Safety and Immunogenicity Study of Hib-MenCY-TT Vaccine Compared to Licensed Hib Conjugate Vaccine

Study Overview
=================
Brief Summary
-----------------
This study evaluates the immunogenicity and consistency of 3 Hib-MenCY-TT vaccine lots and the safety and immunogenicity of Hib-MenCY-TT vaccine compared to a control group receiving licensed Hib conjugate vaccine, when each are co-administered with Pediarix® to healthy infants at 2, 4, and 6 months of age. The study will also evaluate the safety and immunogenicity of Hib-MenCY-TT vaccine compared to a control group receiving licensed Hib conjugate vaccine, when each are co-administered with M-M-R® II and Varivax® at 12 to 15 months of age.

Detailed Description
-----------------
The subjects from this study will participate in one of three cohorts: US Safety and Immunogenicity (Cohort 1): All immunogenicity analyses in the primary and booster phases will be evaluated in this cohort. These subjects will also contribute to the safety analyses in the primary and booster phases. Safety Only (Cohort 2): Only safety objectives will be assessed in the primary and booster phases for this cohort. Non-US Safety and Immunogenicity (Cohort 3): Only descriptive immunogenicity results in the primary and booster phases will be reported for this cohort. These subjects will also contribute to the safety analyses in the primary and booster phases. Treatment allocation: Primary phase: Subjects will be randomized with balanced allocation (1:1:1:1) to 1 of the 4 treatment groups and with a stratification according to the cohort. Assignment to a cohort will be based on study site. Booster phase: Subjects who received Hib-MenCY-TT vaccine in the primary phase will receive a booster dose of Hib-MenCY-TT vaccine. Subjects who received ActHIB in the primary phase will receive a booster dose of PedvaxHIB. During the 3-dose primary vaccination course, co-administration of Prevnar, Synagis, and/or rotavirus vaccine is permitted; co-administration of influenza vaccine is permitted at dose 3. During the booster vaccination, co-administration of Prevnar, hepatitis A vaccine and influenza vaccine is permitted for all subjects in Cohort 1, 2 and 3; and co-administration of measles, mumps, rubella and varicella vaccine is permitted for all subjects in Cohort 2 and 3. The study will be conducted in a double-blind fashion with regard to consistency of the 3 manufacturing lots of Hib-MenCY-TT vaccine and single-blind fashion for Hib-MenCY-TT vaccine versus monovalent Hib vaccine. The parents/guardians will be blinded up to collection of all data pertaining to the period up to one month after booster vaccination. Therefore, the extended safety follow-up after the booster dose will be conducted in an unblinded manner. The person administering the vaccines will ensure that the parent/guardian does not see the vaccine vial used in reconstituting the vaccine. Due to the differences in the presentations of the candidate Hib-MenCY-TT vaccine and control vaccines, it is not possible to blind study personnel who administer the vaccines.

Official Title
-----------------
A Phase III, Randomized, Multinational Study, Double-blinded for the Immunogenicity and Consistency Evaluation of 3 Hib-MenCY-TT Vaccine Lots and Single-blinded and Controlled for the Evaluation of Safety and Immunogenicity of GSK Biologicals' Haemophilus Influenzae Type b and Neisseria Meningitidis Serogroups C and Y-tetanus Toxoid Conjugate Vaccine Combined (Hib-MenCY-TT) Compared to Monovalent Hib Vaccine in Healthy Infants at 2, 4, 6, and 12 to 15 Months of Age.

