Study of a Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 11 Years in Malaysia

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01254422
• Collaborator: (none)
• Enrollment: 250
• Locations: 4
• Arms: 2
• Actual Duration (Months): 25
• Patients Per Site: 62.5
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and immunogenicity of Phase III lots of the CYD dengue vaccine in a pediatric population in Malaysia.

Primary Objectives:

• To describe the safety (in terms of solicited and unsolicited adverse events) of the CYD dengue vaccine in all participants after each injection.

• To describe the antibody response to each dengue virus serotype post-injection 2 and post-injection 3.

Condition or Disease	Intervention/Treatment	Phase
Dengue Fever; Dengue Hemorrhagic Fever	Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, and 4 virus; Biological: Placebo: NaCl 0.9%	Phase 3

Detailed Description

Healthy participants aged 2 to 11 years received 3 vaccinations at pre-determined schedules and were followed-up for at least 6 months after the last vaccination.

Study Design

• Study Type: Interventional
• Actual Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Safety and Immunogenicity of a Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 11 Years in Malaysia
• Actual Study Start Date: Dec 2, 2010
• Actual Primary Completion Date: Sep 28, 2012
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CYD Dengue vaccine group Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Biological: Live, attenuated, recombinant dengue serotypes 1, 2, 3, and 4 virus; 0.5 mL (at 0, 6, and 12 months), Subcutaneous suspension; Other Names: CYD Dengue vaccine
Placebo Comparator: Placebo Group Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.	Biological: Placebo: NaCl 0.9%; 0.5 mL (at 0, 6, and 12 months), Subcutaneous suspension; Other Names: Saline

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Vaccination With Either CYD Dengue Vaccine or a Placebo [Day 0 up to Day 14 post-any and each vaccination]

   Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions: Pain: Incapacitating, unable to perform usual activities; Erythema and Swelling: >=50 millimeter (mm). Grade 3 Solicited systemic reactions: Fever: >=39°Degree Celsius (C); Headache, Malaise, Myalgia, and Asthenia: Significant: Prevents daily activity.

2. Percentage of Flavivirus-Immune Participants Reporting Solicited Injection Site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or Placebo Vaccine [Day 0 up to Day 14 post-each vaccination]

   Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Flavivirus-Immune participants were defined as participants with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype with parental dengue virus strains (serotype 1, 2, 3, and 4) in the baseline sample.

3. Percentage of Flavivirus-Naïve Participants Reporting Solicited Injection-site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or a Placebo Vaccine [Day 0 up to Day 14 post-each vaccination]

   Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Flavivirus-Naive participants were defined as participants without quantified antibodies against Japanese encephalitis and without antibody quantified against all serotypes (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.

4. Percentage of Participants With Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [Pre-Injection 1 and Post-Injections 2 and 3]

   Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each dengue serotype (1,2, 3 and 4) and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).

5. Percentage of Participants With Seropositivity Against at Least One, Two, Three, or the Four Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [Pre-Injection 1 and Post-Injections 2 and 3]

   Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each dengue serotype (1, 2, 3, and 4) and was assessed using the dengue PRNT.

6. Geometric Mean Titers (GMTs) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [Pre-Injection 1 and Post-Injections 2 and 3]

   GMTs of antibodies against the dengue virus serotypes (1, 2, 3, and 4) were assessed using the dengue PRNT.

7. Percentage of Participants With Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo: Flavivirus-Immune Participants [Pre-Injection 1 and Post-Injections 2 and 3]

   Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each serotype (1, 2, 3, and 4) and was assessed using the Dengue PRNT. Flavivirus-Immune participants were defined as participants with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.

8. Percentage of Participants With Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo: Flavivirus-Naive Participants [Pre-Injection 1 and Post-Injections 2 and 3]

   Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each serotype (1, 2, 3, and 4) and was assessed using the Dengue PRNT. Flavivirus naïve participants were defined as participants without quantified antibodies against Japanese encephalitis and without quantified antibodies against all serotypes (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.

