Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children

Study Overview
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Brief Summary
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The purpose of this study is to assess the cellular immune responses following 2 doses given 3 months apart of tetravalent dengue vaccine candidate (TDV) in 4 to 16 years' healthy participants.

Detailed Description
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The vaccine tested in this study was TDV. This study assessed cellular immune responses and safety up to 3 years post second TDV administration to healthy children aged 4 to 16 years and in dengue endemic regions. The study enrolled 200 participants. Participants received: • TDV 0.5 mL subcutaneous (SC) injection into the upper arm at Day 1 (Month 0) and at Day 90 (Month 3). This multi-center trial was conducted in Panama and Philippines. 198 participants received the 2-dose schedule of TDV, and 2 participants received only the first dose of TDV (Day 1). Participants made multiple visits to the clinic and were contacted at least every week for the entire study duration post first injection.

Official Title
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An Open Label, Phase 2 Study to Investigate Cell-mediated Immunity and Safety of a Tetravalent Dengue Vaccine Candidate (TDV) Administered Subcutaneously in Healthy Children Aged 4 to 16 Years

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Biological: TDV


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Is aged 4 to 16 years, inclusive (Latin America) or 4 to 8 years, inclusive (Asia). Are in good health at the time of entry into the study as determined by medical history, physical examination (including vital signs), and clinical judgment of the investigator. Main Exclusion Criteria: Febrile illness (body temperature ≥38°C) or moderate or severe acute illness or infection at the time of enrolment. History or any illness that, in the opinion of the investigator, might interfere with the results of the study or pose an additional risk to the participant due to participation in the study. Receipt of any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1 (Month 0) or planning to receive any vaccines within 28 days after Day 1 (Month 0). Previous participation in any clinical study of a dengue candidate vaccine, or previous receipt of any dengue vaccines (investigational or licensed).