Conditions
-----------------
Haemophilus Influenzae Type b, Neisseria Meningitidis

Intervention / Treatment
-----------------
* Biological: GSK Biologicals' Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine
* Biological: ActHIB
* Biological: PedvaxHIB
* Biological: Pediarix
* Biological: Prevnar
* Biological: M-M-R II
* Biological: Varivax


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects for whom the investigator believes that parents/guardians can and will comply with the requirements of the protocol A male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination. Written informed consent obtained from the parent or guardian of the subject. Healthy subjects as established by medical history and clinical examination before entering into the study. Born after 36 weeks gestation. Infants who have not received a previous dose of hepatitis B vaccine or those who have received only 1 dose of hepatitis B vaccine administered at least 30 days prior to enrollment. Infants may have received a birth dose of Bacillus Calmette-Guérin (BCG) vaccine. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs since birth. Planned administration/ administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of study vaccine(s). (Synagis® [palivizumab, MedImmune], Prevnar (Prevenar), rotavirus vaccine, and influenza vaccine are allowed. Previous vaccination against Neisseria meningitidis, Haemophilus influenzae type b, diphtheria, tetanus, pertussis, and/or poliovirus; more than one previous dose of hepatitis B vaccine. History of Neisseria meningitidis, Haemophilus influenzae type b, diphtheria, tetanus, pertussis, hepatitis B, and/or poliovirus disease. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination (no laboratory testing is required). History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, including dry natural latex rubber. Major congenital defects or serious chronic illness. History of any neurologic disorders or seizures. Acute disease at time of enrollment. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. Concurrent participation in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Additional specific criteria for the US subjects in Cohort 1. In addition, for Cohorts 2 and 3, subjects should not be administered M-M-R II and Varivax if any of these criteria apply: History of measles, mumps, rubella or varicella. Previous vaccination against measles, mumps, rubella or varicella. Hypersensitivity to any component of the vaccines, including gelatin or neomycin. Patients receiving immunosuppressive therapy. Individuals with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems. Individuals with primary and acquired immunodeficiency states. Individuals with a family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated. Individuals with active tuberculosis. Acute disease at time of booster vaccination.

Ages Eligible for Study
-----------------
Minimum Age: 6 Weeks
Maximum Age: 15 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Menhibrix A Group<br>Subjects were primed with 3 doses of Menhibrix vaccine Lot A co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm. | Biological: GSK Biologicals' Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: Pediarix<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age.<br>* Other names: Infanrix penta;Biological: Prevnar<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: M-M-R II<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age.<br>Biological: Varivax<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age<br>|
| Experimental: Menhibrix B Group<br>Subjects were primed with 3 doses of Menhibrix vaccine Lot B co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm. | Biological: GSK Biologicals' Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: Pediarix<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age.<br>* Other names: Infanrix penta;Biological: Prevnar<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: M-M-R II<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age.<br>Biological: Varivax<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age<br>|
| Experimental: Menhibrix C Group<br>Subjects were primed with 3 doses of Menhibrix vaccine Lot C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm. | Biological: GSK Biologicals' Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: Pediarix<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age.<br>* Other names: Infanrix penta;Biological: Prevnar<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: M-M-R II<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age.<br>Biological: Varivax<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age<br>|
| Experimental: Menhibrix Group<br>Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm. | Biological: GSK Biologicals' Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: Pediarix<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age.<br>* Other names: Infanrix penta;Biological: Prevnar<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>Biological: M-M-R II<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age.<br>Biological: Varivax<br>* 1 booster dose by subcutaneous injection at 12 to 15 months of age<br>|