9. GMTs of Flavivirus-Immune Participants Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [Pre-Injection 1 and Post-Injections 2 and 3]

   GMTs of antibodies against the dengue virus serotypes (1, 2, 3, and 4) were assessed using the Dengue PRNT. Flavivirus-Immune participants were defined as participants with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.

10. GMT of Flavivirus-Naïve Participants Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [Pre-Injection 1 and Post- Injections 2 and 3]

    GMTs of antibodies against the dengue virus serotypes (1, 2, 3, and 4) were assessed using the Dengue PRNT. Flavivirus-Naive participants were defined as participants without quantified antibodies against Japanese encephalitis and without antibody quantified against all serotypes (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 11 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Aged 2 to 11 years on the day of inclusion

• Assent form was signed and dated by the participant (for participants ≥ 7 years) and informed consent form was signed and dated by the parent(s) or another legally accepted representative, and by an independent witness if the two parents or legally accepted representative were illiterate

• Participant and parent/legally accepted representative were able to attend all scheduled visits to comply with all trial procedures

• Participants in good health, based on medical history and physical examination

• For a female participant of childbearing potential, use of an effective method of contraception or abstinence for at least 4 weeks prior to the first vaccination, until at least 4 weeks after the last vaccination

Exclusion Criteria:

• Known pregnancy, or a positive urine pregnancy test (for female participant of child-bearing potential only)

• Participation in another clinical trial investigating a vaccine, drug, medical device, or medical procedure in the 4 weeks preceding the first trial vaccination

• Planned participation in another clinical trial during the present trial period

• Planned receipt of any vaccine in the 4 weeks following the trial first vaccination, except for pandemic influenza vaccination

• Receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response

• Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)

• Seropositivity for human immunodeficiency virus (HIV) reported by the parent/legally acceptable representative

• Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine(s) used in the trial or to a vaccine containing any of the same substances

• Chronic illness that, in the opinion of the investigator, was at a stage where it might interfere with trial conduct or completion

• Participants who plan to move to another country/region within the 18 coming months

• Identified as a child (adopted or natural) of the Investigator or of site employees of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Ipoh, Perak		Malaysia	30990
2		Kuala Lumpur		Malaysia	59100
3		Kuching, Sarawak		Malaysia	93586
4		Negeri Sembilan		Malaysia	70300

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Medical Director, Sanofi Pasteur Singapore

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01254422
• Other Study ID Numbers: CYD32; UTN: U1111-1115-6579
• First Posted: Dec 6, 2010
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Sanofi: Dengue fever; Dengue hemorrhagic fever; CYD dengue vaccine
• Additional relevant MeSH terms: Dengue; Hemorrhagic Fevers, Viral; Severe Dengue; Fever; Hyperthermia; Vaccines