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 16 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: Tetravalent Dengue Vaccine (TDV) 0.5 mL<br>TDV 0.5 mL, subcutaneous (SC) injection, on Day 1 (Month 0) and Day 90 (Month 3). | Biological: TDV<br>* TDV SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Cellular Immune Response to 2 Doses of Tetravalent Dengue Vaccine (TDV) at 1 Month Post Second Vaccination | Percentage of participants with cellular immune response were reported. Cellular immune response was defined as an interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Cellular immune response to any peptide pool was reported. The peptide pool included non-structural protein (NS) for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. Percentage of participants with cellular immune response were reported. Cellular immune response was defined as an interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Cellular immune response to any peptide pool was reported. The peptide pool included non-structural protein (NS) for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post second vaccination (Day 120) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Magnitude of Cellular Immune Response Assessed by Number of Spot Forming Cells (SFC)/Million Peripheral Blood Mononuclear Cells (PBMCs) Measured by IFN-γ ELISPOT at 1 Month Post Second Vaccination | The magnitude of cellular immune response was assessed by the number of SFC/million PBMCs for participants with a cellular immune response. Cellular immune response was defined as IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Data (SFC/million PBMC) for participants with a cellular immune response to any peptide pool is reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post second vaccination (Day 120) | 
| Percentage of Participants With Cellular Immune Response to TDV at 1 Month Post First Vaccination, Pre-second Vaccination, 6 Months Post Second Vaccination | Percentage of participants with cellular immune response were reported. Cellular immune response was defined as an IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1 [M0]) and >=5 spots per well. Cellular immune response to any peptide pool was reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post first vaccination (Day 30); 6 month post second vaccination (Day 270) | 
| Magnitude of Cellular Immune Response Assessed by Number of SFC/Million PBMCs Measured by IFN-γ ELISPOT at 1 Month Post First Vaccination, Pre-second Vaccination, 6 Months Post Second Vaccination | The magnitude of cellular immune response was assessed by the number of SFC/million PBMCs for participants with a cellular immune response. Cellular immune response was defined as IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Data (SFC/million PBMC) for participants with a cellular immune response to any peptide pool is reported. The peptide pool included NS protein for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post first vaccination (Day 30); 6 month post second vaccination (Day 270) | 
| Percentage of Participants With Cellular Immune Responses to TDV at 1 Month Post First Vaccination, Pre-second Vaccination, 1 and 6 Months Post Second Vaccination Assessed by Country | Percentage of participants with cellular immune response by country were reported. Cellular immune response was defined as an IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1 [M0]) and >=5 spots per well. Cellular immune response to any peptide pool was reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. Data is reported as per enrollment by country (Panama and Philippines). | 1 month post first vaccination (Day 30); 1 and 6 months post second vaccination (Days 120 Days 270) | 
| Percentage of Participants With Cellular Immune Responses to TDV:1 Month Post First Vaccination, Pre-second Vaccination, 1 and 6 Months Post Second Vaccination, by Dengue Baseline Seropositivity Status | Percentage of participants with cellular immune response by dengue Baseline seropositivity status were reported. Cellular immune response was defined as an IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1 [M0]) and >=5 spots per well. Seropositive at Baseline was defined as a reciprocal neutralizing titer >=10 for one or more dengue serotypes. Seronegative at Baseline was defined as having a reciprocal neutralizing titer <10 for all dengue serotypes. The 4 dengue virus serotypes were dengue virus (DENV)-1, DENV-2, DENV-3 and DENV-4. Cellular immune response to any peptide pool was reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. Data is reported per Baseline seropositivity status of participants (Seropositive and Seronegative). | 1 month post first vaccination (Day 30); 1and 6 months post second vaccination (Days 120 Days 270) | 
| Magnitude of Cellular Immune Response Assessed by Number of SFC/Million PBMCs Measured by IFN-γ ELISPOT at 1 Month Post First, Pre- Second Vaccination, 1 and 6 Months Post Second Vaccination, by Country | The magnitude of cellular immune response by country was assessed by the number of SFC/million PBMCs for participants with a cellular immune response. Cellular immune response was defined as IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Data (SFC/million PBMC) for participants with a cellular immune response to any peptide pool is reported. The peptide pool included NS protein for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. Data is reported as per enrollment by country (Panama and Philippines). | 1 month post first vaccination (Day 30); 1and 6 months post second vaccination (Days 120 Days 270) | 
| Magnitude of Cellular Immune Response Assessed by Number of SFC/Million PBMCs Measured by IFN-γ ELISPOT 1 Month Post First; Pre-second Vaccination; 1 and 6 Months Post Second Vaccination, by Dengue Baseline Seropositivity Status | The magnitude of cellular immune response by dengue Baseline seropositivity status was assessed by the number of SFC/million PBMCs for participants with a cellular immune response. Cellular immune response was defined as IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Seropositive at Baseline was defined as a reciprocal neutralizing titer >=10 for one or more dengue serotypes. Seronegative at Baseline was defined as having a reciprocal neutralizing titer <10 for all dengue serotypes. The 4 dengue virus serotypes were dengue virus (DENV)-1, DENV-2, DENV-3 and DENV-4. Cellular immune response to any peptide pool was reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. Data is reported per Baseline seropositivity status of participants (Seropositive and Seronegative). | 1 month post first vaccination (Day 30); 1and 6 months post second vaccination (Days 120 Days 270) | 