| Active Comparator: ActHIB Group<br>Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm. | Biological: ActHIB<br>* 3-dose intramuscular injection at 2, 4 and 6 months of age.<br>Biological: PedvaxHIB<br>* 1 booster dose by intramuscular injection at 12 to 15 months of age.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Polyribosyl Ribitol Phosphate (PRP) Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Neisseria Meningitidis Serogroup C (MenC) Serum Bactericidal Assay Using Human Complement (hSBA) Antibody Titers | Titers were expressed as Geometric Mean Titers (GMTs) This analysis occured on the cohort 1 : Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Neisseria Meningitidis Serogroup Y (MenY) Serum Bactericidal Assay Using Human Complement (hSBA) Antibody Titers | Titers are expressen as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| hSBA-MenC Antibody Titers | Titers are expressed as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and 42 days after the fourth dose | 
| hSBA-MenY Antibody Titers | Titers are expressed as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and 42 days after the fourth dose | 
| Number of Subjects With Anti-PRP Antibody Concentration Equal to or Above 1.0 Microgram Per Milliliter (µg/mL) | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Number of Subjects With hSBA-MenC Titer Equal to or Above 1:8 | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after the fourth dose | 
| Number of Subjects With hSBA-MenY Titer Equal to or Above 1:8 | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after the fourth dose | 
| Number of Subjects With Anti-measles Antibody Concentrations Equal to or Above 150 Milli-international Units Per Milli-liter (mIU/ML) | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 150 mIU/mL. Co-administration with MMR-II vaccine | 42 days after the fourth dose | 
| Number of Subjects With Anti-PRP Antibody Concentration Equal to or Above 1.0 Microgram Per Milliliter | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after the fourth dose | 
| Number of Subjects With Anti-mumps Titer Equal to or Above 28 Estimated Dose 50 (ED50) | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-mumps antibody titers below 28 ED50 Co-administration with MMR-II vaccine. | 42 days after the fourth dose | 
| Number of Subjects With Anti-rubella Antibody Concentrations Equal to or Above 10 International Units Per Milli-litre (IU/mL) | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 4 IU/mL. Co-administration with MMR-II vaccine. | 42 days after the fourth dose | 
| Number of Subjects With Anti-varicella Titer Equal to or Above 1:5 | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody titer below 1:5. Co-administration with Varivax vaccine. | 42 days after the fourth dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-tetanus (Anti-T) and Anti-diphtheria Toxoid (Anti-D) Antibody Concentrations Equal to or Above 0.1 International Units Per Millilitre (IU/mL) | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Anti-D and Anti-T Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in international units per milliliter (IU/mL). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Number of Subjects With Anti Hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above 10.0 Milli-international Units Per Millilitre (mIU/mL) | Results are stratified by the presence or absence of a birth dose of hepatitis B vaccine. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Anti-HBS Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in milli-International units per milliliter (mIU/mL) Results are stratified by the presence or absence of a birth dose of hepatitis B vaccine. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Number of Subjects With Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibody Concentrations Equal to or Above 5 ELISA Units Per Millilitre (EL.U/mL) | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Anti-PT, Anti-FHA and Anti-PRN Antibody Concentrations | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Number of Subjects With Anti-poliovirus Types 1, 2 and 3 Equal to or Above 8 Estimated Dose 50 (ED50) | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Anti-poliovirus Types 1, 2 and 3 Titers | Titers are expressed as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Number of Subjects With Antibodies to Neisseria Meningitidis Serogroup C and Y Polysaccharide Capsule (Anti-PSC and Anti-PSY) Concentrations Equal to or Above the Cut-off Values | Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 microgram per milliliter (µg/mL) and >=2.0 µg/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Anti-PSC and Anti-PSY Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per milliliter (µg/mL) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after primary vaccination | 
| Number of Subjects With Anti-PRP Antibody Concentrations Equal to or Above the Cut-off Values | Anti-PRP antibody cut-off values assessed were >=0.15 microgram per milliliter (µg/mL) and >=1.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Number of Subjects With Anti-PRP Antibody Concentrations Equal to or Above the Cut-off Values | Anti-PRP antibody cut-off values assessed were >=0.15 microgram per milliliter (µg/mL) and >=1.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and one month after fourth dose vaccination | 
| Anti-PRP Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Anti-PRP Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and one month after fourth dose vaccination | 
