Month 3), 105, 120 (Month 4), 150 (Month 5), 180 (Month 6), 270 (Month 9), 360 (Month 12) | 
| Percentage of Participants with Vaccine Viremia for Each of the Four Vaccine Strains after Vaccination | Vaccine viremia will be assessed for each of the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral ribonucleic acid (RNA) was detected by a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay. | Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4) | 
| Duration of Vaccine Viremia for Each of the Four Vaccine Strains after Vaccination | The duration of vaccine viremia for each vaccine strain is defined as the date when vaccine viremia is last detected (positive result) to date when vaccine viremia is first detected (positive result) + 1 day. It will be assessed for each of the four vaccine strains: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral RNA was detected by qRT-PCR assay. | Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4) | 
| Level of Vaccine Viremia for Each of the Four Vaccine Strains after Vaccination | Vaccine viremia will be assessed for each of the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral RNA was detected by qRT-PCR assay. | Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4) | 
| Number of Participants with Solicited Local (Injection Site) Reactions Following Vaccination | Solicited local AEs (at injection site) will be collected by participants using diary cards within 7 days after vaccination and will include injection site pain [Grade 0 (no pain), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity with or without treatment) and 3 (severe: prevents daily activity with or without treatment)], injection site erythema [Grade 0 (<25 mm), 1 (25 - ≤ 50 mm), 2 (>50 - ≤ 100 mm), 3 (> 100 mm)] and injection site swelling [Grade 0 (<25 mm), 1 (25 - ≤ 50 mm), 2 (>50 - ≤ 100 mm), 3 (> 100 mm)]. | Within 7 days after either of the vaccination given on Day 1 (Month 0) or 90 (Month 3) | 
| Number of Participants with Solicited Systemic Reactions Following Vaccination | Solicited systemic AEs will be collected by participants using diary cards within 14 days after vaccination and will include fever, headache, asthenia, malaise and myalgia. Severity grades are: Grade 0: none, Grade 1: mild (no interference with daily activity), Grade 2: moderate (interference with daily activity with or without treatment), Grade 3: severe (prevents normal daily activity with or without treatment). A systemic AE of fever (defined as body temperature ≥ 100.4°F regardless of method taken) will be derived from a daily temperature reading recorded within 14 days after vaccination. | Within 14 days after either of the vaccination given on Day 1 (Month 0) or 90 (Month 3) | 
| Number of Participants with at Least one Unsolicited Adverse Events (AEs) Following Vaccination | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a study vaccine; it does not necessarily have to have a causal relationship with study vaccine administration. | Within 28 days after either of the vaccination given on Day 1 (Month 0) or 90 (Month 3) | 
| Number of Participants with Serious Adverse Events (SAEs) | A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. | From first vaccination through end of study (Day 360 [Month 12]) | 
| Percentage of Participants With Medically Attended AEs (MAAEs) | MAAEs are defined as AEs leading to a medical visit to or by a healthcare professional, including visits to an emergency department, but not fulfilling seriousness criteria. | From first vaccination through end of study (Day 360 [Month 12]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccine