Immunogenicity and Safety of Tetravalent Dengue Vaccine (TDV) in Adolescents in Non-Endemic Area(s)

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03341637
• Collaborator: (none)
• Enrollment: 400
• Locations: 5
• Arms: 2
• Actual Duration (Months): 13.4
• Patients Per Site: 80
• Patients Per Site Per Month: 6

Study Details

Study Description

Brief Summary

The purpose of this study was to describe the neutralizing antibody response against each dengue serotype at 1 month post second dose of TDV or placebo in dengue-naive adolescent participants.

Condition or Disease	Intervention/Treatment	Phase
Dengue	Biological: Tetravalent Dengue Vaccine (TDV); Biological: Placebo	Phase 3

Detailed Description

The vaccine tested in this study was tetravalent dengue vaccine (TDV). TDV was tested to assess the safety and immunogenicity in healthy adolescents in non-endemic area(s) for dengue.

The study enrolled 400 healthy participants. Participants were randomized in 3:1 ratio to receive:

• TDV 0.5 mL subcutaneous injection

• Placebo normal saline solution (0.9% NaCl) for injection.

In each trial group, participants received 2-dose schedule of TDV or placebo by subcutaneous injection on Days 1 (Month 0) and 90 (Month 3), but not all participants received both doses (8 subjects discontinued the trial before receiving the second dose).

This multi-center trial was conducted in Mexico. The overall time to participate in this study was 270 days. Participants had multiple visits to the clinic including a final visit at Day 270.

Study Design

• Study Type: Interventional
• Actual Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue
• Actual Study Start Date: Dec 14, 2017
• Actual Primary Completion Date: Jan 26, 2019
• Actual Study Completion Date: Jan 26, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tetravalent Dengue Vaccine (TDV) TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose)	Biological: Tetravalent Dengue Vaccine (TDV); TDV subcutaneous injection
Placebo Comparator: Placebo TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	Biological: Placebo; Normal Saline (0.9% NaCl) subcutaneous injection

Outcome Measures

Primary Outcome Measures

1. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120 [One month post second dose (Day 120)]

   GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10.

Secondary Outcome Measures

1. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270 [Six months post second dose (Day 270)]

   GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10.

2. Seropositivity Rates for Each of the 4 Dengue Serotypes [One month and six months post second dose (Day 120 and Day 270)]

   Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4.

3. Seropositivity Rates for Multiple (2, 3 or 4) Dengue Serotypes [One month and six months post second dose (Day 120 and Day 270)]

   Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10.

4. Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity [Within 7 days after each vaccination]

   Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after vaccination and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), redness (erythema) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm) and swelling (edema/induration) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm).

5. Percentage of Participants With Solicited Systemic Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity [Within 14 days after each vaccination]

   Solicited systemic AEs were collected by participants using diary cards within 14 days after vaccination and included fever, headache, tiredness or weakness (asthenia), feeling of discomfort (malaise) and muscle pain (myalgia). Severity scales for headache were none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents normal activity with or without treatment. Severity scales for others were none, mild: no interference with daily activity, moderate: interference with daily activity and severe: prevents daily activity. A systemic AE of fever (defined as ≥38°C or ≥100.4°F) was derived from a daily temperature reading recorded within 14 days after vaccination. Fever was excluded from the overall count as no severity grading was applied for it.

6. Percentage of Participants With Any Unsolicited Adverse Events (AEs) Following Each Vaccination [Within 28 days after each vaccination]

   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.

7. Percentage of Participants With Medically Attended AEs (MAAEs) Throughout the Study [From first vaccination (Day 1) through end of study (Day 270)]

   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.

8. Percentage of Participants With Serious Adverse Events (SAEs) Throughout the Study [From first vaccination (Day 1) through end of study (Day 270)]

   An SAE was defined as any untoward medical occurrence or effect that 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. The participant is aged 12 to 17 years, inclusive;

2. Is in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and the clinical judgment of the Investigator.

3. The participant/the participant's legally authorized representative (LAR) signs and dates a written, informed consent/assent form and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements.

