The purpose of this study is to assess the safety of Takeda's tetravalent dengue vaccine (TDV) (previously DENVax) administered subcutaneously in healthy adults and children. In addition the antibody response to the four dengue virus serotypes will be evaluated.
The vaccine tested in this study was tetravalent dengue vaccine (TDV). TDV was tested to assess safety and immunogenicity in healthy adults and children living in dengue endemic countries. The study enrolled 360 healthy participants. The study was conducted in 2 parts, Part 1 - age descending and and Part 2 - expansion - ages 1.5-11 years. Participants were allocated to one of the four age cohorts in Part 1 (21 to 45 years, 12 to 20 years, 6 to 11 years, and 1.5 to 5 years) and expansion age cohort 1.5-11 years in Part 2. Participants were randomized in 2:1 ratio and in 3: 1 ratio in Part 1 and 2 respectively to receive: * TDV 0.5 mL SC injection * Placebo (inactive solution) - this is a solution that looks like the study drug but has no active ingredient This multi-center trial was conducted worldwide. The overall time to participate in this study was up to 37 months (including screening period). Participants made multiple visits to the clinic including a final visit at Day 1080.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
360
TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). TDV comprised of 4 recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing 2\*10\^4 PFU, 5\*10\^4 PFU, 1\*10\^5 PFU, and 3\*10\^5 PFU respectively, total virus per dose: 4.7\*10\^5 PFU.
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Program For The Study and Control of Tropical Diseases
Medellín, Colombia
Ponce School of Medicine, CAIMED Center
Ponce, Puerto Rico
University of Puerto Rico School of Medicine
San Juan, Puerto Rico
Latin Clinical Trial Center
San Juan, Puerto Rico
Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination Dose by Severity
Solicited local injection site reactions were collected by subject diary and graded based on the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 for pain \[Grade 0 (no pain), 1 (mild), 2 (moderate) and 3 (severe)\] and itching (pruritus) \[Grade 0 (no itching), 1 (mild), 2 (moderate) and 3 (Severe\]. Severity grade for redness (erythema) and swelling (edema/induration) were derived from recorded length of the longest diameter measurement using the FDA Guidance for Industry: Toxicity Grading Scale of Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trial were Grade 0 (\<2.5 cm), 1 (mild: 2.5-5 cm), 2 (moderate: 5.1-10 cm) and 3 (severe: \>10 cm) and Grade 4 (Potentially Life-threatening: necrosis or exfoliative dermatitis).
Time frame: Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination)
Number of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (In Clinic Assessment) Following Either Vaccination Dose by Severity
Solicited local injection site reactions were collected by subject diary and graded based on the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 for pain \[Grade 0 (no pain), 1 (mild), 2 (moderate) and 3 (severe)\] and itching (pruritus) \[Grade 0 (no itching), 1 (mild), 2 (moderate) and 3 (Severe\]. Severity grade for redness (erythema) and swelling (edema/induration) were derived from recorded length of the longest diameter measurement using the FDA Guidance for Industry: Toxicity Grading Scale of Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trial were Grade 0 (\<2.5 cm), 1 (mild: 2.5-5 cm), 2 (moderate: 5.1-10 cm) and 3 (severe: \>10 cm) and Grade 4 (Potentially Life-threatening: necrosis or exfoliative dermatitis).
Time frame: Within 28 days after either of the vaccination given on Day 0 or 90 (Day 28 for first vaccination, Day 118 for second vaccination)
Number of Participants With Solicited Systemic Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination Dose by Severity
Solicited systemic AEs (headache, muscle pain \[myalgia\], joint pain \[arthralgia\], eye pain, sensitivity to light \[photophobia\], tiredness \[fatigue\], body rash, nausea, were recorded in the participant's-diary along with vomiting \[number of times\]), and body temperature). Diary-recorded severity grades were based on the Common Terminology Criteria for Adverse Events (CTCAE). Severity grades were: Mild (Grade 1): transient symptoms, discomfort noticed but was easily tolerated by the participant with no interference to normal daily activities. Moderate (Grade 2): marked symptoms, moderate interference with participant's daily activities. Severe (Grade 3): Considerable interference with participant's daily activities. The CTCAE severity grades for fever and vomiting were derived from the diary-recorded measurements of temperature level and number of episodes, respectively.
