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

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

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

Study Overview

• Status: Completed
• Conditions: Dengue Fever
• Intervention / Treatment: Biological: TDV

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Peoria, Illinois, United States, 61614
      • Optimal Research
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. 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.
2. 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]).
3. 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:

1. 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.
2. Has history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (eg, Guillain-Barré syndrome).

3. Known or suspected impairment/alteration of immune function including:

   1. 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).
   2. 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).
   3. Administration of immunoglobulins and/or any blood products within 3 months prior to Day 1 (Month 0) or planned administration during the trial.
   4. Receipt of immunostimulants within 60 days prior to Day 1 (Month 0).
   5. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (Month 0).
   6. Known Human Immunodeficiency Virus (HIV) infection or HIV-related disease.
   7. Hepatitis C virus infection.
   8. Genetic immunodeficiency.
4. Has planned vaccination (during the trial conduct) against any non-dengue flavivirus (eg, Zika, YF, JE, WN, tick-borne encephalitis, or Murray-Valley encephalitis).
5. Planned travel (during the trial conduct) to any area endemic for dengue.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDV: Flavivirus-naïve; Tetravalent Dengue Vaccine (TDV) 0.5 mL, subcutaneous (SC) injection, once on Day 1 (first dose) and then on Day 90 (second dose). Participants who were flavivirus-naïve were included in this group.	Biological: TDV; TDV subcutaneous injection comprised of 1 molecularly characterized, attenuated dengue virus strain, and 3 chimeric dengue virus strains with potencies of not less than 3.3, 2.7, 4.0, and 4.5 log10 plaque forming units (PFU) per dose of TDV-1, TDV-2, TDV-3, and TDV-4, respectively.
Experimental: TDV: DENV Immune: DENV-1 Positive; TDV 0.5 mL, SC injection, once on Day 1 (first dose) and then on Day 90 (second dose). Participants with serology consistent with primary infection by wild type dengue virus serotype-1 (DENV-1) were included in this group.	Biological: TDV; TDV subcutaneous injection comprised of 1 molecularly characterized, attenuated dengue virus strain, and 3 chimeric dengue virus strains with potencies of not less than 3.3, 2.7, 4.0, and 4.5 log10 plaque forming units (PFU) per dose of TDV-1, TDV-2, TDV-3, and TDV-4, respectively.
Experimental: TDV: DENV Immune: DENV-3 Positive; TDV 0.5 mL, SC injection, once on Day 1 (first dose) and then on Day 90 (second dose). Participants with serology consistent with primary infection by DENV-3 were included in this group.	Biological: TDV; TDV subcutaneous injection comprised of 1 molecularly characterized, attenuated dengue virus strain, and 3 chimeric dengue virus strains with potencies of not less than 3.3, 2.7, 4.0, and 4.5 log10 plaque forming units (PFU) per dose of TDV-1, TDV-2, TDV-3, and TDV-4, respectively.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 15	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by microneutralization test 50% (MNT50).	Day 15
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 30 (Month 1)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 30 (Month 1)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 60 (Month 2)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 60 (Month 2)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 90 (Month 3)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 90 (Month 3)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 105	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 105
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 120 (Month 4)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 120 (Month 4)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 150 (Month 5)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 150 (Month 5)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 180 (Month 6)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 180 (Month 6)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 270 (Month 9)	GMT of neutralizing antibodies were measured for each of the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.	Day 270 (Month 9)
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 360 (Month 12)	GMT of neutralizing antibodies were measured for each of 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 >3 times higher compared with baseline (no peptide) and ≥50 spots per 10^6 peripheral blood mononuclear cells (PBMC) was 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 >3 times higher compared with baseline (no peptide) and ≥50 spots per 10^6 PBMC was 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 was performed in a subset of participants with IFN- γ ELISPOT responses >500 SFC/10^6 cells and availability of sufficient cells. Markers included 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 was 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 was defined as the date when vaccine viremia was last detected (positive result) to date when vaccine viremia was first detected (positive result) + 1 day. It was 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 was 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)
Percentage of Participants With Solicited Local (Injection Site) Reactions Following Each Vaccination	Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after vaccination and included 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)]. Only categories for which there was at least 1 participant are reported.	Within 7 days after each of the vaccine dose given on Day 1 (Month 0) and 90 (Month 3)
Percentage of Participants With Solicited Systemic Reactions Following Each Vaccination	Solicited systemic AEs were 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) was derived from a daily temperature reading recorded within 14 days after vaccination. Only categories for which there was at least 1 participant are reported.	Within 14 days after each of the vaccine dose given on Day 1 (Month 0) and 90 (Month 3)
Percentage of Participants With at Least One Unsolicited Adverse Events (AEs) Following Each 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.	Up to 28 days (day of vaccination + 27 days) after administration of each vaccine dose given on Day 1 (Month 0) and 90 (Month 3)
Percentage of Participants With Serious Adverse Events (SAEs)	A SAE is 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) through end of study (Day 360 [Month 12])
Percentage of Participants With Medically Attended AEs (MAAEs)	MAAEs was 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) through end of study (Day 360 [Month 12])

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Medical Director, Takeda

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2018
• Primary Completion (Actual): March 1, 2021
• Study Completion (Actual): March 1, 2021

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: November 15, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Vaccine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Hemorrhagic Fevers, Viral; Mosquito-Borne Diseases; Dengue
• Other Study ID Numbers: DEN-210

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No