Study Results

Participant Flow

Recruitment Details	Study participants were enrolled from 02 December 2010 to 10 February 2011 at 4 clinical sites in Malaysia.
Pre-assignment Detail	A total of 250 participants who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections (Inj.) of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Period Title: Overall Study
STARTED	199	51
COMPLETED	196	50
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group	Total
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.	Total of all reporting groups
Overall Participants	199	51	250
Age, Customized (Years) [Number]
2 to 5 years	99	26	125
6 to 11 years	100	25	125
Sex: Female, Male (Count of Participants)
Female	103 51.8%	19 37.3%	122 48.8%
Male	96 48.2%	32 62.7%	128 51.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Vaccination With Either CYD Dengue Vaccine or a Placebo
Description	Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions: Pain: Incapacitating, unable to perform usual activities; Erythema and Swelling: >=50 millimeter (mm). Grade 3 Solicited systemic reactions: Fever: >=39°Degree Celsius (C); Headache, Malaise, Myalgia, and Asthenia: Significant: Prevents daily activity.
Time Frame	Day 0 up to Day 14 post-any and each vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety analysis set which included participants who received any dose of CYD dengue vaccine or placebo and were analyzed according to the treatment received at this injection. Here, 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	199	51
Inj. site Pain; Post-Any Inj.	69.3 34.8%	56.9 111.6%
Grade 3 Inj. site Pain; Post-Any Inj.	1.0 0.5%	0.0 0%
Inj. site Erythema; Post-Any Inj.	46.7 23.5%	49.0 96.1%
Grade 3 Inj. site Erythema; Post-Any Inj.	0.5 0.3%	0.0 0%
Inj. site Swelling; Post-Any Inj.	38.7 19.4%	35.3 69.2%
Grade 3 Inj. site Swelling; Post-Any Inj.	0.5 0.3%	0.0 0%
Inj. site Pain; Post-Inj. 1	41.4 20.8%	27.5 53.9%
Grade 3 Inj. site Pain; Post-Inj. 1	0.5 0.3%	0.0 0%
Inj. site Erythema; Post-Inj. 1	22.2 11.2%	23.5 46.1%
Grade 3 Inj. site Erythema; Post-Inj. 1	0.5 0.3%	0.0 0%
Inj. site Swelling; Post-Inj. 1	18.7 9.4%	21.6 42.4%
Grade 3 Inj. site Swelling; Post-Inj. 1	0.0 0%	0.0 0%
Inj. site Pain; Post-Inj. 2	48.2 24.2%	26.0 51%
Grade 3 Inj. site Pain; Post-Inj. 2	0.5 0.3%	0.0 0%
Inj. site Erythema; Post-Inj. 2	33.0 16.6%	32.0 62.7%
Grade 3 Inj. site Erythema; Post-Inj. 2	0.0 0%	0.0 0%
Inj. site Swelling; Post-Inj. 2	15.2 7.6%	10.0 19.6%
Grade 3 Inj. site Swelling; Post-Inj. 2	0.0 0%	0.0 0%
Inj. site Pain; Post-Inj. 3	40.0 20.1%	38.0 74.5%
Grade 3 Inj. site Pain; Post-Inj. 3	0.5 0.3%	0.0 0%
Inj. site Erythema; Post-Inj. 3	23.6 11.9%	24.0 47.1%
Grade 3 Inj. site Erythema; Post-Inj. 3	0.0 0%	0.0 0%
Inj. site Swelling; Post-Inj. 3	20.0 10.1%	24.0 47.1%
Grade 3 Inj. site Swelling; Post-Inj. 3	0.5 0.3%	0.0 0%
Asthenia; Post-Any Inj.	47.2 23.7%	33.3 65.3%
Grade 3 Asthenia; Post-Any Inj.	3.0 1.5%	0.0 0%
Fever; Post-Any Inj.	29.3 14.7%	19.6 38.4%
Grade 3 Fever; Post-Any Inj.	6.6 3.3%	3.9 7.6%
Headache; Post-Any Inj.	52.3 26.3%	39.2 76.9%
Grade 3 Headache; Post-Any Inj.	2.0 1%	2.0 3.9%
Malaise; Post-Any Inj.	54.3 27.3%	41.2 80.8%
Grade 3 Malaise; Post-Any Inj.	3.5 1.8%	0.0 0%
Myalgia; Post-Any Inj.	37.7 18.9%	31.4 61.6%
Grade 3 Myalgia; Post-Any Inj.	2.5 1.3%	0.0 0%
Asthenia; Post-Inj. 1	28.1 14.1%	19.6 38.4%
Grade 3 Asthenia; Post-Inj. 1	2.0 1%	0.0 0%
Fever; Post-Inj. 1	12.6 6.3%	8.2 16.1%
Grade 3 Fever; Post-Inj. 1	2.0 1%	4.1 8%
Headache; Post-Inj. 1	37.2 18.7%	27.5 53.9%
Grade 3 Headache; Post-Inj. 1	1.5 0.8%	0.0 0%
Malaise; Post-Inj. 1	36.4 18.3%	29.4 57.6%
Grade 3 Malaise; Post-Inj. 1	2.5 1.3%	0.0 0%
Myalgia; Post-Inj. 1	22.7 11.4%	23.5 46.1%
Grade 3 Myalgia; Post-Inj. 1	2.0 1%	0.0 0%
Asthenia; Post-Inj. 2	23.9 12%	6.0 11.8%
Grade 3 Asthenia; Post-Inj. 2	0.5 0.3%	0.0 0%
Fever; Post-Inj. 2	15.2 7.6%	10.2 20%
Grade 3 Fever; Post-Inj. 2	2.5 1.3%	0.0 0%
Headache; Post-Inj. 2	31.0 15.6%	16.0 31.4%
Grade 3 Headache; Post-Inj. 2	0.5 0.3%	2.0 3.9%
Malaise; Post-Inj. 2	27.9 14%	6.0 11.8%
Grade 3 Malaise; Post-Inj. 2	0.5 0.3%	0.0 0%
Myalgia; Post-Inj. 2	18.8 9.4%	8.0 15.7%
Grade 3 Myalgia; Post-Inj. 2	0.5 0.3%	0.0 0%
Asthenia; Post-Inj. 3	19.0 9.5%	12.0 23.5%
Grade 3 Asthenia; Post-Inj. 3	1.5 0.8%	0.0 0%
Fever; Post-Inj. 3	9.5 4.8%	2.0 3.9%
Grade 3 Fever; Post-Inj. 3	3.7 1.9%	0.0 0%
Headache; Post-Inj. 3	22.6 11.4%	14.0 27.5%
Grade 3 Headache; Post-Inj. 3	1.5 0.8%	0.0 0%
Malaise; Post-Inj. 3	20.5 10.3%	12.0 23.5%
Grade 3 Malaise; Post-Inj. 3	1.5 0.8%	0.0 0%
Myalgia; Post-Inj. 3	17.4 8.7%	10.0 19.6%
Grade 3 Myalgia; Post-Inj. 3	1.0 0.5%	0.0 0%

