Immunogenicity and Safety of Tetravalent Dengue Vaccine (TDV) Administered With a Yellow Fever Vaccine in Adults

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03342898
• Collaborator: (none)
• Enrollment: 900
• Locations: 11
• Arms: 3
• Actual Duration (Months): 14.7
• Patients Per Site: 81.8
• Patients Per Site Per Month: 5.6

Study Details

Study Description

Brief Summary

The main purpose of this study is to assess the immunogenicity and safety of the concomitant and sequential administration of yellow fever (YF) vaccine and tetravalent dengue vaccine (TDV) in healthy participants aged 18 to 60 years living in country non-endemic for both dengue and YF.

Condition or Disease	Intervention/Treatment	Phase
Dengue	Biological: YF-17D; Biological: TDV; Drug: Placebo	Phase 3

Detailed Description

The vaccine tested in this study is TDV also known as TAK-003 (DENVax). TDV with concomitant and sequential administration of yellow fever (YF-17D) vaccine will be tested to assess immunogenicity and safety in healthy adult participants in non-endemic area(s) for both dengue and YF.

The study will enroll 900 healthy participants. Participants will be randomized to 3 groups in 1:1:1 ratio and will be administered concomitantly and sequentially. The 3 groups are:

• Group 1: YF-17D vaccine + placebo concomitantly administered on Day 1, first dose of TDV administered on Day 90 and second dose of TDV administered on Day 180.

• Group 2: first dose of TDV + placebo concomitantly administered on Day 1, second dose of TDV administered on Day 90 and YF-17D vaccine administered on Day 180.

• Group 3: first dose of TDV + YF-17D vaccine concomitantly administered on Day 1, second dose of TDV administered on Day 90 and placebo administered on Day 180.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 360 days. Participants will make multiple visits to the clinic with a 6-month follow up including a final visit at Day 360 for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 900 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Observer-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the Immunogenicity and Safety of a Tetravalent Dengue Vaccine Candidate and a Yellow Fever YF-17D Vaccine Administered Concomitantly and Sequentially in Healthy Subjects Aged 18 to 60 Years in Non-Endemic Country(Ies)
• Actual Study Start Date: Feb 28, 2018
• Actual Primary Completion Date: May 9, 2018
• Actual Study Completion Date: May 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: YF-17D + Placebo/TDV/TDV YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	Biological: YF-17D; YF-17D SC injection.; Biological: TDV; TDV SC injection.; Other Names: TAK-003 DENVax ; Drug: Placebo; Normal Saline (0.9% NaCl) SC injection.
Experimental: Group 2: TDV + Placebo/TDV/YF-17D TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	Biological: YF-17D; YF-17D SC injection.; Biological: TDV; TDV SC injection.; Other Names: TAK-003 DENVax ; Drug: Placebo; Normal Saline (0.9% NaCl) SC injection.
Experimental: Group 3: TDV + YF-17D/TDV/Placebo TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.	Biological: YF-17D; YF-17D SC injection.; Biological: TDV; TDV SC injection.; Other Names: TAK-003 DENVax ; Drug: Placebo; Normal Saline (0.9% NaCl) SC injection.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Are YF and Dengue Virus (DENV)-Naive at Baseline and Are Seroprotected Against YF on Day 30 as Measured by Plaque Reduction Neutralization Test (PRNT) [Day 30]

   Seroprotection was defined as reciprocal anti-YF neutralizing antibody titer ≥10. Immunological naivety to YF and DENV was defined as Baseline reciprocal neutralizing antibody titers <10 for YF and for the 4 dengue serotypes. The 95% CI was calculated using exact Clopper-Pearson method.

Secondary Outcome Measures

1. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes on Days 30, 90, 120, 180 and 210 in Participants YF and DENV-naive at Baseline [Pre-second and -third vaccination (Days 90 and 180, respectively); and 1 month post -first, second, and third vaccination (Days 30, 120, and 210, respectively)]

   GMTs of neutralizing antibodies was measured by microneutralization test 50% [MNT50] for each of the 4 dengue serotypes. The 4 DENV serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.

2. Percentage of Participants Who Are Seropositive for Each of the 4 Dengue Serotypes on Days 30, 90, 120, 180 and 210 in Participants YF and DENV-naive at Baseline [Pre-second and -third vaccination (Days 90 and 180, respectively); and 1-month post -first, -second, and -third vaccination (Days 30, 120, and 210, respectively)]

   Seropositivity rate was defined as the percentage of seropositive participants as derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. Seropositivity for each dengue serotype were analyzed and was summarized as: DENV-1, DENV-2, DENV-3, and DENV-4.

3. Percentage of Participants Who Are Seropositive for Multiple (2, 3 or 4) Dengue Serotypes on Days 30, 90, 120, 180 and 210 in Participants YF and DENV-naive at Baseline [Pre-second and -third vaccination (Days 90 and 180, respectively); and 1-month post -first, second, and -third vaccination (Days 30, 120, and 210, respectively)]

   Seropositivity rate was defined as the percentage of seropositive participants, as derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. Seropositivity for multiple dengue serotypes were summarized in the following categories: at least bivalent, at least trivalent and tetravalent.

4. Percentage of YF and DENV-naive Participants at Baseline Who Are Seroprotected Against YF on Day 210 as Measured by PRNT [1-month post third vaccination (Day 210)]

   Seroprotection was defined as reciprocal anti-YF neutralizing antibody titer ≥10.

5. Geometric Mean Titers (GMTs) of Anti-YF Neutralizing Antibodies at Day 30 in Participants YF and DENV-Naive at Baseline [1-month post-first vaccination (Day 30)]

   Geometric mean titers of YF neutralizing antibodies was measured by plaque reduction neutralization test.

6. Geometric Mean Titers (GMTs) of Anti-YF Neutralizing Antibodies at Day 210 in Participants YF and DENV-Naive at Baseline [1-month post-third vaccination (Day 210)]

   Geometric mean titers of YF neutralizing antibodies was measured by plaque reduction neutralization test.

7. Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) Following Each Vaccination Dose by Severity [Within 7 Days of each Vaccination (day of vaccination + 6 days)]

   An AE is 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. Solicited local injection site AEs recorded from participant's-diary. Severity grade at injection site for pain: Grade 0 (No Pain), 1 (did not interfere with daily activity), 2 (interference with daily activity with or without treatment) and 3 (prevents daily activity with or without treatment). For erythema: grade 0 (<25 mm), 1 (>25-≤50 mm), 2 (>50-≤100 mm) and 3 (>100 mm). For swelling: grade 0 (<25 mm), 1 (>25-≤50 mm), 2 (>50-≤100 mm) and 3 (>100 mm). Percentages were rounded off for each category. For the first vaccination (Vac.) YF is given in Arm 1 (A1) and TDV is given in Arm 2 (A2). A1 = YF for Group 1, Placebo for Group 2, and YF for Group 3; A2 = Placebo for Group 1, TDV for Group 2, and TDV for Group 3.

8. Percentage of Participants With Solicited Systemic Adverse Events Following Each Vaccination Dose by Severity [Within 14 Days of each Vaccination (day of vaccination + 13 days)]

   Solicited systemic AEs (fever, headache, asthenia, malaise, and myalgia) recorded from participant's-diary. Severity grades for headache are grade 0 (none), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity with or without treatment) and 3 (severe: prevents normal activity with or without treatment). Severity grades for asthenia, malaise and myalgia is grade 0 (none), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity), 3 (severe: prevents daily activity). Fever is defined as greater than or equal to 38º C or 100.4º C. Fever was excluded from the overall count as no severity grading was applied for it. Percentages were rounded off for each category.

9. Percentage of Participants With Any Unsolicited Adverse Events (AEs) [Within 28 days (day of vaccination + 27 days) after each vaccination]

   An AE is 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.

10. Percentage of Participants With Medically Attended Adverse Events (MAAEs) [From first vaccination (Day 1) through end of study (Day 360)]

    MAAEs are defined as AEs leading to an unscheduled visit to or by a healthcare professional including visits to an emergency department, but not fulfilling seriousness criteria.

11. Percentage of Participants With Serious Adverse Events (SAEs) [From first vaccination (Day 1) through end of study (Day 360)]

    An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, is an important medical event that may require intervention to prevent any of the above mentioned criteria and/or may expose the subject to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Is aged 18 to 60 years inclusive, at the time of randomization.

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.

Exclusion Criteria:

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

2. Has contraindications, warnings and/or precautions to vaccination with the YF-17D vaccine as specified within the product information (especially history of thymus dysfunction).

3. Female participant who are pregnant or breastfeeding

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

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

6. Is intent to travel to dengue or YF endemic countries during the trial period.

7. Has received any other vaccines 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 non-trial vaccine within 28 days of trial vaccine administration.

8. Has previous and planned vaccination (during the trial conduct), against any flavivirus including dengue, YF, Japanese encephalitis (JE) or tick-borne encephalitis viruses.

9. Has previous participation in any clinical trial of a dengue or other flavivirus (e.g., West Nile [WN] virus) candidate vaccine, except for participants who received placebo in those trials.

10. Has a current or previous infection with a flavivirus such as dengue, Zika, YF, JE, WN fever, or Saint Louis encephalitis viruses and participants with a history of prolonged (≥1 year) habitation in a dengue endemic area.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Coastal Clinical Research Inc	Mobile	Alabama	United States	36608
2	Empire Clinical Research	Pomona	California	United States	91767
3	Advanced Clinical Research	Meridian	Idaho	United States	83462
4	Johnson County Clin-Trials	Lenexa	Kansas	United States	66219
5	Center for Pharmaceutical Research	Kansas City	Missouri	United States	64114
6	Meridian Clinical Research LLC	Omaha	Nebraska	United States	68134
7	Regional Clinical Research Inc.	Endwell	New York	United States	13760
8	Rapid Medical Research Inc	Cleveland	Ohio	United States	44122
9	Tekton Research	Austin	Texas	United States	78745
10	Advanced Clinical Research	West Jordan	Utah	United States	84088
11	Clinical Research Associates of Tidewater	Norfolk	Virginia	United States	23507

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Study Protocol - Nov 28, 2018
• Statistical Analysis Plan - Oct 21, 2019

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03342898
• Other Study ID Numbers: DEN-305; U1111-1201-5257
• First Posted: Nov 17, 2017
• Last Update Posted: Oct 8, 2020
• Last Verified: Sep 1, 2020

• 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; Yellow Fever

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 11 investigative sites in the United States from 28 Feb 2018 to 22 May 2019.
Pre-assignment Detail	Healthy participants were enrolled in 1:1:1 ratio in 3 parallel groups. Participants received concomitant and sequential administration of yellow fever (YF) vaccine and tetravalent dengue vaccine (TDV) in Groups 1, 2 and 3.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Period Title: Overall Study
STARTED	300	300	300
COMPLETED	246	247	246
NOT COMPLETED	54	53	54

