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

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

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.

Study Overview

• Status: Completed
• Conditions: Dengue Fever; Dengue Hemorrhagic Fever; Dengue Virus; Dengue Diseases
• Intervention / Treatment: Biological: CYD Dengue vaccine; Biological: NaCl + influenza virus or hepatitis A vaccine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1198
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169608
  • Singapore, Singapore, 119074
  • Singapore, Singapore, 529889
  • Singapore, Singapore, 308433
  • Singapore, Singapore, 229899

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CYD Dengue Vaccine Group; Participant's received the CYD Dengue Vaccine at 0, 6, and 12 months as first, second, and third vaccinations, respectively.	Biological: CYD Dengue vaccine; 0.5 mL, Subcutaneous on Day 0, Months 6 and 12; Other Names: Sanofi Pasteur's CYD Dengue Vaccine
Sham Comparator: Placebo Group; 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; 0.5 mL, Subcutaneous (Intramuscular - Hepatitis A); Other Names: NaCl 0.9%; Vaxigrip®; Havrix® pediatric formulation

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Sanofi Pasteur, a Sanofi Company

Publications and helpful links

General Publications

• Harenberg A, Begue S, Mamessier A, Gimenez-Fourage S, Ching Seah C, Wei Liang A, Li Ng J, Yun Toh X, Archuleta S, Wilder-Smith A, Shek LP, Wartel-Tram A, Bouckenooghe A, Lang J, Crevat D, Caillet C, Guy B. Persistence of Th1/Tc1 responses one year after tetravalent dengue vaccination in adults and adolescents in Singapore. Hum Vaccin Immunother. 2013 Nov;9(11):2317-25. doi: 10.4161/hv.25562. Epub 2013 Jul 9.
• Leo YS, Wilder-Smith A, Archuleta S, Shek LP, Chong CY, Leong HN, Low CY, Oh ML, Bouckenooghe A, Wartel TA, Crevat D. Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore. Hum Vaccin Immunother. 2012 Sep;8(9):1259-71. doi: 10.4161/hv.21224. Epub 2012 Aug 16.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2009
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 14, 2014

Study Registration Dates

• First Submitted: April 13, 2009
• First Submitted That Met QC Criteria: April 13, 2009
• First Posted (Estimate): April 14, 2009

Study Record Updates

• Last Update Posted (Actual): March 21, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Dengue virus; Dengue fever; Dengue Hemorrhagic fever; Dengue diseases; Sanofi Pasteur's CYD Dengue Vaccine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Wounds and Injuries; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Body Temperature Changes; Heat Stress Disorders; Hyperthermia; Fever; Hemorrhagic Fevers, Viral; Dengue; Severe Dengue; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: CYD28; 2014-001713-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org