2. Primary Outcome

Title	Percentage of Flavivirus-Immune Participants Reporting Solicited Injection Site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or Placebo Vaccine
Description	Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Flavivirus-Immune participants were defined as participants with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype with parental dengue virus strains (serotype 1, 2, 3, and 4) in the baseline sample.
Time Frame	Day 0 up to Day 14 post-each vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety analysis set. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	111	31
Injection site Pain; Post-Injection 1	44.5 22.4%	29.0 56.9%
Injection site Erythema; Post-Injection 1	14.5 7.3%	29.0 56.9%
Injection site Swelling; Post-Injection 1	13.6 6.8%	22.6 44.3%
Asthenia; Post-Injection 1	27.9 14%	25.8 50.6%
Fever; Post-Injection 1	12.7 6.4%	13.3 26.1%
Malaise; Post-Injection 1	38.2 19.2%	38.7 75.9%
Myalgia; Post-Injection 1	22.7 11.4%	25.8 50.6%
Headache; Post-Injection 1	36.9 18.5%	29.0 56.9%
Injection site Pain; Post-Injection 2	48.2 24.2%	32.3 63.3%
Injection site Erythema; Post-Injection 2	25.5 12.8%	29.0 56.9%
Injection site Swelling; Post-Injection 2	9.1 4.6%	16.1 31.6%
Asthenia; Post-Injection 2	21.8 11%	9.7 19%
Fever; Post-Injection 2	18.2 9.1%	9.7 19%
Malaise; Post-Injection 2	29.1 14.6%	3.2 6.3%
Myalgia; Post-Injection 2	19.1 9.6%	12.9 25.3%
Headache; Post-Injection 2	31.8 16%	12.9 25.3%
Injection site Pain; Post-Injection 3	34.3 17.2%	41.9 82.2%
Injection site Erythema; Post-Injection 3	21.3 10.7%	22.6 44.3%
Injection site Swelling; Post-Injection 3	15.7 7.9%	22.6 44.3%
Asthenia; Post-Injection 3	13.9 7%	16.1 31.6%
Fever; Post-Injection 3	10.5 5.3%	0.0 0%
Malaise; Post-Injection 3	18.5 9.3%	16.1 31.6%
Myalgia; Post-Injection 3	14.8 7.4%	16.1 31.6%
Headache; Post-Injection 3	19.4 9.7%	19.4 38%