Baseline Characteristics

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo	Total
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.	Total of all reporting groups
Overall Participants	300	300	300	900
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.7 (12.41)	40.0 (12.91)	41.4 (12.67)	41.0 (12.67)
Sex: Female, Male (Count of Participants)
Female	167 55.7%	170 56.7%	176 58.7%	513 57%
Male	133 44.3%	130 43.3%	124 41.3%	387 43%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	26 8.7%	25 8.3%	31 10.3%	82 9.1%
Not Hispanic or Latino	272 90.7%	270 90%	266 88.7%	808 89.8%
Unknown or Not Reported	2 0.7%	5 1.7%	3 1%	10 1.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1%	2 0.7%	2 0.7%	7 0.8%
Asian	3 1%	4 1.3%	7 2.3%	14 1.6%
Native Hawaiian or Other Pacific Islander	2 0.7%	0 0%	1 0.3%	3 0.3%
Black or African American	77 25.7%	103 34.3%	84 28%	264 29.3%
White	205 68.3%	186 62%	201 67%	592 65.8%
More than one race	5 1.7%	0 0%	2 0.7%	7 0.8%
Unknown or Not Reported	5 1.7%	5 1.7%	3 1%	13 1.4%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.3 (9.29)	170.1 (9.05)	170.5 (8.85)	170.6 (9.07)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	82.40 (15.40)	78.52 (14.65)	80.87 (16.94)	80.60 (15.75)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.00 (4.29)	27.07 (4.30)	27.66 (4.49)	27.58 (4.37)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Are YF and Dengue Virus (DENV)-Naive at Baseline and Are Seroprotected Against YF on Day 30 as Measured by Plaque Reduction Neutralization Test (PRNT)
Description	Seroprotection was defined as reciprocal anti-YF neutralizing antibody titer ≥10. Immunological naivety to YF and DENV was defined as Baseline reciprocal neutralizing antibody titers <10 for YF and for the 4 dengue serotypes. The 95% CI was calculated using exact Clopper-Pearson method.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

Yellow Fever Per-Protocol Set (YF PPS) included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and Day 30, and who had no major protocol violations. Overall number analyzed are participants with data available for analyses at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	211	234	229
Number (95% Confidence Interval) [percentage of participants]	99.5 33.2%	9.8 3.3%	99.1 33%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: YF-17D + Placebo/TDV/TDV, Group 3: TDV + YF-17D/TDV/Placebo
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of the immune response was performed only between YF + TDV (Group 3) and YF + Placebo (Group 1) at Day 120. Non-inferiority between Group 3 and Group 1 was concluded if the upper bound of the 95% CI for the seroprotection rate difference (Group 1 - Group 3) was less than 5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Seroprotection Rate Difference
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -1.85 to 2.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Newcombe score method was used to compute the 95% CI of the seroprotection rate difference.

2. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes on Days 30, 90, 120, 180 and 210 in Participants YF and DENV-naive at Baseline
Description	GMTs of neutralizing antibodies was measured by microneutralization test 50% [MNT50] for each of the 4 dengue serotypes. The 4 DENV serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.
Time Frame	Pre-second and -third vaccination (Days 90 and 180, respectively); and 1 month post -first, second, and third vaccination (Days 30, 120, and 210, respectively)

Outcome Measure Data

Analysis Population Description

Per-Protocol Set (PPS) included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and >=1 post-Baseline immunogenicity measurement, and who had no major protocol violations.Number analyzed are participants with data available at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	192	208	189
Day 30, DENV-1	6.0	226.2	119.4
Day 30, DENV-2	7.7	5431.1	650.8
Day 30, DENV-3	5.8	172.0	70.9
Day 30, DENV-4	6.1	142.0	49.8
Day 90, DENV-1	6.0	147.5	95.1
Day 90, DENV-2	7.8	2846.5	1547.2
Day 90, DENV-3	5.9	73.1	70.1
Day 90, DENV-4	5.9	56.1	49.1
Day 120, DENV-1	403.9	297.1	182.6
Day 120, DENV-2	4691.3	2616.1	1947.7
Day 120, DENV-3	636.4	131.4	104.5
Day 120, DENV-4	678.5	111.8	97.7
Day 180, DENV-1	251.4	227.0	147.0
Day 180, DENV-2	2413.5	1959.3	1800.0
Day 180, DENV-3	342.3	84.9	75.8
Day 180, DENV-4	358.4	83.7	69.6
Day 210, DENV-1	267.5	679.9	138.2
Day 210, DENV-2	2248.0	3798.1	1688.0
Day 210, DENV-3	301.8	406.4	64.3
Day 210, DENV-4	347.4	436.5	56.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 2: TDV + Placebo/TDV/YF-17D, Group 3: TDV + YF-17D/TDV/Placebo
	Comments	Day 120, DENV-1
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of the immune response was performed only between TDV + YF (Group 3) and TDV + Placebo (Group 2) at Day 120. Non-inferiority between Group 3 and Group 2 was concluded if the upper bound of the 95% CI for the GMT ratio (Group 2/Group 3) was less than 2.0.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 1.19 to 2.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis of variance (ANOVA) model was used for analysis, including log-transformed value of titer as the dependent variable and trial group as a factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 2: TDV + Placebo/TDV/YF-17D, Group 3: TDV + YF-17D/TDV/Placebo
	Comments	Day 120, DENV-2
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of the immune response was performed only between TDV + YF (Group 3) and TDV + Placebo (Group 2) at Day 120. Non-inferiority between Group 3 and Group 2 was concluded if the upper bound of the 95% CI for the GMT ratio (Group 2/Group 3) was less than 2.0.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.3
	Confidence Interval	() 95%; 1.03 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANOVA model was used for analysis, including log-transformed value of titer as the dependent variable and trial group as a factor.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group 2: TDV + Placebo/TDV/YF-17D, Group 3: TDV + YF-17D/TDV/Placebo
	Comments	Day 120, DENV-3
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of the immune response was performed only between TDV + YF (Group 3) and TDV + Placebo (Group 2) at Day 120. Non-inferiority between Group 3 and Group 2 was concluded if the upper bound of the 95% CI for the GMT ratio (Group 2/Group 3) was less than 2.0.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.3
	Confidence Interval	() 95%; 0.99 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANOVA model was used for analysis, including log-transformed value of titer as the dependent variable and trial group as a factor.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Group 2: TDV + Placebo/TDV/YF-17D, Group 3: TDV + YF-17D/TDV/Placebo
	Comments	Day 120, DENV-4
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of the immune response was performed only between TDV + YF (Group 3) and TDV + Placebo (Group 2) at Day 120. Non-inferiority between Group 3 and Group 2 was concluded if the upper bound of the 95% CI for the GMT ratio (Group 2/Group 3) was less than 2.0.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANOVA model was used for analysis, including log-transformed value of titer as the dependent variable and trial group as a factor.

