Study of a Booster Injection of Pentaxim™ Vaccine Administered With Dengue Vaccine in Healthy Toddlers

Study Overview
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Brief Summary
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The aim of the study was to assess whether the second CYD dengue vaccination could be administered concomitantly with the booster vaccination of a pediatric combination vaccine (Pentaxim™) during the same day visit but in 2 different sites of administration. Primary Objective: To demonstrate the non-inferiority of the antibody response against all antigens (diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b (Hib)) in participants receiving one booster dose of Pentaxim™ vaccine administered concomitantly with the second dose of CYD dengue vaccine compared to participants receiving one booster dose of Pentaxim™ vaccine administered concomitantly with placebo. Secondary Objectives: To describe the safety of Pentaxim™ vaccine administered concomitantly with the second dose of CYD dengue vaccine, or administered concomitantly with placebo. To describe the safety of the CYD dengue vaccine after the second dose of CYD dengue vaccine administered concomitantly with Pentaxim™ vaccine (at Visit 05) or administered alone (at Visit 06). To describe the safety of the CYD dengue vaccine in all participants after each dose. To describe the antibody response to each dengue virus serotype (post-Dose 2 and post-Dose 3) after the second dose of CYD dengue vaccine administered concomitantly with Pentaxim vaccine (at Visit 05) or administered alone (at Visit 06). To describe the antibody response to each dengue virus serotype post-Dose 2 and post-Dose 3.

Detailed Description
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Participants required 8 or 9 clinic visits and received a total of 7 injections. The dengue post-vaccinal viremia was assessed at Visit 2 from a subset of toddlers. The dengue immunogenicity was assessed 28 days after CYD dengue dose 2 and dose 3 from a subset of toddlers. Participants were followed-up for safety after each vaccine dose and for 6 months after the last dengue vaccination.

Official Title
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Immunogenicity and Safety of a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With Tetravalent Dengue Vaccine in Healthy Toddlers Aged 15 to 18 Months in Mexico

Conditions
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Dengue, Dengue Hemorrhagic Fever

Intervention / Treatment
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* Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus
* Biological: DTaP IPV//Hib vaccine
* Biological: Placebo
* Biological: Measles, mumps, and rubella vaccine
* Biological: Pneumococcal vaccine
* Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus
* Biological: DTaP IPV//Hib vaccine
* Biological: Placebo
* Biological: Measles, mumps, and rubella vaccine
* Biological: Pneumococcal vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 9 to 12 months on the day of inclusion. Born at full term of pregnancy (>= 37 weeks) and with a birth weight >= 2.5 kg. Participant in good health, based on medical history and physical examination. Documentation of completion of the primary vaccination series with Pentaxim vaccine with the 3 doses received between 2 and 8 months of age. Informed consent form had been signed and dated by both parents or other legally acceptable representative (and by 2 mandatory witnesses as required by local regulations). Participant and parent/guardian attended all scheduled visits and 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 any trial vaccination. Previous vaccination against flavivirus diseases, measles, mumps, rubella, previous booster vaccination against pneumococcal diseases, diphtheria, tetanus, pertussis, Hib and/or polio. 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). Personal seropositivity for human immunodeficiency virus (HIV) or hepatitis C as reported by the parent(s)/legally acceptable representative. History of pertussis and/or Hib infection as reported by the parent(s)/legally acceptable representative. Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances. History of contraindication to the receipt of vaccines containing components of Pentaxim vaccine (diphtheria toxoid, tetanus toxoid, pertussis toxoid, filamentous hemagglutinin, polyribosylribitol phosphate [PRP] and polio) or of measles, mumps and rubella vaccine and of pneumococcal vaccine. Thrombocytopenia, as reported by the parent(s)/legally acceptable representative. Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination. History of central nervous system disorder or disease, including seizures. 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 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.