3. Primary Outcome

Title	Percentage of Flavivirus-Naïve Participants Reporting Solicited Injection-site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or a Placebo Vaccine
Description	Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Flavivirus-Naive participants were defined as participants without quantified antibodies against Japanese encephalitis and without antibody quantified against all serotypes (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.
Time Frame	Day 0 up to Day 14 post-each vaccination

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety analysis set. Here, ''overall number of participants analyzed" signifies participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	88	20
Injection site Pain; Post-Injection 1	37.5 18.8%	25.0 49%
Injection site Erythema; Post-Injection 1	31.8 16%	15.0 29.4%
Injection site Swelling; Post-Injection 1	25.0 12.6%	20.0 39.2%
Asthenia; Post-Injection 1	28.4 14.3%	10.0 19.6%
Fever; Post-Injection 1	12.5 6.3%	0.0 0%
Malaise; Post-Injection 1	34.1 17.1%	15.0 29.4%
Myalgia; Post-Injection 1	22.7 11.4%	20.0 39.2%
Headache; Post-Injection 1	37.5 18.8%	25.0 49%
Injection site Pain; Post-Injection 2	48.3 24.3%	15.8 31%
Injection site Erythema; Post-Injection 2	42.5 21.4%	36.8 72.2%
Injection site Swelling; Post-Injection 2	23.0 11.6%	0.0 0%
Asthenia; Post-Injection 2	26.4 13.3%	0.0 0%
Fever; Post-Injection 2	11.5 5.8%	11.1 21.8%
Malaise; Post-Injection 2	26.4 13.3%	10.5 20.6%
Myalgia; Post-Injection 2	18.4 9.2%	0.0 0%
Headache; Post-Injection 2	29.9 15%	21.1 41.4%
Injection site Pain; Post-Injection 3	47.1 23.7%	31.6 62%
Injection site Erythema; Post-Injection 3	26.4 13.3%	26.3 51.6%
Injection site Swelling; Post-Injection 3	25.3 12.7%	26.3 51.6%
Asthenia; Post-Injection 3	25.3 12.7%	5.3 10.4%
Fever; Post-Injection 3	8.2 4.1%	5.3 10.4%
Malaise; Post-Injection 3	23.0 11.6%	5.3 10.4%
Myalgia; Post-Injection 3	20.7 10.4%	0.0 0%
Headache; Post-Injection 3	26.4 13.3%	5.3 10.4%

4. Primary Outcome

Title	Percentage of Participants With Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo
Description	Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each dengue serotype (1,2, 3 and 4) and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
Time Frame	Pre-Injection 1 and Post-Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set which included participants who received at least one injection of CYD dengue vaccine or placebo and had at least one valid post-injection serology result. Here, 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	196	50
Serotype 1; Pre-Injection 1	31.1 15.6%	32.0 62.7%
Serotype 1; Post-Injection 2	90.3 45.4%	34.0 66.7%
Serotype 1; Post-Injection 3	96.4 48.4%	30.0 58.8%
Serotype 2; Pre-Injection 1	27.6 13.9%	30.0 58.8%
Serotype 2; Post-Injection 2	94.9 47.7%	34.0 66.7%
Serotype 2; Post-Injection 3	96.9 48.7%	34.0 66.7%
Serotype 3; Pre-Injection 1	36.7 18.4%	36.7 72%
Serotype 3; Post-Injection 2	98.5 49.5%	32.0 62.7%
Serotype 3; Post-Injection 3	99.0 49.7%	34.0 66.7%
Serotype 4; Pre-Injection 1	24.0 12.1%	30.0 58.8%
Serotype 4; Post-Injection 2	91.8 46.1%	32.0 62.7%
Serotype 4; Post-Injection 3	98.0 49.2%	28.0 54.9%