| Number of Subjects With hSBA-MenC and hSBA-MenY Titers Equal to or Above the Cut-off Values | hSBA-MenC/Y antibody cut-off values assessed were >=1:4 and >=1:8 The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Number of Subjects With hSBA-MenC and hSBA-MenY Titers Equal to or Above the Cut-off Values | hSBA-MenC/Y antibody cut-off values assessed were >=1:4 and >=1:8. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and one month after fourth dose vaccination | 
| hSBA-MenC and hSBA-MenY Antibody Titers | Titres are expressed as Geometric Mean Titers (GMTs). The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| hSBA-MenC and hSBA-MenY Antibody Titers | Titers are expressed as Geometric Mean Titers (GMTs) The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and one month after fourth dose vaccination | 
| Number of Subjects With Anti-PSC and Anti-PSY Antibody Concentrations Equal to or Above the Cut-off Values | Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 microgram per milliliter (µg/mL) and >=2.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Number of Subjects With Anti-PSC and Anti-PSY Antibody Concentrations Equal to or Above the Cut-off Values | Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 µg/mL and >=2.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and one month after fourth dose vaccination | 
| Anti-PSC and Anti-PSY Antibodies Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per milliliter (µg/mL). The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Anti-PSC and Anti-PSY Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL). The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and one month after fourth dose vaccination | 
| Number of Subjects With Anti-PRP Antibody Concentrations Equal to or Above the Cut-off Value | Anti-PRP antibody cut-off values assessed were >=0.15 µg/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Anti-PRP Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after the primary vaccination course and prior to the fourth dose vaccination | 
| Number of Subjects With hSBA-MenC and hSBA-MenY Antibody Titers Equal to or Above the Cut-off Values | hSBA-MenC and hSBA-MenY antibody cut-off values assessed were >=1:4 and >=1:8. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | One month after the primary vaccination course | 
| Number of Subjects With Anti-PSC and Anti-PSY Antibody Concentrations Equal to or Above the Cut-off Values | Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 µg/mL and >=2.0 µg/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and 42 days after fourth dose vaccination | 
| Anti-PSC and Anti-PSY Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and 42 days after fourth dose vaccination | 
| Number of Subjects With Anti-PRP Antibody Concentrations Equal to or Above 0.15 Microgram Per Milliliter (µg/mL) | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and 42 days after fourth vaccination | 
| Anti-PRP Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth vaccination and 42 days after fourth vaccination | 
| Number of Subjects With hSBA-MenC and hSBA-MenY Antibody Concentrations Equal to or Above 1:4 | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination and 42 days after fourth vaccination | 
| Number of Subjects With Anti-measles Antibody Concentrations Equal to or Above 200 Milli-international Units Per Millilitre (mIU/mL) | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 150 mIU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Anti-measles Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in milli-international units per milliliter (mIU/mL). The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 150 mIU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Number of Subjects With Anti-mumps Titer Equal to or Above the Cut-off Values | Anti-mumps antibody cut-off values assessed were >=28 estimated dose 50 (ED50) and >=51 ED50. The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-mumps antibody titers below 24 ED50. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Anti-mumps Antibody Titers | Titers are expressed as Geometric Mean Titers (GMTs). The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody titers below 24 ED50. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Number of Subjects With Anti-rubella Antibody Concentrations Equal to or Above 4 International Units Per Millilitre (IU/mL) | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-rubella antibody concentrations below 4 IU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Anti-rubella Antibody Concentrations | Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in international units per milliliter (IU/mL). The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-rubella antibody concentrations below 4 IU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Number of Subjects With Anti-varicella Titer Equal to or Above 1:40 | The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-rubella antibody concentrations below 1:5 This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Anti-varicella Antibody Titers | Titers are expressed as Geometric Mean Titers (GMTs) The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-varicella antibody titers below 1:5 This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | 42 days after fourth vaccination | 
