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Study of Yellow Fever Vaccine Administered With Tetravalent Dengue Vaccine in Healthy Toddlers

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ClinicalTrials.gov Identifier: NCT01436396
Recruitment Status : Completed
First Posted : September 19, 2011
Results First Posted : July 29, 2019
Last Update Posted : July 29, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Sanofi Pasteur, a Sanofi Company )

Study Description
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Brief Summary:

The study was designed to evaluate whether the first CYD dengue vaccination can be administered concomitantly with Stamaril® yellow fever vaccine during the same day and visit, but at 2 different sites of administration.

Primary Objective:

  • To demonstrate the non-inferiority of the immune response against Yellow Fever (YF) in flavivirus (FV) non-immune subjects at baseline receiving one dose of Stamaril vaccine administered concomitantly with the first dose of CYD dengue vaccine compared to participants receiving one dose of Stamaril vaccine concomitantly with placebo.

Secondary Objectives:

  • To assess the non-inferiority of YF immune response 28 days post-Stamaril vaccination based on seroconversion rates regardless of the FV status of participants at baseline.
  • To describe the YF immune response 28 days post-Stamaril vaccination in both groups.
  • To describe the antibody (Ab) response to each dengue virus serotype 28 days post CYD dengue vaccine (Visit [V] 05 and V07), following CYD dengue vaccine Dose 1 and Dose 2 from Group 2 versus following CYD dengue vaccine Dose 2 and Dose 3 for Group 1 (effect of YF vaccination).
  • To describe the safety of Stamaril vaccine administered concomitantly with the first dose of CYD dengue vaccine, or Stamaril administered concomitantly with placebo.
  • To describe the safety of CYD dengue vaccine after the first dose of CYD dengue vaccine administered concomitantly with Stamaril vaccine or CYD vaccine administered alone.
  • To describe the safety of the CYD dengue vaccine in all participants after each dose.

Condition or disease Intervention/treatment Phase
Dengue Dengue Hemorrhagic Fever Yellow Fever Biological: Live, attenuated dengue serotype 1, 2, 3, and 4 virus Biological: Yellow fever vaccine Biological: Measles, mumps, and rubella (MMR) vaccine Biological: Pneumococcal Conjugated Vaccine Biological: Hepatitis A Pediatric Vaccine Biological: Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine Biological: Yellow Fever Vaccine Biological: Placebo (NaCl) Biological: Measles, mumps, and rubella vaccine Phase 3

Detailed Description:
All participants received a total of 9 injections during the study. Vaccine immunogenicity assessments for dengue neutralizing antibodies was performed in a randomized subset of participants. All participants were followed-up for safety during the study and for 6 months after the last CYD dengue vaccination.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 792 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: To ensure that objective safety data were obtained, the trial was designed using an observer-blind methodology since the products were visually different and may be recognized. For first trial vaccination (V01), the person who administered the injections knew which products were administered while either the participant or parent nor the Investigator in charge of safety evaluation knew which products were administered.
Primary Purpose: Prevention
Official Title: Immunogenicity and Safety of Yellow Fever Vaccine (Stamaril®) Administered Concomitantly With Tetravalent Dengue Vaccine in Healthy Toddlers at 12-13 Months of Age in Colombia and Peru
Actual Study Start Date : September 7, 2011
Actual Primary Completion Date : September 2013
Actual Study Completion Date : September 2, 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dengue Fever

Arms and Interventions
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Arm Intervention/treatment
Experimental: CYD Dengue Vaccine Group
Participants received the Stamaril® and the CYD dengue vaccine (Injection 1) at enrolment (Month [M] 0) at age 12 to 13 months; measles, mumps and rubella vaccine, pneumococcal conjugated vaccine, hepatitis A vaccine at M1 (age 13 to 14 months); CYD dengue vaccine (Injection 2) at M6 (age 18 to 19 months); diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenza type b (DTaP-IPV/Hib) vaccine at M7 (age 19 to 20 months); and CYD dengue vaccine (Injection 3) at M12 (age 24 to 25 months); and hepatitis A vaccine at M13 (age 25 to 26 months).
 Biological: Live, attenuated dengue serotype 1, 2, 3, and 4 virus
0.5 mL, subcutaneous at age 12, 18, and 24 months
Other Name: CYD Dengue Vaccine

Biological: Yellow fever vaccine
0.5 mL subcutaneous in the deltoid at age 12 to 13 months.
Other Name: Stamaril®

Biological: Measles, mumps, and rubella (MMR) vaccine
0.5 mL, subcutaneous at age 12 to 13 months.
Other Name: MMR vaccine

Biological: Pneumococcal Conjugated Vaccine
0.5 mL, intramuscular at age 13 to 14 months

Biological: Hepatitis A Pediatric Vaccine
0.5 mL, intramuscular at age 13 to 14 months and 25 to 26 months

