Study of Sanofi Pasteur's CYD Dengue Vaccine in Healthy Subjects in Singapore

Study Overview
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Brief Summary
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Primary Objectives: To evaluate safety after each CYD Dengue vaccination in terms of injection site and systemic reactogenicity. To evaluate the occurrence of Serious Adverse Events (SAEs) throughout the trial period. To evaluate the humoral immune response to each CYD Dengue serotype after each vaccination in a subset of participants. Secondary Objectives: To evaluate the persistence of the humoral immune response during 4 years after the last vaccination in a subset of participants.

Detailed Description
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This was a multicenter trial involving three vaccinations one each at 0, 6 and 12 months over a period of 1 year, and a 4-year follow-up following the last vaccination.

Official Title
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Immunogenicity and Large-Scale Safety of Tetravalent Dengue Vaccine in Healthy Subjects Aged 2 to 45 Years in Singapore

Conditions
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Dengue Fever, Dengue Hemorrhagic Fever, Dengue Virus, Dengue Diseases

Intervention / Treatment
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* Biological: CYD Dengue vaccine
* Biological: NaCl + influenza virus or hepatitis A vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Aged from 2 to 45 years on the day of inclusion. Participant in good health, based on medical history and physical examination. Provision of informed consent form (and assent form for participants aged 6 to 12 years) signed by the participant and by the parent(s) or another legally acceptable representative for participants aged less than 21 years. Participants and parent(s)/legally acceptable representative able to attend all scheduled visits and comply with all trial procedures. For a woman of child-bearing potential, avoid becoming pregnant (use of an effective method of contraception or abstinence) for at least 4 weeks before the first vaccination until 4 weeks after the last vaccination. Exclusion Criteria : Febrile illness (temperature >= 37.5°C) or moderate or severe acute illness/infection on the day of the first vaccination, according to Investigator judgment. For a woman of child-bearing potential, known pregnancy or positive urine pregnancy test on the day of inclusion. Breast-feeding woman. Known systemic hypersensitivity to any of the components of the trial vaccines (especially egg proteins or neomycin) or history of a life-threatening reaction to the trial vaccines or to a vaccine containing any of the same substances. Personal or family history of thymic pathology or myasthenia. Previous hepatitis A vaccination (for children only). Known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the past 6 months, or long-term systemic corticosteroid therapy. Chronic illness at a stage that could interfere with trial conduct or completion, in the opinion of the Investigator. Receipt of blood or blood-derived products in the past 3 months that might interfere with the assessment of immune response. Participation in another clinical trial investigating a vaccine, drug, medical device, or a medical procedure in the 4 weeks preceding the first trial vaccination. Planned participation in another clinical trial during the 18 coming months. Receipt of any vaccine in the 4 weeks preceding the first trial vaccination. Planned receipt of any vaccine in the 4 weeks following the first trial vaccination. Participant deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized without his/her consent. Current or past alcohol abuse or drug addiction that may interfere with the participants ability to comply with trial procedures. Participant who plans to move to another country within the 18 coming months.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYD Dengue Vaccine Group<br>Participant's received the CYD Dengue Vaccine at 0, 6, and 12 months as first, second, and third vaccinations, respectively. | Biological: CYD Dengue vaccine<br>* 0.5 mL, Subcutaneous on Day 0, Months 6 and 12<br>* Other names: Sanofi Pasteur's CYD Dengue Vaccine;|
| Sham Comparator: Placebo Group<br>All participants received a placebo at first vaccination (Month 0). Participants <12 years received hepatitis A at second (Month 6) and third (Month 12) vaccinations. Participants >= 12 years received influenza vaccine of Northern and Southern hemisphere formulations at second (Month 6) and third (Month 12) vaccinations. | Biological: NaCl + influenza virus or hepatitis A vaccine<br>* 0.5 mL, Subcutaneous (Intramuscular - Hepatitis A)<br>* Other names: Havrix® pediatric formulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of All Participants Reporting Solicited Injection-site and Systemic Reactions Following Each Injection With CYD Dengue Vaccine or Placebo | Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions (2-11 years): Pain, incapacitating, unable to perform usual activities; Erythema and Swelling, >=5 cm. Grade 3 Solicited injection site reactions (adolescents and adults: >=12 years): Pain, significant; prevents daily activity; Erythema and Swelling: >10 cm. Grade 3 Solicited systemic reactions (all participants): Fever, >=39.0°C; Headache, Malaise, Myalgia, and Asthenia: significant; prevents daily activity. | Day 0 up to 14 days post-any and each injection | 
| Percentage of Participants by Age Group (2-11 Years, 12-17 Years, 18-45 Years) Reporting Solicited Injection-site and Systemic Reactions Following Each Injection (Inj.) With CYD Dengue Vaccine or Placebo | Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. | Day 0 up to 14 days post-each injection | 
| Percentage of All Participants Who Achieved Seropositivity Against Each of the Dengue Virus Serotypes Before and After Each Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotype (parental strains) was assessed using a dengue plaque reduction neutralization test (PRNT) assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1, 2, and 3 and 28 days Post-Injection 1, 2, and 3 | 
| Percentage of Participants by Age Group (2-11 Years, 12-17 Years, 18-45 Years) Who Achieved Seropositivity Against Each of the Dengue Virus Serotypes Before and After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotypes (parental strains) was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1 and 28 days Post-Injection 3 | 
| Percentage of Participants by Age Group (2-11 Years, 12-17 Years, 18-45 Years) Who Achieved Seropositivity Against at Least 1, 2, 3, or 4 of the Dengue Virus Serotypes Before and After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against at least 1, 2, 3, or 4 dengue virus serotypes (parental strains) was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1 and 28 days Post-Injection 3 | 