3. Secondary Outcome

Title	Percentage of Participants Who Are Seropositive for Each of the 4 Dengue Serotypes on Days 30, 90, 120, 180 and 210 in Participants YF and DENV-naive at Baseline
Description	Seropositivity rate was defined as the percentage of seropositive participants as derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. Seropositivity for each dengue serotype were analyzed and was summarized as: DENV-1, DENV-2, DENV-3, and DENV-4.
Time Frame	Pre-second and -third vaccination (Days 90 and 180, respectively); and 1-month post -first, -second, and -third vaccination (Days 30, 120, and 210, respectively)

Outcome Measure Data

Analysis Population Description

PPS included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and >=1 post-Baseline immunogenicity measurement, and who had no major protocol violations. Number analyzed are participants with data available at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	192	208	189
Day 30, DENV-1	6.5 2.2%	93.3 31.1%	87.6 29.2%
Day 30, DENV-2	15.8 5.3%	95.9 32%	88.1 29.4%
Day 30, DENV-3	4.3 1.4%	88.1 29.4%	80.5 26.8%
Day 30, DENV-4	7.1 2.4%	89.6 29.9%	78.4 26.1%
Day 90, DENV-1	8.3 2.8%	90.4 30.1%	89.4 29.8%
Day 90, DENV-2	14.6 4.9%	97.1 32.4%	94.2 31.4%
Day 90, DENV-3	5.7 1.9%	84.6 28.2%	90.5 30.2%
Day 90, DENV-4	6.3 2.1%	84.6 28.2%	89.4 29.8%
Day 120, DENV-1	99.4 33.1%	99.5 33.2%	99.4 33.1%
Day 120, DENV-2	99.4 33.1%	98.5 32.8%	99.4 33.1%
Day 120, DENV-3	98.9 33%	98.5 32.8%	98.3 32.8%
Day 120, DENV-4	99.4 33.1%	99.0 33%	97.7 32.6%
Day 180, DENV-1	99.0 33%	97.1 32.4%	95.8 31.9%
Day 180, DENV-2	100.0 33.3%	97.6 32.5%	99.5 33.2%
Day 180, DENV-3	99.5 33.2%	92.8 30.9%	96.3 32.1%
Day 180, DENV-4	99.0 33%	96.6 32.2%	96.8 32.3%
Day 210, DENV-1	100.0 33.3%	99.5 33.2%	96.6 32.2%
Day 210, DENV-2	100.0 33.3%	99.5 33.2%	99.4 33.1%
Day 210, DENV-3	100.0 33.3%	99.5 33.2%	93.2 31.1%
Day 210, DENV-4	99.4 33.1%	99.5 33.2%	94.3 31.4%

4. Secondary Outcome

Title	Percentage of Participants Who Are Seropositive for Multiple (2, 3 or 4) Dengue Serotypes on Days 30, 90, 120, 180 and 210 in Participants YF and DENV-naive at Baseline
Description	Seropositivity rate was defined as the percentage of seropositive participants, as derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. Seropositivity for multiple dengue serotypes were summarized in the following categories: at least bivalent, at least trivalent and tetravalent.
Time Frame	Pre-second and -third vaccination (Days 90 and 180, respectively); and 1-month post -first, second, and -third vaccination (Days 30, 120, and 210, respectively)

Outcome Measure Data

Analysis Population Description

PPS included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and >=1 post-Baseline immunogenicity measurement, and who had no major protocol violations. Number analyzed are participants with data available at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	192	208	189
Day 30, At Least Bivalent	5.4 1.8%	96.9 32.3%	90.8 30.3%
Day 30, At Least Trivalent	4.9 1.6%	91.7 30.6%	81.6 27.2%
Day 30, Tetravalent	3.8 1.3%	79.3 26.4%	65.9 22%
Day 90, At Least Bivalent	6.3 2.1%	95.7 31.9%	94.7 31.6%
Day 90, At Least Trivalent	5.7 1.9%	87.0 29%	88.9 29.6%
Day 90, Tetravalent	5.7 1.9%	75.5 25.2%	82.0 27.3%
Day 120, At Least Bivalent	99.4 33.1%	99.5 33.2%	99.4 33.1%
Day 120, At Least Trivalent	99.4 33.1%	99.5 33.2%	98.3 32.8%
Day 120, Tetravalent	98.9 33%	97.0 32.3%	97.7 32.6%
Day 180, At Least Bivalent	99.5 33.2%	99.0 33%	98.9 33%
Day 180, At Least Trivalent	99.0 33%	97.6 32.5%	98.4 32.8%
Day 180, Tetravalent	99.0 33%	88.0 29.3%	91.5 30.5%
Day 210, At Least Bivalent	100.0 33.3%	99.5 33.2%	98.9 33%
Day 210, At Least Trivalent	100.0 33.3%	99.5 33.2%	96.0 32%
Day 210, Tetravalent	99.4 33.1%	99.5 33.2%	89.2 29.7%

5. Secondary Outcome

Title	Percentage of YF and DENV-naive Participants at Baseline Who Are Seroprotected Against YF on Day 210 as Measured by PRNT
Description	Seroprotection was defined as reciprocal anti-YF neutralizing antibody titer ≥10.
Time Frame	1-month post third vaccination (Day 210)

Outcome Measure Data

Analysis Population Description

PPS included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and >=1 post-Baseline immunogenicity measurement, and who had no major protocol violations. Overall number analyzed: participants with data available for analyses at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	171	188	176
Number (95% Confidence Interval) [percentage of participants]	100.0 33.3%	98.4 32.8%	98.9 33%

6. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Anti-YF Neutralizing Antibodies at Day 30 in Participants YF and DENV-Naive at Baseline
Description	Geometric mean titers of YF neutralizing antibodies was measured by plaque reduction neutralization test.
Time Frame	1-month post-first vaccination (Day 30)

Outcome Measure Data

Analysis Population Description

YF PPS included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and Day 30, and who had no major protocol violations. Overall number analyzed are participants with data available for analyses at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	211	234	229
Geometric Mean (95% Confidence Interval) [titer]	4245.7	6.0	4321.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: YF-17D + Placebo/TDV/TDV, Group 3: TDV + YF-17D/TDV/Placebo
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of the immune response was performed only between YF + TDV (Group 3) and YF + Placebo (Group 1) at Day 30. Non-inferiority between Group 3 and Group 1 was concluded if the upper bound of the 95% CI for the GMT ratio (Group 1/Group 3) was less than 2.0.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	ANOVA model was used for analyses, including the log-transformed value of titer as the dependent variable and trial group as a factor.

7. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Anti-YF Neutralizing Antibodies at Day 210 in Participants YF and DENV-Naive at Baseline
Description	Geometric mean titers of YF neutralizing antibodies was measured by plaque reduction neutralization test.
Time Frame	1-month post-third vaccination (Day 210)

Outcome Measure Data

Analysis Population Description

PPS included all participants YF and DENV-naïve at Baseline who received >=1 dose of trial vaccine, with data available for Baseline and >=1 post-Baseline immunogenicity measurement, and who had no major protocol violations. Overall number analyzed: participants with data available for analyses at given time point within pre-specified visit window.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	171	188	176
Geometric Mean (95% Confidence Interval) [titer]	2341.6	3078.2	1089.1

8. Secondary Outcome

Title	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) Following Each Vaccination Dose by Severity
Description	An AE is 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. Solicited local injection site AEs recorded from participant's-diary. Severity grade at injection site for pain: Grade 0 (No Pain), 1 (did not interfere with daily activity), 2 (interference with daily activity with or without treatment) and 3 (prevents daily activity with or without treatment). For erythema: grade 0 (<25 mm), 1 (>25-≤50 mm), 2 (>50-≤100 mm) and 3 (>100 mm). For swelling: grade 0 (<25 mm), 1 (>25-≤50 mm), 2 (>50-≤100 mm) and 3 (>100 mm). Percentages were rounded off for each category. For the first vaccination (Vac.) YF is given in Arm 1 (A1) and TDV is given in Arm 2 (A2). A1 = YF for Group 1, Placebo for Group 2, and YF for Group 3; A2 = Placebo for Group 1, TDV for Group 2, and TDV for Group 3.
Time Frame	Within 7 Days of each Vaccination (day of vaccination + 6 days)