Biological: Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine
0.5 mL, intramuscular at age 19 to 20 months
Other Name: DTaP IPV//Hib Vaccine
Experimental: Placebo Group
Participants received the Stamaril® vaccine and placebo matched to CYD vaccine (Injection 1) at enrolment (M0) (age 12 to 13 months); measles, mumps, and rubella vaccine, pneumococcal conjugate vaccine and hepatitis A vaccine at M1 (age 13 to 14 months); CYD dengue vaccine (Injection 2) at M6 (age 18 to 19 months); DTaP IPV/Hib vaccine at M7 (age19 to 20 months); and CYD dengue vaccine (Injection 3) at M12 (age 24 to 25 months); and hepatitis A vaccine at M13 (age 25 to 26 months).
 Biological: Live, attenuated dengue serotype 1, 2, 3, and 4 virus
0.5 mL, subcutaneous at age 18 to 19 and 24 to 25 months
Other Name: CYD dengue vaccine

Biological: Yellow Fever Vaccine
0.5 mL, subcutaneous at age 12 to 13 months
Other Name: Stamaril®

Biological: Placebo (NaCl)
0.5 mL, subcutaneous at age 12 to 13 months
Other Name: NaCl 0.9%

Biological: Measles, mumps, and rubella vaccine
0.5 mL, subcutaneous at age 13 to 14 months
Other Name: MMR vaccine

Biological: Pneumococcal Conjugated Vaccine
0.5 mL, intramuscular at age 13 to 14 months

Biological: Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine
0.5 mL, intramuscular at age 19 to 20 months
Other Name: DTaP IPV//Hib Vaccine

Biological: Hepatitis A Pediatric Vaccine
0.5 mL, intramuscular at age 13 to 14 months and 25 to 26 months


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Flavi Virus (FV) Non-immune Participants With Seroconversion Against YF Antigen After Vaccination With Yellow Fever (YF) Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: 28 days Post-Injection 1 ]
    Neutralizing antibodies against YF were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay. Seroconversion was defined as YF antibodies >=10 (1/dilution [dil]) in flavivirus non-immune participants (defined as those with YF antibodies <10 [1/dil] for all serotypes (Serotype 1, 2, 3 and 4) with parental dengue virus strains and for YF virus).


Secondary Outcome Measures :
  1. Percentage of All Participants With Seroconversion Against YF Antigen After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: 28 days Post-Injection 1 ]
    Neutralizing antibodies against YF were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay. Seroconversion was defined as YF antibodies >= 10 (1/dil) in participants YF-seronegative at baseline or 4-fold increase from pre- to post-YF antibody titers in participants YF-seropositive at baseline.

  2. Geometric Mean Titers (GMTs) of YF Antibodies in All Participants Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28-days Post-Injection 1 ]
    GMTs against YF were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay.

  3. Geometric Mean Titer Ratios (GMTRs) of YF Antibodies in All Participants Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28- days Post-Injection 1 ]
    GMTs ratios against YF were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay.

  4. Percentage of All Participants With YF Antibody Titers of >=10 (1/Dil) Before and After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28-days Post-Injection 1 ]
    Neutralizing antibodies against YF were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay. Seroconversion was defined as YF antibodies >=10 (1/dil) regardless of the flavivirus status of participants at baseline.

  5. GMTs of Dengue Virus Antibodies Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28-days Post-Injections 2 and 3 ]
    GMTs against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay.

  6. GMTRs of Dengue Virus Antibodies Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28-days Post-Injections 2 and 3 ]
    GMTRs against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay.

  7. Percentage of Participants With Antibody Titer >= 10 (1/Dil) Against Each Serotype With Parental Dengue Virus Strains After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28-days Post-Injections 2 and 3 ]
    Neutralizing antibodies against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay. Seroconversion was defined as antibody titers >= 10 (1/dil) against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains.

  8. Percentage of Participants With Antibody Titer >= 10 (1/Dil) Against at Least 1, 2, 3, or 4 Serotypes With Parental Dengue Virus Strains After YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28 days Post-Injections 2 and 3 ]
    Neutralizing antibodies against at least 1, 2, 3, or 4 serotypes (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay.

  9. GMTs of Dengue Virus Antibodies of FV Immune Participants Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28 days Post-Injections 2 and 3 ]
    GMTs against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay. FV immune participants at baseline were defined as those participants with >= 10 (1/dil) for at least 1 serotype with the parental dengue virus strain or for YF virus.

  10. GMTs of Dengue Virus Antibodies of FV-Non Immune (Naïve) Participants Following Vaccination With YF Vaccine Non Immune (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28 days Post-Injections 2 and 3 ]
    GMTs against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay. FV-non-immune participants at baseline were defined as those participants with <10 (1/dil) for all serotypes (Serotype 1, 2, 3 and 4) with parental dengue virus strains and for YF virus.