| Number of Subjects With Anti-H1N1, Anti-H3N2 and Anti-influenza-B (Anti B) Antibody Titers Equal to or Above 1:40 | anti-H1N1, anti-H3N2 and anti-influenza-B (anti B) antibody were measured by hemagglutination inhibition assay (HIA), in subjects who received 2 doses of influenza vaccine within the same influenza season of which at least one dose is concomitant with the study vaccine. For the purposes of this study, concomitant administration of influenza vaccine was defined as administration within 28 days before to 7 days after administration of study vaccines. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. | Prior to the fourth dose vaccination and one month after the fourth dose vaccination | 
| Number of Subjects Reporting Fever Above 39.5 Degrees Celsius/103.1 Degrees Fahrenheit | Fever is defined as temperature (rectal or axillary/tympanic) above 39.5 degrees Celsius (°C) or 103.1 degrees Fahrenheit (°F). | In the 4-day (Day 0-3) follow-up period after primary vaccination course | 
| Number of Subjects Reporting Fever Above 39.5 Degrees Celsius/103.1 Degrees Fahrenheit | Fever is defined as temperature (rectal or axillary/tympanic) above 39.5 degrees Celsius (°C) or 103.1 degrees Fahrenheit (°F). | In the 4-day (Day0-3) follow-up period after the fourth dose | 
| Number of Subjects Reporting Solicited Local and General Symptoms | Solicited local symptoms assessed were pain, redness and swelling. Solicited genral symptoms assessed were fever, irritability/fussiness, drowsiness and loss of appetite. Fever is defined as temperature (rectal or axillary/tympanic) equal to or above 38.0°C. | Within the 4 days (Day 0-3) following each dose of the primary vaccination course | 
| Number of Subjects Reporting Solicited Local and General Symptoms | Solicited local symptoms assessed were pain, redness, swelling and an increase in limb circumference. Solicited general symptoms assessed were fever, irritability/fussiness, drowsiness and lost of appetite. Fever is defined as temperature (rectal or axillary/tympanic) equal to or above 38.0°C | Within the 4 days (Day 0-3) post-vaccination period following the fourth dose | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | Within 31 days (Day 0-30) following the primary vaccination course | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | Within 31 days (Day 0-30) following the fourth dose | 
| Number of Subjects Reporting Increased Circumferential Swelling at the Injection Limb(s) | Increased circumferential swelling defined as either swelling with a diameter of >50 mm or a >50 mm increase in the circumference of the mid-limb when compared to the baseline (pre-vaccination) measurement, or any diffuse swelling that interferes with or prevents everyday activities (for example, active playing, eating, sleeping). | Within 4 days (Day 0 to Day 3) after fourth dose vaccination | 
| Number of Subjects Reporting General Symptoms Specific to Measles, Mumps, Rubella and Varicella Vaccination | Symptoms assessed were fever, rash/exanthem, parotid/salivary gland swelling, and any suspected signs of meningism including febrile convulsions. Fever is defined as temperature (rectal or axillary/tympanic) equal to or above 38.0°C. | Within 43 days (Day 0 through Day 42) after vaccination | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. | From Dose 0 through 6 months after the last primary dose or untill administration of the fourth dose | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. | From the fourth dose through the end of the 6-month safety follow-up | 
| Number of Subjects Reporting New Onset of Chronic Illness(es) (NOCDs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. | From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose | 
| Number of Subjects Reporting New Onset of Chronic Illness(es) (NOCDs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. | From the fourth dose through the end of the 6-month safety follow-up | 
| Number of Subjects Reporting Rash | Rash assessed was hives, idiopathic thrombocytopenic purpura, petechiae. | From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose | 
| Number of Subjects Reporting Rash | Rash assessed was hives, idiopathic thrombocytopenic purpura, petechiae. | From the fourth dose through the end of the 6-month safety follow-up | 
| Number of Subjects Reporting Adverse Events Resulting in Emergency Room (ER) Visits | Emergency room (ER) visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis. | From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose | 
| Number of Subjects Reporting Adverse Events Resulting in Physicians (MD) Office Visits. | Physicians (MD) office visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis. | From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose | 
| Number of Subjects Reporting Adverse Events Resulting in Emergency Room (ER) Visits | Emergency room (ER) visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis. | From the fourth dose through the end of the 6-month safety follow-up | 
| Number of Subjects Reporting Adverse Events Resulting in Physicians (MD) Office Visits | Physicians (MD) office visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis. | From the fourth dose through the end of the 6-month safety follow-up | 
| Number of Subjects With Anti-PRP Antibody Concentration Equal to or Above 1.0 Microgram Per Milliliter (µg/mL). | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination | 
| Number of Subjects With hSBA-MenC and hSBA-MenY Antibody Titer Equal to or Above 1:8. | This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis. | Prior to the fourth dose vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Primary and booster vaccination, Neisseria meningitidis, Hib disease, Meningococcal vaccine, Meningococcal disease, Children, Immunogenicity, Safety, Infants