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

Phase 3

Completed

Conditions: Dengue Hemorrhagic Fever
Dengue
Yellow Fever

Interventions: Biological: Live, attenuated dengue serotype 1, 2, 3, and 4 virus
Biological: Yellow Fever Vaccine
Biological: Measles, mumps, and rubella (MMR) vaccine
Biological: Placebo (NaCl)
Biological: Pneumococcal Conjugated Vaccine
Biological: Measles, mumps, and rubella vaccine
Biological: Hepatitis A Pediatric Vaccine
Biological: Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine

Registration Number: NCT01436396

Lead Sponsor: Sanofi Pasteur, a Sanofi Company

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 792

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CYD Dengue Vaccine Group	Live, attenuated dengue serotype 1, 2, 3, and 4 virus	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).
CYD Dengue Vaccine Group	Yellow Fever Vaccine	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).
Placebo Group	Live, attenuated dengue serotype 1, 2, 3, and 4 virus	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).
CYD Dengue Vaccine Group	Pneumococcal Conjugated Vaccine	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).
CYD Dengue Vaccine Group	Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine	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).
Placebo Group	Pneumococcal Conjugated Vaccine	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).
CYD Dengue Vaccine Group	Measles, mumps, and rubella (MMR) vaccine	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).
CYD Dengue Vaccine Group	Hepatitis A Pediatric Vaccine	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).
Placebo Group	Diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae vaccine	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).
Placebo Group	Yellow Fever Vaccine	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).
Placebo Group	Measles, mumps, and rubella vaccine	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).
Placebo Group	Hepatitis A Pediatric Vaccine	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).
Placebo Group	Placebo (NaCl)	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).

Primary Outcome Measures

Name	Time	Method
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	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

Name	Time	Method
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	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.
GMTRs of Dengue Virus Antibodies Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo	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.
GMTs of Dengue Virus Antibodies of FV Immune Participants Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo	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.
Percentage of All Participants With Seroconversion Against YF Antigen After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo	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.
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	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.
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	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.
GMTs of Dengue Virus Antibodies Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo	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.
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	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.
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	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.
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	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.
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	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.
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	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.
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	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.