Outcome Measure Data

Analysis Population Description

Safety Set included all randomized participants who received at least 1 dose of the trial vaccines. Number analyzed are participants with data available for the category. Only categories with at least one participant are reported.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	300	300	300
After Vac. 1, Any Local AEs, A1	13.1 4.4%	16.8 5.6%	27.3 9.1%
After Vac. 1, Any Local AEs, A2	13.1 4.4%	44.2 14.7%	48.9 16.3%
After Vac. 1, Pain: Any Severity, A1	12.1 4%	16.5 5.5%	24.1 8%
After Vac. 1, Pain: Any Severity, A2	12.8 4.3%	40.0 13.3%	42.2 14.1%
After Vac. 1, Pain: Mild, A1	9.0 3%	13.7 4.6%	21.3 7.1%
After Vac. 1, Pain: Mild, A2	10.0 3.3%	35.1 11.7%	34.0 11.3%
After Vac. 1, Pain: Moderate, A1	3.1 1%	2.5 0.8%	2.1 0.7%
After Vac. 1, Pain: Moderate, A2	2.4 0.8%	4.6 1.5%	6.7 2.2%
After Vac. 1, Pain: Severe, A1	0 0%	0.4 0.1%	0.7 0.2%
After Vac. 1, Pain: Severe, A2	0.3 0.1%	0.4 0.1%	1.4 0.5%
After Vac. 1, Erythema: Any Severity, A1	2.4 0.8%	1.8 0.6%	3.9 1.3%
After Vac. 1, Erythema: Any Severity, A2	0.7 0.2%	19.6 6.5%	19.5 6.5%
After Vac. 1,Erythema:Mild:2.5-5(cm), A1	1.7 0.6%	1.8 0.6%	3.9 1.3%
After Vac. 1,Erythema:Mild:2.5-5(cm), A2	0 0%	17.5 5.8%	18.8 6.3%
After Vac. 1,Erythema:Moderate:>5-<=10(cm), A1	0.3 0.1%	0 0%	0 0%
After Vac. 1,Erythema:Moderate:>5-<=10(cm), A2	0.7 0.2%	1.8 0.6%	0.4 0.1%
After Vac. 1,Erythema:Severe:>10(cm), A1	0.3 0.1%	0 0%	0 0%
After Vac. 1,Erythema:Severe:>10(cm), A2	0 0%	0 0%	0.4 0.1%
After Vac. 1, Erythema: Missing Severity, A2	0 0%	0.4 0.1%	0 0%
After Vac. 1, Swelling: Any Severity, A1	0.7 0.2%	1.1 0.4%	2.1 0.7%
After Vac. 1, Swelling: Any Severity, A2	0.3 0.1%	4.2 1.4%	5.3 1.8%
After Vac. 1,Swelling:Mild:2.5-5(cm), A1	0.3 0.1%	1.1 0.4%	1.8 0.6%
After Vac. 1,Swelling:Mild:2.5-5(cm), A2	0 0%	4.2 1.4%	4.6 1.5%
After Vac. 1,Swelling:Moderate:>5-<=10(cm), A1	0 0%	0 0%	0.4 0.1%
After Vac. 1,Swelling:Moderate:>5-<=10(cm), A2	0.3 0.1%	0 0%	0.4 0.1%
After Vac. 1,Swelling:Severe:>10(cm), A1	0.3 0.1%	0 0%	0 0%
After Vac. 1,Swelling:Severe:>10(cm), A2	0 0%	0 0%	0.4 0.1%
After Vac. 2, Any Local AEs	31.1 10.4%	35.9 12%	35.7 11.9%
After Vac. 2, Pain: Any Severity	27.8 9.3%	30.1 10%	31.7 10.6%
After Vac. 2, Pain: Mild	23.6 7.9%	25.8 8.6%	27.8 9.3%
After Vac. 2, Pain: Moderate	3.4 1.1%	3.5 1.2%	2.8 0.9%
After Vac. 2, Pain: Severe	0.8 0.3%	0.8 0.3%	1.2 0.4%
After Vac. 2, Erythema: Any Severity	12.3 4.1%	14.5 4.8%	13.1 4.4%
After Vac. 2,Erythema:Mild:2.5-5(cm)	10.7 3.6%	10.5 3.5%	10.7 3.6%
After Vac. 2,Erythema:Moderate:>5-<=10(cm)	1.1 0.4%	3.1 1%	2.4 0.8%
After Vac. 2,Erythema:Severe:>10(cm)	0.4 0.1%	0 0%	0 0%
After Vac. 2, Erythema: Missing Severity	0 0%	0.8 0.3%	0 0%
After Vac. 2, Swelling: Any Severity	2.7 0.9%	5.9 2%	5.6 1.9%
After Vac. 2,Swelling:Mild:2.5-5(cm)	2.3 0.8%	4.3 1.4%	4.8 1.6%
After Vac. 2,Swelling:Moderate:>5-<=10(cm)	0.4 0.1%	1.6 0.5%	0.8 0.3%
After Vac. 3, Any Local AEs	27.8 9.3%	10.4 3.5%	10.6 3.5%
After Vac. 3, Pain: Any Severity	24.9 8.3%	10.4 3.5%	9.7 3.2%
After Vac. 3, Pain: Mild	20.3 6.8%	9.1 3%	7.9 2.6%
After Vac. 3, Pain: Moderate	4.2 1.4%	0.9 0.3%	0.9 0.3%
After Vac. 3, Pain: Severe	0.4 0.1%	0.4 0.1%	0.9 0.3%
After Vac. 3, Erythema: Any Severity	9.7 3.2%	0.4 0.1%	0.9 0.3%
After Vac. 3,Erythema:Mild:2.5-5(cm)	8.5 2.8%	0 0%	0.4 0.1%
After Vac. 3,Erythema:Moderate:>5-<=10(cm)	0.4 0.1%	0.4 0.1%	0 0%
After Vac. 3,Erythema:Severe:>10(cm)	0 0%	0 0%	0.4 0.1%
After Vac. 3, Erythema: Missing Severity	0.8 0.3%	0 0%	0 0%
After Vac. 3, Swelling: Any Severity	4.2 1.4%	0 0%	0 0%
After Vac. 3,Swelling:Mild:2.5-5(cm)	3.4 1.1%	0 0%	0 0%
After Vac. 3, Swelling: Missing Severity	0.8 0.3%	0 0%	0 0%

9. Secondary Outcome

Title	Percentage of Participants With Solicited Systemic Adverse Events Following Each Vaccination Dose by Severity
Description	Solicited systemic AEs (fever, headache, asthenia, malaise, and myalgia) recorded from participant's-diary. Severity grades for headache are grade 0 (none), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity with or without treatment) and 3 (severe: prevents normal activity with or without treatment). Severity grades for asthenia, malaise and myalgia is grade 0 (none), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity), 3 (severe: prevents daily activity). Fever is defined as greater than or equal to 38º C or 100.4º C. Fever was excluded from the overall count as no severity grading was applied for it. Percentages were rounded off for each category.
Time Frame	Within 14 Days of each Vaccination (day of vaccination + 13 days)