4. Individuals who can comply with trial procedures and are available for the duration of follow-up.

Exclusion Criteria:

1. Has an elevated oral temperature (≥38°C or 100.4°F) within 3 days of the intended date of vaccination.

2. Known hypersensitivity or allergy to any of the vaccine components.

3. Behavioral or cognitive impairment or psychiatric disease that, in the opinion of the Investigator, may interfere with the participant's ability to participate in the trial.

4. Has any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (e.g., Guillain-Barre syndrome).

5. History or any illness that, in the opinion of the Investigator, might interfere with the results of the trial or pose additional risk to the participant due to participation in the trial.

6. Has known or suspected impairment/alteration of immune function, including:

7. Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (M0) (use of inhaled, intranasal, or topical corticosteroids is allowed).

8. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥ 2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (M0).

9. Administration of immunoglobulins and/or any blood products within the 3 months prior to Day 1 (M0) or planned administration during the trial.

10. Receipt of immune-stimulants within 60 days prior to Day 1 (M0).

11. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (M0).

12. Human immunodeficiency virus (HIV) infection or HIV-related disease.

13. Genetic immunodeficiency.

14. Has abnormalities of splenic or thymic function.

15. Has a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding.

16. Has any serious chronic or progressive disease according to judgment of the Investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).

17. Has body mass index (BMI) greater than or equal to 35 kg/m^2 (= weight in kg/[height in square meters]).

18. Individuals participating in any clinical trial with another investigational product 30 days prior to Day 1 (M0) or intent to participate in another clinical trial at any time during the conduct of this trial.

19. Has received any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of trial vaccine administration.

20. Individuals involved in the trial conduct or their first degree relatives.

21. Has history of substance or alcohol abuse within the past 2 years.

22. Female participants who are pregnant or breastfeeding.

23. Females of childbearing potential who are sexually active, and who have not used any of the acceptable contraceptive methods for at least 2 months prior to Day 1 (M0).

24. Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method up to 6 weeks after the last dose of trial vaccine. In addition, they must be advised not to donate ova during this period.

25. Any positive or indeterminate pregnancy test.

26. Previous and planned vaccination (during the trial conduct), against any flaviviruses including dengue, yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne encephalitis.

27. Previous participation in any clinical trial of a dengue or other flavivirus (eg, West Nile [WN] virus) candidate vaccine, except for participants who received placebo in those trials.

28. Participants with documented or suspected disease caused by a flavivirus such as dengue, Zika, YF, JE, WN fever, tick-borne encephalitis or Murray Valley encephalitis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Biodextra, S.A. de C.V.	Ciudad de Mexico		Mexico	09360
2	Instituto Nacional de Pediatria (INP)	Mexico City		Mexico	04530
3	Hospital Infantil de Mexico Federico Gomez	Mexico City		Mexico	06720
4	Mexico Centre for Clinical Research	Mexico City		Mexico	ZC 03100
5	Centro de Atencion E Investigacion Medica (CAIMED) Mexico DF	Mexico City		Mexico

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Study Protocol - Mar 9, 2019
• Statistical Analysis Plan - Jan 30, 2019

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03341637
• Other Study ID Numbers: DEN-315; U1111-1192-7827; RNEC-2017-DEN-315; 2018-003980-77
• First Posted: Nov 14, 2017
• Last Update Posted: Aug 15, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Dengue

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 5 investigative sites in Mexico from 14-Dec-2017 to 26-Jan-2019.
Pre-assignment Detail	Healthy volunteers were enrolled in a 3:1 ratio into 2 parallel study groups: 1 study group received 2 doses of Tetravalent Dengue vaccine (TDV) and another group received 2 doses of TDV matching placebo subcutaneously (SC).