| Geometric Mean Titers (GMTs) of Antibodies in All Participants Against Each Serotype With the Parental Dengue Virus Strain Before and Following Each Vaccination With CYD Dengue Vaccine or Placebo | GMTs against each serotype with the parental dengue virus strains were assessed using a dengue PRNT assay. | Pre-Injection 1, 2, and 3 and 28 days Post-Injection 1, 2, and 3 | 
| GMTs of Antibodies by Age Groups (2-11 Years, 12-17 Years, 18-45 Years) Against Each Serotype With the Parental Dengue Virus Strain Before and Following the Third Vaccination With CYD Dengue Vaccine | GMTs against each dengue virus serotype (parental strains) were assessed using a dengue PRNT assay. | Pre-Injection 1 and 28 days Post-Injection 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Aged 2 to 11 Years Who Achieved Seropositivity Against Each of the Dengue Virus Serotypes Before and up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotypes (parental strains) was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants Aged 12 to 17 Years Old Who Achieved Seropositivity Against Each of the Dengue Virus Serotypes Before and up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotypes (parental stains) was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with antibody titers >=10 (1/dilution). | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants Aged 18 to 45 Years Who Achieved Seropositivity Against Each of the Dengue Virus Serotypes Before and up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each dengue virus serotypes (parental stains) was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants Aged 2 to 11 Years Old Who Achieved Seropositivity Against At Least 1, 2, 3, or 4 of the Dengue Virus Serotypes Before and After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against at least 1, 2, 3, or 4 dengue virus serotypes was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants Aged 12 to 17 Years Old Who Achieved Seropositivity Against at Least 1, 2, 3, or 4 of the Dengue Virus Serotypes Before and After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against at least 1, 2, 3, or 4 dengue virus serotypes was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants Aged 18 to 45 Years Old Who Achieved Seropositivity Against at Least 1, 2, 3, or 4 of the Dengue Virus Serotypes Before and After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against at least 1, 2, 3, or 4 dengue virus serotypes was assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| GMTs of Antibodies in Participants 2 to 11 Years Old Against Each Serotype With the Parental Dengue Virus Strain Before and Following the Third Vaccination With CYD Dengue Vaccine | GMTs against each serotype with the dengue virus strain (parental strains) were assessed using a dengue PRNT assay. | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| GMTs of Antibodies in Participants 12 to 17 Years Old Against Each Serotype With the Parental Dengue Virus Strain Before and Following the Third Vaccination With CYD Dengue Vaccine or Placebo | GMTs against each serotype with the dengue virus strain (parental strains) were assessed using a dengue PRNT assay. | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| GMTs of Antibodies in Participants 18 to 45 Years Old Against Each Serotype With the Parental Dengue Virus Strain Before and Following the Third Vaccination With CYD Dengue Vaccine or Placebo | GMTs against each serotype with the dengue virus strain were assessed using a dengue PRNT assay. | Pre-Injection 1, 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants (Aged 2 to 11 Years) Immune to Dengue at Baseline Who Are Seropositive for Each of the Dengue Virus Serotypes up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each serotype with the dengue virus strain were assessed using a dengue PRNT assay. Seropositive participants were defined as participants with antibody titers >=10 (1/dilution). Dengue participants immune at baseline was defined as those participants with titers >=10 (1/dilution) against at least one dengue serotype at baseline. | 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants (Aged 2 to 11 Years) Naïve to Dengue at Baseline Who Are Seropositive for Each of the Dengue Virus Serotypes up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each serotype with the dengue virus strain were assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). Dengue participants naïve at baseline was defined as those participants with titers <10 (1/dilution) against all dengue serotypes at baseline. | 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants (Aged 12 to 17 Years) Immune to Dengue at Baseline Who Are Seropositive for Each of the Dengue Virus Serotypes up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each serotype with the dengue virus strain were assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). Dengue participants immune at baseline was defined as those participants with titers >=10 (1/dilution) against at least one dengue serotype at baseline. | 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants (Aged 12 to 17 Years) Naïve to Dengue at Baseline Who Are Seropositive for Each of the Dengue Virus Serotypes up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each serotype with the dengue virus strain were assessed using a PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). Dengue participants naïve at baseline was defined as those participants with titers <10 (1/dilution) against all dengue serotypes at baseline. | 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants (Aged 18 to 45 Years) Immune to Dengue at Baseline Who Are Seropositive for Each of the Dengue Virus Serotypes up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each serotype with the dengue virus strain were assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). Dengue participants immune at baseline was defined as those participants with titers >=10 (1/dilution) against at least one dengue serotype at baseline. | 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 
| Percentage of Participants (Aged 18 to 45 Years) Naïve to Dengue at Baseline Who Are Seropositive for Each of the Dengue Virus Serotypes up to 4 Years After the Third Vaccination With CYD Dengue Vaccine or Placebo | Seropositivity against each serotype with the dengue virus strain were assessed using a dengue PRNT assay. Seropositive participants were defined as participants with neutralizing antibody titers >=10 (1/dilution). Dengue participants naïve at baseline was defined as those participants with titers <10 (1/dilution) against all dengue serotypes at baseline. | 28 days Post-Injection 3, at 1 year follow up, 2 year follow up, 3 year follow up and 4 year follow up (assessed post-injection 3 during the follow up duration of 4 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue virus, Dengue fever, Dengue Hemorrhagic fever, Dengue diseases, Sanofi Pasteur's CYD Dengue Vaccine