Outcome Measure Data

Analysis Population Description

Safety Set included all randomized participants who received at least 1 dose of the trial vaccines. Number analyzed are participants with data available for the category. Only categories with at least one participant are reported.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	300	300	300
After Vaccination 1, Any Systemic AEs	43.6 14.5%	49.8 16.6%	51.8 17.3%
After Vaccination 1, Headache: Any Severity	31.8 10.6%	33.0 11%	39.9 13.3%
After Vaccination 1, Headache: Mild	21.5 7.2%	22.5 7.5%	26.0 8.7%
After Vaccination 1, Headache: Moderate	8.7 2.9%	8.4 2.8%	9.3 3.1%
After Vaccination 1, Headache: Severe	1.7 0.6%	2.1 0.7%	4.6 1.5%
After Vaccination 1, Asthenia: Any Severity	17.6 5.9%	21.1 7%	20.3 6.8%
After Vaccination 1, Asthenia: Mild	10.0 3.3%	11.2 3.7%	13.9 4.6%
After Vaccination 1, Asthenia: Moderate	5.5 1.8%	7.7 2.6%	4.6 1.5%
After Vaccination 1, Asthenia: Severe	2.1 0.7%	2.1 0.7%	1.8 0.6%
After Vaccination 1, Malaise: Any Severity	20.8 6.9%	20.7 6.9%	24.5 8.2%
After Vaccination 1, Malaise: Mild	12.8 4.3%	11.6 3.9%	13.8 4.6%
After Vaccination 1, Malaise: Moderate	6.2 2.1%	4.6 1.5%	8.5 2.8%
After Vaccination 1, Malaise: Severe	1.7 0.6%	4.6 1.5%	2.1 0.7%
After Vaccination 1, Myalgia: Any Severity	23.2 7.7%	29.5 9.8%	29.4 9.8%
After Vaccination 1, Myalgia: Mild	15.6 5.2%	19.6 6.5%	19.1 6.4%
After Vaccination 1, Myalgia: Moderate	5.5 1.8%	7.0 2.3%	8.5 2.8%
After Vaccination 1, Myalgia: Severe	2.1 0.7%	2.8 0.9%	1.8 0.6%
After Vaccination 1, Fever: Any Severity	1.4 0.5%	6.0 2%	1.1 0.4%
After Vaccination 1,Fever:38.0-<38.5	0.3 0.1%	3.6 1.2%	0.4 0.1%
After Vaccination 1,Fever:38.5-<39.0	0.3 0.1%	1.8 0.6%	0.7 0.2%
After Vaccination 1,Fever:39.0-<39.5	0.3 0.1%	0.4 0.1%	0 0%
After Vaccination 1,Fever:39.5-<40.0	0 0%	0.4 0.1%	0 0%
After Vaccination 1,Fever:≥41.0	0.3 0.1%	0 0%	0 0%
After Vaccination 2, Any Systemic AEs	33.3 11.1%	29.3 9.8%	31.7 10.6%
After Vaccination 2, Headache: Any Severity	22.7 7.6%	15.6 5.2%	21.0 7%
After Vaccination 2, Headache: Mild	13.3 4.4%	10.2 3.4%	11.9 4%
After Vaccination 2, Headache: Moderate	6.4 2.1%	4.3 1.4%	7.1 2.4%
After Vaccination 2, Headache: Severe	3.0 1%	1.2 0.4%	2.0 0.7%
After Vaccination 2, Asthenia: Any Severity	13.3 4.4%	8.6 2.9%	11.5 3.8%
After Vaccination 2, Asthenia: Mild	8.3 2.8%	2.7 0.9%	6.7 2.2%
After Vaccination 2, Asthenia: Moderate	3.8 1.3%	4.3 1.4%	2.4 0.8%
After Vaccination 2, Asthenia: Severe	1.1 0.4%	1.6 0.5%	2.4 0.8%
After Vaccination 2, Malaise: Any Severity	14.0 4.7%	9.8 3.3%	9.9 3.3%
After Vaccination 2, Malaise: Mild	7.6 2.5%	4.3 1.4%	4.4 1.5%
After Vaccination 2, Malaise: Moderate	4.5 1.5%	4.3 1.4%	4.0 1.3%
After Vaccination 2, Malaise: Severe	1.9 0.6%	1.2 0.4%	1.6 0.5%
After Vaccination 2, Myalgia: Any Severity	20.8 6.9%	18.8 6.3%	20.2 6.7%
After Vaccination 2, Myalgia: Mild	14.4 4.8%	13.3 4.4%	12.3 4.1%
After Vaccination 2, Myalgia: Moderate	5.3 1.8%	4.3 1.4%	5.2 1.7%
After Vaccination 2, Myalgia: Severe	1.1 0.4%	1.2 0.4%	2.8 0.9%
After Vaccination 2, Fever: Any Severity	3.1 1%	1.2 0.4%	1.2 0.4%
After Vaccination 2,Fever:38.0-<38.5	1.5 0.5%	0.4 0.1%	0.4 0.1%
After Vaccination 2,Fever:38.5-<39.0	1.2 0.4%	0.8 0.3%	0.4 0.1%
After Vaccination 2,Fever:39.0-<39.5	0.4 0.1%	0 0%	0 0%
After Vaccination 2,Fever:39.5-<40.0	0 0%	0 0%	0.4 0.1%
After Vaccination 3, Any Systemic AEs	24.4 8.1%	27.4 9.1%	22.8 7.6%
After Vaccination 3, Headache: Any Severity	17.2 5.7%	17.4 5.8%	20.2 6.7%
After Vaccination 3, Headache: Mild	10.1 3.4%	11.3 3.8%	13.6 4.5%
After Vaccination 3, Headache: Moderate	6.3 2.1%	4.8 1.6%	4.8 1.6%
After Vaccination 3, Headache: Severe	0.8 0.3%	1.3 0.4%	1.8 0.6%
After Vaccination 3, Asthenia: Any Severity	10.5 3.5%	9.1 3%	7.0 2.3%
After Vaccination 3, Asthenia: Mild	6.3 2.1%	7.4 2.5%	3.9 1.3%
After Vaccination 3, Asthenia: Moderate	3.8 1.3%	1.7 0.6%	2.6 0.9%
After Vaccination 3, Asthenia: Severe	0.4 0.1%	0 0%	0.4 0.1%
After Vaccination 3, Malaise: Any Severity	11.3 3.8%	13.5 4.5%	11.4 3.8%
After Vaccination 3, Malaise: Mild	6.3 2.1%	9.1 3%	7.9 2.6%
After Vaccination 3, Malaise: Moderate	3.8 1.3%	3.5 1.2%	2.6 0.9%
After Vaccination 3, Malaise: Severe	1.3 0.4%	0.9 0.3%	0.9 0.3%
After Vaccination 3, Myalgia: Any Severity	12.6 4.2%	12.2 4.1%	7.9 2.6%
After Vaccination 3, Myalgia: Mild	7.6 2.5%	7.8 2.6%	4.8 1.6%
After Vaccination 3, Myalgia: Moderate	3.8 1.3%	3.9 1.3%	2.6 0.9%
After Vaccination 3, Myalgia: Severe	1.3 0.4%	0.4 0.1%	0.4 0.1%
After Vaccination 3, Fever: Any Severity	1.3 0.4%	0 0%	1.3 0.4%
After Vaccination 3,Fever:38.0-<38.5	0.9 0.3%	0 0%	0.9 0.3%
After Vaccination 3,Fever:38.5-<39.0	0.4 0.1%	0 0%	0 0%
After Vaccination 3,Fever:39.0-<39.5	0 0%	0 0%	0.4 0.1%