| Percentage of Participants With Cellular Immune Response to TDV in Participants >10 Years of Age | Percentage of participants with cellular immune response in participants >10 years of age were reported. Cellular immune response was defined as an IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1 [M0]) and >=5 spots per well. Cellular immune response to any peptide pool was reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. SFC/million PBMC for any peptide pool is reported in participants >10 years of age. | Day 14 | 
| Magnitude of Cellular Immune Response Assessed by Number of SFC/Million PBMCs Measured by IFN-γ ELISPOT in Participants >10 Years of Age | The magnitude of cellular immune response was assessed by the number of SFC/million PBMCs for participants with a cellular immune response. Cellular immune response was defined as IFN-γ ELISPOT response that was >3 times higher compared to Baseline (Day 1) and ≥ 5 spots per well. Cellular immune response to any peptide pool was reported. The peptide pool included NS for each of the dengue serotype: DENV-1, DENV-2, DENV-3 and DENV-4. SFC/million PBMC for any peptide pool is reported in participants >10 years of age. | Day 14 | 
| Phenotype Characterization of Cellular Immune Response Assessed by Percentage of Total T Cells of Cellular Response to DENV-2 NS Proteins at 1 Month Post First, Pre-second Vaccination, 1 and 6 Months Post Second Vaccination | The phenotype characterization of cellular immune response was assessed by intracellular cytokine staining (ICS) by the frequency of total cluster of differentiation 4 (CD4)+ and CD8+ T cells and was performed in a subset of participants with IFN- γ ELISPOT responses >500 SFC/million cells and availability of sufficient cells. The peptide pools included NS for the DENV-2 serotype. Data are presented for the different expression profiles of interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) cytokines for each peptide pool. Data is reported based on the type of T cells present in participants at the time of analysis (CD4+ T cells and CD8+ T cells). | 1 month post first vaccination (Day 30); 1and 6 months post second vaccination (Days 120 Days 270) | 
| Phenotype Characterization of Cellular Immune Response Assessed by Percentage of Total T Cells of Cellular Response DENV-2 NS Proteins,1 Month Post First, Pre Second Vaccination;1 and 6 Months Post Second Vaccination, by Country | The phenotype characterization of cellular immune response by country was assessed by ICS by the frequency of total CD4+ and CD8+ T cells and was performed in a subset of participants with IFN- γ ELISPOT responses >500 SFC/million cells and availability of sufficient cells. The peptide pools included NS for the DENV-2 serotype. Data are presented for the different expression profiles of IFN-γ, IL-2 and TNF-α cytokines for each peptide pool. Data is reported per country (Panama and Philippines) based on the type of T cells present in participants at the time of analysis (CD4+ T cells and CD8+ T cells). | 1 month post first vaccination (Day 30); 1and 6 months post second vaccination (Days 120 Days 270) | 
| Phenotype Characterization of Cellular Immune Response by Percentage of Total T Cells DENV-2 NS Proteins at 1 Month Post First, Pre Second Vaccination,1 and 6 Months Post Second Vaccination, by Dengue Baseline Seropositivity Status | The phenotype characterization of cellular immune response by dengue Baseline seropositivity status was assessed by the frequency of total CD4+ and CD8+ T cells and was performed in a subset of participants with IFN- γ ELISPOT responses >500 SFC/million cells and availability of sufficient cells. Seropositive was defined as a reciprocal neutralizing titer (MNT50) >=10 for one or more dengue serotypes. Seronegative was defined as titer value of <10 for all 4 serotypes. The peptide pools included NS for the DENV-2 serotype. Data are presented for the different expression profiles of IFN-γ, IL-2 and TNF-α cytokines for each peptide pool. Data is reported per Baseline seropositivity status (Seropositive and Seronegative) based on the type of T cells present in participants at the time of analysis (CD4+ T cells and CD8+ T cells). | 1 month post first vaccination (Day 30); 1and 6 months post second vaccination (Days 120 Days 270) | 
| Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at 1 Month Post First Vaccination, Pre Second Vaccination, and 1, 6 Months Post Second Vaccination and Then Annually Up to 3 Years | GMT of neutralizing antibodies was measured by microneutralization test (MTN). The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post first vaccination (Day 30); pre second vaccination (Day 90); 1 and 6 months post second vaccination (Days 120 and 270); annually up to 3 years (Years 1, 2 and 3) | 
| Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes at 1 Month Post First Vaccination, Pre-second Vaccination, and 1, 6 Months Post Second Vaccination and Then Annually up to 3 Years | Seropositive was defined as a reciprocal neutralizing titer ≥10. The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. | 1 month post first vaccination (Day 30); pre second vaccination (Day 90); 1 and 6 months post second vaccination (Days 120 and 270); annually up to 3 years (Years 1, 2 and 3) | 
| Percentage of Participants Seropositive for Multiple Dengue Serotypes at 1 Month Post First Vaccination, Pre Second Vaccination, 1, 6 Months Post Second Vaccination and Annually up to 3 Years | Seropositive was defined as a reciprocal neutralizing titer ≥10. The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositive for multiple dengue serotypes were summarized in the following categories: tetravalent and at least trivalent. | 1 month post first vaccination (Day 30); pre second vaccination (Day 90); 1 and 6 months post second vaccination (Days 120 and 270); annually up to 3 years (Years 1, 2 and 3) | 
| Percentage of Participants Experiencing Unsolicited Adverse Events (AE) | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a trial vaccine; it does not necessarily have to have a causal relationship with trial vaccine administration. | Up to 28 days (day of vaccination + 27 days) after administration of each vaccine dose on Day 1 [Month 0] and Day 90 [Month 3] | 
| Percentage of Participants With Medically Attended AEs (MAAEs) | MAAEs were 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 (Day 1) up to 6 months post second vaccination (Day 270) | 
| Percentage of Participants With Serious Adverse Events (SAEs) | A SAE was defined as 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 (Day 1) up to end of study (Approximately 3 years) | 
| Percentage of Participants With Virologically Confirmed Dengue | Participants with febrile illness defined as fever ≥38°C on any 2 of 3 consecutive days were evaluated for dengue. Virologically confirmed dengue was defined as febrile illness with a positive serotype-specific RT-PCR (i.e. positive dengue detection RT-PCR). | From first vaccination (Day 1) up to 6 months post second vaccination (Day 270) | 

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