  11. Percentage of FV-immune Participants With Antibody Titer >= 10 (1/Dil) Against Each Serotype With Parental Dengue Virus Strains After YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28 days Post-Injections 2 and 3 ]
    Neutralizing antibodies against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay. FV-immune participants at baseline were defined as those participants with >= 10 (1/dil) for at least 1 serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strain or for YF virus.

  12. Percentage of FV Non-immune (Naïve) Participants With Antibody Titer >= 10 (1/Dil) Against Each Serotype With the Parental Dengue Virus Strains After YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Pre-Injection 1 and 28 days Post-Injections 2 and 3 ]
    Neutralizing antibodies against each serotype (Serotype 1, 2, 3 and 4) with the parental dengue virus strains were assessed using a dengue PRNT assay. FV non-immune participants at baseline were defined as those participants with <10 (1/dil) for all serotypes (Serotype 1, 2, 3 and 4) with parental dengue virus strains and for YF virus.

  13. Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Injection With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo [ Time Frame: Day 0 up to 14 days post any Inj., Post Inj. 1, Post Inj. 2 and Post Inj. 3 ]
    Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost and Irritability. Grade 3 Solicited injection site reactions: Tenderness: cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling: >=50 millimeter (mm). Grade 3 Solicited systemic reactions: Fever: >39.5°celsius; Vomiting: >= episodes per 24 hours or requiring parenteral hydration; Crying abnormal: >3 hours; Drowsiness: sleeping most of the time or difficult to wake up; Appetite lost: refuses >=3 feeds/meals or refuses most feeds/meals; Irritability: inconsolable. Solicited Injection site reaction were reported separately for Stamaril®, CYD and placebo vaccine.


Eligibility Criteria
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Ages Eligible for Study:   12 Months to 13 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Aged 12 to 13 months on the day of inclusion.
  • Born at full term of pregnancy (>=37 weeks) and with a birth weight >=2.5 kg as reported by the parent/legally acceptable representative.
  • Participant in good health, based on medical history and physical examination.
  • Participant had completed his/her vaccination schedule according to the official immunization calendar of Colombia and/or Peru, respectively.
  • Informed consent form had been signed and dated by the parent(s) or other legally acceptable representative (and by 2 independent witnesses if required by local regulations).
  • Participant and parent/legally acceptable representative/tutor able to attend all scheduled visits and to comply with all trial procedures.

Exclusion Criteria:

  • 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 first trial vaccination.
  • Previous vaccination against YF, hepatitis A, or measles, mumps and rubella.
  • 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 weeks or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months).
  • Personal known seropositivity for human immunodeficiency virus (HIV) as reported by the parent/legally acceptable representative.
  • History of previous maternal vaccination against YF as reported by the parent/legally acceptable representative.
  • Personal history of YF or dengue infection/disease as reported by the parent/legally acceptable representative.
  • Known systemic hypersensitivity to any of the vaccine components of the vaccines that were used in the trial, or history of a life-threatening reaction to the vaccines used in the trial or to vaccines containing any of the same substances.
  • History of contraindication to receipt of vaccines containing components of Stamaril® (yellow fever vaccine), measles, mumps and rubella vaccine, hepatitis A vaccine, pneumococcal conjugated vaccine or of diphtheria (D) toxoid, tetanus (T) toxoid, pertussis toxoid (PT), filamentous hemagglutinin (FHA), polyribosylribitol phosphate (PRP) and polio or other diphtheria, tetanus and pertussis vaccine (e.g., DTwP).
  • Thrombocytopenia, as reported by the parent/legally acceptable representative.
  • Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular (IM) vaccination.
  • History of central nervous system disorder or disease, including seizures.
  • Personal history of thymic pathology (e.g., thymoma), and/or thymectomy.
  • Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere with trial conduct or completion.
  • Identified as a child (adopted or natural) of the Investigator or of 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01436396


Locations
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Colombia
Cali, Colombia
Peru
Lima, Peru
Sponsors and Collaborators
Sanofi Pasteur, a Sanofi Company
Investigators
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Study Director: Medical Director Sanofi Pasteur Inc.
More Information
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Additional Information:

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Responsible Party: Sanofi Pasteur, a Sanofi Company
ClinicalTrials.gov Identifier: NCT01436396    
Other Study ID Numbers: CYD29
U1111-1116-4913 ( Other Identifier: WHO )
2014-001714-26 ( EudraCT Number )
First Posted: September 19, 2011    Key Record Dates
Results First Posted: July 29, 2019
Last Update Posted: July 29, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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://www.clinicalstudydatarequest.com
Keywords provided by Sanofi ( Sanofi Pasteur, a Sanofi Company ):
Dengue
Dengue Hemorrhagic Fever
CYD Dengue Vaccines
 Yellow Fever
Stamaril®
Flavivirus Infections
Additional relevant MeSH terms:
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Dengue
Hemorrhagic Fevers, Viral
Yellow Fever
Severe Dengue
Fever
Body Temperature Changes
Arbovirus Infections
 Virus Diseases
Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Vaccines
Immunologic Factors
Physiological Effects of Drugs