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 12 Months

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYD Dengue Vaccine Group 1<br>Participants received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), a booster dose of Pentaxim vaccine was administered concomitantly with the second injection of CYD dengue vaccine at Month 6 (15 to 18 months of age), placebo at Month 7 (16 to 19 months of age) to maintain the blind, and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months). | Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus<br>* 0.5 mL, subcutaneous at age 9 to 12, 15 to 18 and 21 to 24 months.<br>* Other names: CYD Dengue Vaccine;Biological: DTaP IPV//Hib vaccine<br>* 0.5 mL, intramuscular<br>* Other names: Pentaxim™;Biological: Placebo<br>* 0.5 mL, subcutaneous<br>* Other names: NaCl;Biological: Measles, mumps, and rubella vaccine<br>* 0.5 mL, subcutaneous<br>* Other names: Trimovax®;Biological: Pneumococcal vaccine<br>* 0.5 mL, intramuscular<br>* Other names: Prevenar®;|
| Experimental: CYD Dengue Vaccine Group 2<br>Participants received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a MMR vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), the Pentaxim vaccine was administered concomitantly with placebo at Month 6 (15 to 18 months of age) to maintain the blind, a second injection of CYD dengue vaccine at Month 7 (16 to 19 months of age), and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months). | Biological: Live, attenuated, recombinant dengue serotype 1, 2, 3, and 4 virus<br>* 0.5 mL, subcutaneous at age 9 to 12, 16 to 19 and 21 to 24 months<br>* Other names: CYD Dengue Vaccine;Biological: DTaP IPV//Hib vaccine<br>* 0.5 mL, intramuscular<br>* Other names: Pentaxim™;Biological: Placebo<br>* 0.5 mL, subcutaneously<br>* Other names: NaCl;Biological: Measles, mumps, and rubella vaccine<br>* 0.5 mL, subcutaneous<br>* Other names: Trimovax®;Biological: Pneumococcal vaccine<br>* 0.5 mL, intramuscular<br>* Other names: Prevenar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroprotection or Booster Response After a Booster Injection (Inj.) of Diphtheria, Tetanus, Acellular Pertussis(DTaP)-Inactivated Polio Virus (IPV)//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine | Antibodies (Ab) against diphtheria, tetanus toxoid, pertussis toxoid (PT), and filamentous hemaglutinin (FHA) was measured by enzyme-linked immunosorbent assay (ELISA), polyribosylribitol phosphate (PRP) by Farr-type radioimmunoassay, and poliovirus types 1, 2, and 3 by seroneutralization assay. Seroprotection was defined as >=0.1 International Unit (IU)/mL for diphtheria toxoid and tetanus toxoid, >=8 1/dil for poliovirus types 1, 2, and 3, and >=1.0 μg/mL for PRP. Booster response to PT and FHA: participants whose pre-vaccination Ab titers were < lower limit of quantitation (LLOQ), a booster response occurred if they had post-vaccination levels >=4* LLOQ; participants whose pre-vaccination Ab concentrations were >=LLOQ but <4* LLOQ, a booster response occurred if they had a 4-fold increase (post/pre-vaccination levels >=4); for participants whose pre-vaccination Ab concentrations were >=4* LLOQ, a booster response occurred if they had a 2-fold increase (post/pre-vaccination >=2). | 28 days post-injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers Against Each Serotype With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine | Geometric mean titers of antibodies against the dengue virus serotypes were measured by dengue plaque reduction neutralization test (PRNT). | Pre-injection 1 and 28 days post-injection 2 and 3 | 
| Geometric Mean Titer Ratios Against Each Serotype With the Parental of Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine | Geometric mean titers of antibodies against the dengue virus serotypes were measured by dengue PRNT. | Pre-injection 1 and 28 days post-injection 2 and 3 | 
| Percentage of Participants With a Seropositivity Against Each Serotype With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly With CYD Dengue Vaccine | Seropositivity against each dengue virus serotype (parental strains) were measured by dengue PRNT. Seropositivity was defined as antibody titers >=10 (1/dilution). | Pre-injection 1 and 28 days post-injection 2 and 3 | 
| Percentage of Participants With Seropositivity Against at Least One, Two, Three, or Four Serotypes With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV// Hib (Pentaxim™) Administered With CYD Dengue Vaccine | Seropositivity against each dengue virus serotype (parental strains) were measured by dengue PRNT. Seropositivity was defined as antibody titers >=10 (1/dilution). | Pre-injection 1 and 28 days post-injection 2 and 3 | 
| Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following the First Injection With CYD Dengue Vaccine | Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability. Grade (Grd) 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 mm. Grade 3 Solicited systemic reactions: Fever: >39.5 degree Celsius (°C); Vomiting: >=6 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. | Day 0 up to Day 14 post-first injection | 
| Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following a Booster Injection of DTaP-IPV// Hib (Pentaxim™) Administered Concomitantly With Either CYD Dengue Vaccine or a Placebo Vaccine | 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 mm. Grade 3 Solicited systemic reactions: Fever: >39.5°C; Vomiting: >=6 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; and Extensive swelling, severe. | Day 0 up to Day 14 post-booster injection | 
| Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following a Second Injection of CYD Dengue Vaccine or a Placebo Vaccine | 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 mm. Grade 3 Solicited systemic reactions: Fever: >39.5°C; Vomiting: >=6 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. | Day 0 up to Day 14 post-second injection | 
| Percentage of Participants Reporting Solicited Injection-site and Systemic Reactions Following a Third Injection of CYD Dengue Vaccine | 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 mm. Grade 3 Solicited systemic reactions: Fever: >39.5°C; Vomiting: >=6 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. | Day 0 up to Day 14 post-third injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue, Dengue Hemorrhagic Fever, CYD Dengue Vaccines, Pentaxim™