10. Secondary Outcome

Title	Percentage of Participants With Any Unsolicited Adverse Events (AEs)
Description	An AE is 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.
Time Frame	Within 28 days (day of vaccination + 27 days) after each vaccination

Outcome Measure Data

Analysis Population Description

Safety Set included all randomized participants who received at least 1 dose of the trial vaccines. Number analyzed is the number of participants with data available for analyses at the given timepoint.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	300	300	300
After First Vaccination	11.7 3.9%	17.3 5.8%	14.0 4.7%
After Second Vaccination	8.8 2.9%	10.4 3.5%	9.1 3%
After Third Vaccination	4.4 1.5%	5.4 1.8%	4.7 1.6%

11. Secondary Outcome

Title	Percentage of Participants With Medically Attended Adverse Events (MAAEs)
Description	MAAEs are defined as AEs leading to an unscheduled 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 360)

Outcome Measure Data

Analysis Population Description

Safety Set included all randomized participants who received at least 1 dose of the trial vaccines.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	300	300	300
Number [percentage of participants]	14.3 4.8%	15.3 5.1%	15.3 5.1%

12. Secondary Outcome

Title	Percentage of Participants With Serious Adverse Events (SAEs)
Description	An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, is an important medical event that may require intervention to prevent any of the above mentioned criteria and/or may expose the subject to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.
Time Frame	From first vaccination (Day 1) through end of study (Day 360)

Outcome Measure Data

Analysis Population Description

Safety Set included all randomized participants who received at least 1 dose of the trial vaccines.

Arm/Group Title	Group 1: YF-17D + Placebo/TDV/TDV	Group 2: TDV + Placebo/TDV/YF-17D	Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).	TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.	TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
Measure Participants	300	300	300
Number [percentage of participants]	4.3 1.4%	3.3 1.1%	2.3 0.8%

Adverse Events

Time Frame	All-Cause Mortality and Serious Adverse Events: From first vaccination (Day 1) through end of study (Day 360); Other Adverse Events: From any vaccination (Day 1, Day 90, and Day 180) up to 28 days post vaccination.
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	Group 1: YF-17D + Placebo/TDV/TDV		Group 2: TDV + Placebo/TDV/YF-17D		Group 3: TDV + YF-17D/TDV/Placebo
Arm/Group Description	YF-17D vaccine, 0.5 mL injection, subcutaneously (SC) plus YF 17D + TDV placebo-matching 0.5 mL, injection, SC on Day 1, followed by TDV, 0.5 mL, injection, SC on Day 90 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 180 (second dose).		TDV, 0.5 mL, injection, SC plus TDV placebo-matching, 0.5 mL injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on Day 90 (second dose), followed by YF-17D vaccine, 0.5 mL, injection, SC on Day 180.		TDV, 0.5 mL, injection, SC plus YF-17D vaccine, 0.5 mL, injection, SC on Day 1 (first dose), followed by TDV, 0.5 mL, injection, SC on day 90 (second dose), followed by TDV + YF 17D placebo-matching, 0.5 mL, injection, SC on Day 180.
All Cause Mortality
	Group 1: YF-17D + Placebo/TDV/TDV		Group 2: TDV + Placebo/TDV/YF-17D		Group 3: TDV + YF-17D/TDV/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/300 (0%)		1/300 (0.3%)		1/300 (0.3%)
Serious Adverse Events
	Group 1: YF-17D + Placebo/TDV/TDV		Group 2: TDV + Placebo/TDV/YF-17D		Group 3: TDV + YF-17D/TDV/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/300 (4.3%)		10/300 (3.3%)		7/300 (2.3%)
Cardiac disorders
Cardiac arrest	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Endocrine disorders
Hypothyroidism	0/300 (0%)		0/300 (0%)		1/300 (0.3%)
Gastrointestinal disorders
Abdominal pain	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Alcoholic pancreatitis	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Inguinal hernia	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Large intestinal obstruction	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Megacolon	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Peptic ulcer	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Peptic ulcer haemorrhage	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
General disorders
Systemic inflammatory response syndrome	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/300 (0%)		0/300 (0%)		1/300 (0.3%)
Immune system disorders
Allergy to arthropod sting	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Infections and infestations
Pneumonia	0/300 (0%)		1/300 (0.3%)		2/300 (0.7%)
Abscess intestinal	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Urinary tract infection	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Gastrointestinal anastomotic leak	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Humerus fracture	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Traumatic fracture	0/300 (0%)		0/300 (0%)		1/300 (0.3%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/300 (0%)		1/300 (0.3%)		0/300 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal proliferative breast lesion	2/300 (0.7%)		0/300 (0%)		0/300 (0%)
Aesthesioneuroblast oma	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Invasive ductal breast carcinoma	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Neuroendocrine tumour	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Papillary thyroid cancer	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/300 (0%)		1/300 (0.3%)		1/300 (0.3%)
Psychiatric disorders
Anxiety	1/300 (0.3%)		1/300 (0.3%)		0/300 (0%)
Alcohol withdrawal syndrome	0/300 (0%)		0/300 (0%)		1/300 (0.3%)
Drug abuse	0/300 (0%)		0/300 (0%)		1/300 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/300 (0%)		1/300 (0.3%)		1/300 (0.3%)
Social circumstances
Organ donor	1/300 (0.3%)		0/300 (0%)		0/300 (0%)
Other (Not Including Serious) Adverse Events
	Group 1: YF-17D + Placebo/TDV/TDV		Group 2: TDV + Placebo/TDV/YF-17D		Group 3: TDV + YF-17D/TDV/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/300 (3.7%)		23/300 (7.7%)		19/300 (6.3%)
General disorders
Injection site bruising	4/300 (1.3%)		5/300 (1.7%)		10/300 (3.3%)
Injection site pruritus	3/300 (1%)		7/300 (2.3%)		8/300 (2.7%)
Infections and infestations
Upper respiratory tract infection	6/300 (2%)		13/300 (4.3%)		4/300 (1.3%)

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.