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National University Hospital
Singapore, Singapore
Changi General Hospital
Singapore, Singapore
Faculty of Tropical Medicine, Mahidol University
Bangkok, Bangkok, Thailand
Phramongkutklao Hospital
Bangkok, Bangkok, Thailand
Time frame: Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination)
Number of Participants With Any Solicited AE Following Either Vaccination Dose
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. Solicited local injection site reactions included pain, itching, erythema, edema and solicited systemic AEs include myalgia, arthralgia, eye pain, photophobia, fatigue, body rash, nausea, vomiting, and fever.
Time frame: Within 14 days after either of the vaccination given on Day 0 or 90 (Day 14 for first vaccination, Day 104 for second vaccination)
Number of Participants With at Least One Unsolicited AE Following Either Vaccination Dose by Severity
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. The severity of all unsolicited AEs was evaluated by the Investigator (using the Common Terminology Criteria for Adverse Events \[CTCAE\] v4.03) as follows. Mild (Grade 1): Transient symptoms, discomfort noticed but was easily tolerated by the participant with no interference to normal daily activities. Moderate (Grade 2): Marked symptoms, moderate interference with participant's daily activities. Severe (Grade 3): Considerable interference with participant's daily activities.
Time frame: Unsolicited AEs were collected within 28 days of all vaccinations. Serious AEs were collected throughout the study up to Day 1080
Seropositivity Rate to Each of the Four Dengue Serotypes at Day 120
Seropositivity rate, defined as the percentage of participants seropositive, was derived from titers of dengue-neutralizing antibodies. Participants were classified by titer after Day 0 as seropositive or seronegative. Seropositive was defined as a MNT50 titre value of ≥10 for any serotype and seronegative was defined as titre value of less than (\<) 10 for all 4 serotypes. Seropositivity was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, TDV-4.
Time frame: 30 days after second vaccination (Day 120)
Part I: Number of Participants Positive for Vaccine Viremia for Each of Four Vaccine Strain Serotypes After the Each Vaccination
Vaccine viremia was assessed for each of the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4 for Part-1. Vaccine viral ribonucleic acid (RNA) was detected by a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay.
Time frame: Days 0, 7, 14, 90, 97, and 104
Part I: Duration of Vaccine Viremia
Time frame: Days 0, 7, 14, 90, 97, and 104
Part I: Titers of Vaccine Viremia
Time frame: Days 0, 7, 14, 90, 97, and 104
Seropositivity Rate to Each of the Four Dengue Serotypes
Seropositivity rate, defined as the percentage of participants seropositive, was derived from titers of dengue-neutralizing antibodies. Participants were classified by titer after Day 0 as seropositive or seronegative. Seropositive was defined as a MNT50 titre value of ≥10 and seronegative was defined as titre value of less than (\<) 10. Seropositivity was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, TDV-4.
Time frame: Day 28 and Day 90 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1
Seroconversion Rate to Each of the Four Dengue Serotypes
Seroconversion rate was defined as the percentage of participants with microneutralization test 50% (MNT50) titer ≥10 or, if the titer on Day 0 was ≥10, a 4-fold rise in antibody titer.
Time frame: Day 28, 90 and 120 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1
Geometric Mean Neutralizing Antibody Titers (GMTs) of All Four Dengue Serotypes
GMTs were assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3, and TDV-4.
Time frame: Day 28, 90 and 120 (Parts 1 and 2) and Days 180, 360, 720 and 1080 in Part 1
Geometric Mean Fold Rise (GMFR) of Dengue Neutralizing Antibody Titers for Each of the 4 Dengue Serotypes
Time frame: Day 28 and Day 90 (Parts 1 and 2) and Days 120, 180, 360, 720 and 1080 in Part 1
Number of Participants With Confirmed Dengue Fever
Dengue fever was assessed in participants who had 3 consecutive days of fever \>38°C and tested positive for dengue virus by polymerase chain reaction (PCR) analysis.
Time frame: Day 1 to Day 1080