5. Primary Outcome

Title	Percentage of Participants With Seropositivity Against at Least One, Two, Three, or the Four Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo
Description	Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each dengue serotype (1, 2, 3, and 4) and was assessed using the dengue PRNT.
Time Frame	Pre-Injection 1 and Post-Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	196	50
At least 1 serotype; Pre-Injection 1	44.9 22.6%	48.0 94.1%
At least 1 serotype; Post-Injection 2	100.0 50.3%	46.0 90.2%
At least 1 serotype; Post-Injection 3	100.0 50.3%	42.0 82.4%
At least 2 serotypes; Pre-Injection 1	29.1 14.6%	28.0 54.9%
At least 2 serotypes; Post-Injection 2	99.0 49.7%	34.0 66.7%
At least 2 serotypes; Post-Injection 3	100.0 50.3%	32.0 62.7%
At least 3 serotypes; Pre-Injection 1	25.5 12.8%	28.0 54.9%
At least 3 serotypes; Post-Injection 2	96.4 48.4%	28.0 54.9%
At least 3 serotypes; Post-Injection 3	98.5 49.5%	30.0 58.8%
All 4 serotypes; Pre-Injection 1	19.9 10%	24.0 47.1%
All 4 serotypes; Post-Injection 2	80.1 40.3%	24.0 47.1%
All 4 serotypes; Post-Injection 3	91.8 46.1%	22.0 43.1%

6. Primary Outcome

Title	Geometric Mean Titers (GMTs) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo
Description	GMTs of antibodies against the dengue virus serotypes (1, 2, 3, and 4) were assessed using the dengue PRNT.
Time Frame	Pre-Injection 1 and Post-Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set. Here, 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	196	50
Serotype 1; Pre-Injection 1	15.3	18.6
Serotype 1; Post-Injection 2	119	21.0
Serotype 1; Post-Injection 3	151	18.9
Serotype 2; Pre-Injection 1	15.9	18.6
Serotype 2; Post-Injection 2	160	17.9
Serotype 2; Post-Injection 3	180	16.3
Serotype 3; Pre-Injection 1	15.6	15.9
Serotype 3; Post-Injection 2	196	15.9
Serotype 3; Post-Injection 3	193	16.3
Serotype 4; Pre-Injection 1	9.92	12.3
Serotype 4; Post-Injection 2	110	13.3
Serotype 4; Post-Injection 3	114	10.9

7. Primary Outcome

Title	Percentage of Participants With Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo: Flavivirus-Immune Participants
Description	Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each serotype (1, 2, 3, and 4) and was assessed using the Dengue PRNT. Flavivirus-Immune participants were defined as participants with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.
Time Frame	Pre-Injection 1 and Post-Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	109	31
Serotype 1; Pre-Injection 1	56.0 28.1%	51.6 101.2%
Serotype 1; Post-Injection 2	96.3 48.4%	48.4 94.9%
Serotype 1; Post-Injection 3	97.2 48.8%	41.9 82.2%
Serotype 2; Pre-Injection 1	49.5 24.9%	48.4 94.9%
Serotype 2; Post-Injection 2	96.3 48.4%	54.8 107.5%
Serotype 2; Post-Injection 3	97.2 48.8%	48.4 94.9%
Serotype 3; Pre-Injection 1	66.1 33.2%	60.0 117.6%
Serotype 3; Post-Injection 2	100.0 50.3%	51.6 101.2%
Serotype 3; Post-Injection 3	99.1 49.8%	48.4 94.9%
Serotype 4; Pre-Injection 1	43.1 21.7%	48.4 94.9%
Serotype 4; Post-Injection 2	97.2 48.8%	45.2 88.6%
Serotype 4; Post-Injection 3	100.0 50.3%	41.9 82.2%