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Period Title: Overall Study
STARTED	100	300
COMPLETED	95	296
NOT COMPLETED	5	4

Baseline Characteristics

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)	Total
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	Total of all reporting groups
Overall Participants	100	300	400
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.3 (1.57)	14.3 (1.69)	14.3 (1.66)
Sex: Female, Male (Count of Participants)
Female	51 51%	176 58.7%	227 56.8%
Male	49 49%	124 41.3%	173 43.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	100 100%	300 100%	400 100%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	55 55%	148 49.3%	203 50.8%
Multiracial	45 45%	152 50.7%	197 49.3%
Region of Enrollment (Count of Participants)
Mexico	100 100%	300 100%	400 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	159.6 (8.94)	159.0 (8.68)	159.2 (8.74)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	57.60 (14.045)	56.84 (12.708)	57.03 (13.041)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.42 (4.237)	22.39 (4.266)	22.40 (4.254)

Outcome Measures

1. Primary Outcome

Title	Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120
Description	GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10.
Time Frame	One month post second dose (Day 120)

Outcome Measure Data

Analysis Population Description

Per Protocol Set (PPS): all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. Number analyzed: participants with data available at given time-point.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	82	271
DENV-1	5.3	327.9
DENV-2	6.0	1742.5
DENV-3	5.2	119.5
DENV-4	5.1	142.7

2. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270
Description	GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10.
Time Frame	Six months post second dose (Day 270)

Outcome Measure Data

Analysis Population Description

PPS: all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. Number analyzed: participants with data available at given time-point.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	82	271
DENV-1	5.4	134.7
DENV-2	5.2	740.9
DENV-3	5.3	45.8
DENV-4	5.0	37.5

3. Secondary Outcome

Title	Seropositivity Rates for Each of the 4 Dengue Serotypes
Description	Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4.
Time Frame	One month and six months post second dose (Day 120 and Day 270)

Outcome Measure Data

Analysis Population Description

PPS: all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. Number analyzed: participants with data available at given time-point.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	82	271
Day 120 (Month 4): DENV-1	1.4 1.4%	100.0 33.3%
Day 120 (Month 4): DENV-2	8.3 8.3%	100.0 33.3%
Day 120 (Month 4): DENV-3	1.4 1.4%	100.0 33.3%
Day 120 (Month 4): DENV-4	1.4 1.4%	99.6 33.2%
Day 270 (Month 9): DENV-1	2.7 2.7%	98.4 32.8%
Day 270 (Month 9): DENV-2	1.4 1.4%	99.6 33.2%
Day 270 (Month 9): DENV-3	2.7 2.7%	92.1 30.7%
Day 270 (Month 9): DENV-4	0 0%	89.4 29.8%

4. Secondary Outcome

Title	Seropositivity Rates for Multiple (2, 3 or 4) Dengue Serotypes
Description	Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10.
Time Frame	One month and six months post second dose (Day 120 and Day 270)

Outcome Measure Data

Analysis Population Description

PPS: all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. Number analyzed: participants with data available at given time-point.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	82	271
Day 120 (Month 4): At Least Bivalent	1.4 1.4%	100.0 33.3%
Day 120 (Month 4): At Least Trivalent	1.4 1.4%	100.0 33.3%
Day 120 (Month 4): Tetravalent	1.4 1.4%	99.6 33.2%
Day 270 (Month 9): At Least Bivalent	0 0%	99.2 33.1%
Day 270 (Month 9): At Least Trivalent	0 0%	94.5 31.5%
Day 270 (Month 9): Tetravalent	0 0%	85.8 28.6%

5. Secondary Outcome

Title	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity
Description	Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after vaccination and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), redness (erythema) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm) and swelling (edema/induration) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm).
Time Frame	Within 7 days after each vaccination

Outcome Measure Data

Analysis Population Description

Safety Set included of all participants who received at least 1 dose of trial vaccine. Number analyzed is the number of participants with data available at the given timepoint. Only categories for which there was at least 1 participant are reported.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	100	300
After First Vaccination, Any Solicited Local AEs	34.3 34.3%	56.2 18.7%
After First Vaccination, Pain:Mild	26.3 26.3%	44.8 14.9%
After First Vaccination, Pain:Moderate	7.1 7.1%	9.7 3.2%
After First Vaccination, Pain:Severe	1.0 1%	0.7 0.2%
After First Vaccination, Erythema:Mild	0 0%	5.7 1.9%
After First Vaccination, Swelling:Mild	0 0%	4.3 1.4%
After Second Vaccination, Any Solicited Local AEs	30.9 30.9%	52.2 17.4%
After Second Vaccination, Pain:Mild	24.5 24.5%	35.6 11.9%
After Second Vaccination, Pain:Moderate	5.3 5.3%	13.2 4.4%
After Second Vaccination, Pain:Severe	1.1 1.1%	3.1 1%
After Second Vaccination, Erythema:Mild	0 0%	4.1 1.4%
After Second Vaccination, Swelling:Mild	0 0%	1.7 0.6%
After Second Vaccination, Swelling:Moderate	0 0%	0.3 0.1%

