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

Phase 2

Completed

• Conditions: Dengue Fever
• Interventions: Biological: TDV

• Registration Number: NCT03746015
• Lead Sponsor: Takeda

Brief Summary

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

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 Timeline

• Study First Submitted: 2018-11-13
• Study First Submitted QC: 2018-11-15
• Study First Posted: 2018-11-19
• Study Start: 2018-12-28
• Primary Completion: 2021-03-01
• Study Completion: 2021-03-01
• Disposition First Submitted: 2022-02-23
• Disposition First Submitted QC: 2022-02-23
• Disposition First Posted: 2022-02-25
• Status Verified: 2024-03
• Results First Submitted: 2024-03-12
• Results First Submitted QC: 2024-03-12
• Last Update Submitted: 2024-03-12
• Results First Posted: 2024-04-10
• Last Update Posted: 2024-04-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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]).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TDV: DENV Immune: DENV-1 Positive	TDV	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.
TDV: Flavivirus-naïve	TDV	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.
TDV: DENV Immune: DENV-3 Positive	TDV	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.

Primary Outcome Measures

Name	Time	Method
Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 15	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).
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 30 (Month 1)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 60 (Month 2)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 120 (Month 4)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 150 (Month 5)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 105	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 360 (Month 12)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 270 (Month 9)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 90 (Month 3)	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.
GMT of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 180 (Month 6)	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Interferon-gamma (IFN-γ) Enzyme-linked Immunospot (ELISpot) Responses to Tetravalent Dengue Vaccine (TDV)	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)	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.
Number of Spot Forming Cells [SFC]/10^6 Peripheral Blood Mononuclear Cells (PBMC) of IFN-γ ELISpot Responses to TDV	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)	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.
Phenotype Characterization of Cellular Immune Response to TDV Assessed by Intracellular Cytokine Staining (ICS)	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 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).
Percentage of Participants With Vaccine Viremia for Each of the Four Vaccine Strains After Vaccination	Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4)	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.
Duration of Vaccine Viremia for Each of the Four Vaccine Strains After Vaccination	Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4)	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.
Percentage of Participants With Solicited Local (Injection Site) Reactions Following Each Vaccination	Within 7 days after each of the vaccine dose given on Day 1 (Month 0) and 90 (Month 3)	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.
Percentage of Participants With Serious Adverse Events (SAEs)	From first vaccination (Day 1) through end of study (Day 360 [Month 12])	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.
Level of Vaccine Viremia for Each of the Four Vaccine Strains After Vaccination	Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4)	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.
Percentage of Participants With Solicited Systemic Reactions Following Each Vaccination	Within 14 days after each of the vaccine dose given on Day 1 (Month 0) and 90 (Month 3)	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.
Percentage of Participants With at Least One Unsolicited Adverse Events (AEs) Following Each Vaccination	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)	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.
Percentage of Participants With Medically Attended AEs (MAAEs)	From first vaccination (Day 1) through end of study (Day 360 [Month 12])	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.

Trial Locations

Locations (2)

Optimal Research; 🇺🇸 Peoria, Illinois, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States