8. Primary Outcome

Title	Percentage of Participants With Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo: Flavivirus-Naive Participants
Description	Seropositivity was defined as participants achieving neutralizing antibody titers >=10 (1/dilution) against each serotype (1, 2, 3, and 4) and was assessed using the Dengue PRNT. Flavivirus naïve participants were defined as participants without quantified antibodies against Japanese encephalitis and without quantified antibodies against all serotypes (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.
Time Frame	Pre-Injection 1 and Post-Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	87	19
Serotype 1; Pre-Injection 1	0.0 0%	0.0 0%
Serotype 1; Post-Injection 2	82.8 41.6%	10.5 20.6%
Serotype 1; Post-Injection 3	95.4 47.9%	10.5 20.6%
Serotype 2; Pre-Injection 1	0.0 0%	0.0 0%
Serotype 2; Post-Injection 2	93.1 46.8%	0.0 0%
Serotype 2; Post-Injection 3	96.6 48.5%	10.5 20.6%
Serotype 3; Pre-Injection 1	0.0 0%	0.0 0%
Serotype 3; Post-Injection 2	96.6 48.5%	0.0 0%
Serotype 3; Post-Injection 3	98.9 49.7%	10.5 20.6%
Serotype 4; Pre-Injection 1	0.0 0%	0.0 0%
Serotype 4; Post-Injection 2	85.1 42.8%	10.5 20.6%
Serotype 4; Post-Injection 3	95.4 47.9%	5.3 10.4%

9. Primary Outcome

Title	GMTs of Flavivirus-Immune Participants Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo
Description	GMTs of antibodies against the dengue virus serotypes (1, 2, 3, and 4) were assessed using the Dengue PRNT. Flavivirus-Immune participants were defined as participants with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.
Time Frame	Pre-Injection 1 and Post-Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	109	31
Serotype 1; Pre-Injection 1	37.5	41.7
Serotype 1; Post-Injection 2	248	45.4
Serotype 1; Post-Injection 3	247	33.5
Serotype 2; Pre-Injection 1	39.9	41.6
Serotype 2; Post-Injection 2	306	39.0
Serotype 2; Post-Injection 3	292	30.0
Serotype 3; Pre-Injection 1	38.8	33.2
Serotype 3; Post-Injection 2	296	32.4
Serotype 3; Post-Injection 3	287	29.5
Serotype 4; Pre-Injection 1	17.1	21.3
Serotype 4; Post-Injection 2	152	21.7
Serotype 4; Post-Injection 3	155	16.5

10. Primary Outcome

Title	GMT of Flavivirus-Naïve Participants Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo
Description	GMTs of antibodies against the dengue virus serotypes (1, 2, 3, and 4) were assessed using the Dengue PRNT. Flavivirus-Naive participants were defined as participants without quantified antibodies against Japanese encephalitis and without antibody quantified against all serotypes (1, 2, 3, and 4) with parental dengue virus strains in the baseline sample.
Time Frame	Pre-Injection 1 and Post- Injections 2 and 3

Outcome Measure Data

Analysis Population Description

Analysis was performed on Full analysis set. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure.

Arm/Group Title	CYD Dengue Vaccine Group	Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.	Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
Measure Participants	87	19
Serotype 1; Pre-Injection 1	5.00	5.00
Serotype 1; Post-Injection 2	47.1	5.98
Serotype 1; Post-Injection 3	81.6	7.38
Serotype 2; Pre-Injection 1	5.00	5.00
Serotype 2; Post-Injection 2	71.4	5.00
Serotype 2; Post-Injection 3	97.5	6.03
Serotype 3; Pre-Injection 1	5.00	5.00
Serotype 3; Post-Injection 2	116	5.00
Serotype 3; Post-Injection 3	117	6.17
Serotype 4; Pre-Injection 1	5.00	5.00
Serotype 4; Post-Injection 2	73.3	5.95
Serotype 4; Post-Injection 3	78.0	5.54