6. Secondary Outcome

Title	Percentage of Participants With Solicited Systemic Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity
Description	Solicited systemic AEs were collected by participants using diary cards within 14 days after vaccination and included fever, headache, tiredness or weakness (asthenia), feeling of discomfort (malaise) and muscle pain (myalgia). Severity scales for headache were none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents normal activity with or without treatment. Severity scales for others were none, mild: no interference with daily activity, moderate: interference with daily activity and severe: prevents daily activity. A systemic AE of fever (defined as ≥38°C or ≥100.4°F) was derived from a daily temperature reading recorded within 14 days after vaccination. Fever was excluded from the overall count as no severity grading was applied for it.
Time Frame	Within 14 days after each vaccination

Outcome Measure Data

Analysis Population Description

Safety Set included of all participants who received at least 1 dose of trial vaccine. Number analyzed is the number of participants with data available at the given timepoint. Only categories for which there was at least 1 participant are reported.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	100	300
After First Vaccination: Any Solicited Systemic AE	58.6 58.6%	66.6 22.2%
After First Vaccination: Headache-Mild	25.3 25.3%	31.4 10.5%
After First Vaccination: Headache-Moderate	18.2 18.2%	10.4 3.5%
After First Vaccination: Headache-Severe	1.0 1%	2.7 0.9%
After First Vaccination: Asthenia-Mild	20.2 20.2%	24.7 8.2%
After First Vaccination: Asthenia-Moderate	13.1 13.1%	7.7 2.6%
After First Vaccination: Asthenia-Severe	2.0 2%	2.3 0.8%
After First Vaccination: Malaise-Mild	20.2 20.2%	18.7 6.2%
After First Vaccination: Malaise-Moderate	11.1 11.1%	7.7 2.6%
After First Vaccination: Malaise-Severe	2.0 2%	1.3 0.4%
After First Vaccination: Myalgia-Mild	26.3 26.3%	36.1 12%
After First Vaccination: Myalgia-Moderate	13.1 13.1%	10.7 3.6%
After First Vaccination: Myalgia-Severe	1.0 1%	1.0 0.3%
After First Vaccination:Fever-Any	5.1 5.1%	6.7 2.2%
After First Vaccination:Fever (38.0°C-<38.5°C)	3.0 3%	3.0 1%
After First Vaccination:Fever (38.5°C-<39.0°C)	2.0 2%	2.3 0.8%
After First Vaccination:Fever (39.0°C-<39.5°C)	0.0 0%	1.0 0.3%
After First Vaccination:Fever (39.5°C-<40.0°C)	0.0 0%	0.3 0.1%
After Second Vaccine: Any Solicited Systemic AEs	45.7 45.7%	49.3 16.4%
After Second Vaccination: Headache-Mild	20.2 20.2%	24.3 8.1%
After Second Vaccination: Headache-Moderate	6.4 6.4%	8.4 2.8%
After Second Vaccination: Headache-Severe	3.2 3.2%	2.7 0.9%
After Second Vaccination: Asthenia-Mild	22.3 22.3%	19.9 6.6%
After Second Vaccination: Asthenia-Moderate	4.3 4.3%	6.8 2.3%
After Second Vaccination: Asthenia-Severe	1.1 1.1%	1.4 0.5%
After Second Vaccination: Malaise-Mild	12.8 12.8%	16.2 5.4%
After Second Vaccination: Malaise-Moderate	6.4 6.4%	5.1 1.7%
After Second Vaccination: Malaise-Severe	4.3 4.3%	2.4 0.8%
After Second Vaccination: Myalgia-Mild	21.3 21.3%	25.7 8.6%
After Second Vaccination: Myalgia-Moderate	8.5 8.5%	6.8 2.3%
After Second Vaccination: Myalgia-Severe	1.1 1.1%	2.4 0.8%
After Second Vaccination:Fever-Any	3.2 3.2%	6.8 2.3%
After Second Vaccination:Fever (38.0°C-<38.5°C)	1.1 1.1%	3.7 1.2%
After Second Vaccination:Fever (38.5°C-<39.0°C)	1.1 1.1%	2.0 0.7%
After Second Vaccination:Fever (39.0°C-<39.5°C)	1.1 1.1%	0.7 0.2%
After Second Vaccination:Fever (39.5°C-<40.0°C)	0.0 0%	0.3 0.1%