Adverse Events

Time Frame	Adverse events (AEs) were collected from Day 0 (post-vaccination) up to 6 months post-Injection 3 (up to 18 months)
Adverse Event Reporting Description	Analysis was performed on Safety analysis set.
Arm/Group Title	CYD Dengue Vaccine Group		Placebo Group
Arm/Group Description	Participants received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.		Participants received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
All Cause Mortality
	CYD Dengue Vaccine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/199 (0%)		0/51 (0%)
Serious Adverse Events
	CYD Dengue Vaccine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/199 (5.5%)		7/51 (13.7%)
Congenital, familial and genetic disorders
Fibrous dysplasia of bone	0/199 (0%)	0	1/51 (2%)	1
Gastrointestinal disorders
Abdominal pain	1/199 (0.5%)	1	0/51 (0%)	0
Infections and infestations
Acute tonsillitis	1/199 (0.5%)	1	0/51 (0%)	0
Enterocolitis infectious	1/199 (0.5%)	1	0/51 (0%)	0
Gastroenteritis rotavirus	2/199 (1%)	2	0/51 (0%)	0
Gastroenteritis viral	0/199 (0%)	0	1/51 (2%)	1
Lobar pneumonia	1/199 (0.5%)	1	0/51 (0%)	0
Pharyngotonsillitis	1/199 (0.5%)	1	0/51 (0%)	0
Pneumonia	1/199 (0.5%)	1	1/51 (2%)	1
Scarlet fever	1/199 (0.5%)	1	0/51 (0%)	0
Viral infection	1/199 (0.5%)	1	0/51 (0%)	0
Viral pharyngitis	1/199 (0.5%)	1	1/51 (2%)	1
Injury, poisoning and procedural complications
Overdose	1/199 (0.5%)	1	0/51 (0%)	0
Skull fractured base	0/199 (0%)	0	1/51 (2%)	1
Nervous system disorders
Febrile convulsion	1/199 (0.5%)	1	0/51 (0%)	0
VIIth nerve paralysis	0/199 (0%)	0	1/51 (2%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/199 (0.5%)	1	2/51 (3.9%)	3
Other (Not Including Serious) Adverse Events
	CYD Dengue Vaccine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	138/199 (69.3%)		29/51 (56.9%)
Gastrointestinal disorders
Vomiting	7/199 (3.5%)	7	3/51 (5.9%)	3
General disorders
Pyrexia	14/199 (7%)	14	1/51 (2%)	1
Injection site Pain; Post-Any	138/199 (69.3%)	138	29/51 (56.9%)	29
Injection site Erythema; Post-Any	93/199 (46.7%)	93	25/51 (49%)	25
Injection site Swelling; Post-Any	77/199 (38.7%)	77	18/51 (35.3%)	18
Asthenia; Post-Any Injection	94/199 (47.2%)	94	17/51 (33.3%)	17
Fever; Post-Any Injection	58/198 (29.3%)	58	10/51 (19.6%)	10
Malaise; Post-Any Injection	108/199 (54.3%)	108	21/51 (41.2%)	21
Infections and infestations
Upper respiratory tract infection	50/199 (25.1%)	61	11/51 (21.6%)	15
Musculoskeletal and connective tissue disorders
Myalgia; Post-Any Injection	75/199 (37.7%)	75	16/51 (31.4%)	16
Nervous system disorders
Headache; Post-Any Injection	104/199 (52.3%)	104	20/51 (39.2%)	20
Respiratory, thoracic and mediastinal disorders
Cough	24/199 (12.1%)	27	1/51 (2%)	1

Limitations/Caveats

None reported

More Information

Certain Agreements

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

Sponsor must have the opportunity to review at least 60 days prior to submission for publication or presentation. If review indicates that potentially patentable subject matter would be disclosed, publication or public disclosure may be delayed for a maximum of an additional 60 days to allow for filing the necessary patent applications.