7. Secondary Outcome

Title	Percentage of Participants With Any Unsolicited Adverse Events (AEs) Following Each Vaccination
Description	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.
Time Frame	Within 28 days after each vaccination

Outcome Measure Data

Analysis Population Description

Safety Set included of all participants who received at least 1 dose of trial vaccine. Number analyzed is the number of participants with data available at the given timepoint. Only categories for which there was at least 1 participant are reported.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	100	300
After First Vaccination	25.0 25%	30.0 10%
After Second Vaccination	17.9 17.9%	23.2 7.7%

8. Secondary Outcome

Title	Percentage of Participants With Medically Attended AEs (MAAEs) Throughout the Study
Description	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.
Time Frame	From first vaccination (Day 1) through end of study (Day 270)

Outcome Measure Data

Analysis Population Description

Safety Set included of all participants who received at least 1 dose of trial vaccine.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	100	300
Number [percentage of participants]	38.0 38%	47.3 15.8%

9. Secondary Outcome

Title	Percentage of Participants With Serious Adverse Events (SAEs) Throughout the Study
Description	An SAE was defined as any untoward medical occurrence or effect that 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.
Time Frame	From first vaccination (Day 1) through end of study (Day 270)

Outcome Measure Data

Analysis Population Description

Safety Set included of all participants who received at least 1 dose of trial vaccine.

Arm/Group Title	Placebo	Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
Measure Participants	100	300
Number [percentage of participants]	2.0 2%	0.3 0.1%

Adverse Events

Time Frame	Unsolicited AEs: Within 28 days after Vaccination; MAAEs and SAEs: From first vaccination (Day 1) through end of study (Day 270)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		Tetravalent Dengue Vaccine (TDV)
Arm/Group Description	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).		TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).
All Cause Mortality
	Placebo		Tetravalent Dengue Vaccine (TDV)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/100 (0%)		0/300 (0%)
Serious Adverse Events
	Placebo		Tetravalent Dengue Vaccine (TDV)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/100 (2%)		1/300 (0.3%)
Gastrointestinal disorders
Abdominal pain	0/100 (0%)		1/300 (0.3%)
Infections and infestations
Appendicitis	1/100 (1%)		0/300 (0%)
Urinary tract infection	0/100 (0%)		1/300 (0.3%)
Injury, poisoning and procedural complications
Ankle fracture	1/100 (1%)		0/300 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Tetravalent Dengue Vaccine (TDV)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/100 (38%)		112/300 (37.3%)
Gastrointestinal disorders
Gastritis	3/100 (3%)		7/300 (2.3%)
Infections and infestations
Viral upper respiratory tract infection	14/100 (14%)		43/300 (14.3%)
Nasopharyngitis	6/100 (6%)		24/300 (8%)
Viral pharyngitis	7/100 (7%)		15/300 (5%)
Pharyngitis	4/100 (4%)		10/300 (3.3%)
Pharyngitis bacterial	2/100 (2%)		9/300 (3%)
Gastroenteritis	2/100 (2%)		8/300 (2.7%)
Upper respiratory tract infection bacterial	1/100 (1%)		9/300 (3%)
Nervous system disorders
Syncope	2/100 (2%)		9/300 (3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.