Hib-MenCY-TT Vaccine Study Compared to Licensed Hib and Meningococcal Serogroup C Conjugate Vaccines

Study Overview
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Brief Summary
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This study is evaluating the safety and immunogenicity of Hib-MenCY-TT vaccine compared to control groups receiving licensed Hib or MenC conjugate vaccines, each administered at 2, 4, 6, and 12 to 15 months of age. Co-administration with live, attenuated measles, mumps, and rubella combination vaccine; and with live, attenuated varicella vaccine will be assessed with administration of the booster dose. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, September 2007.

Detailed Description
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The study will be conducted in 2 stages: a 3-dose primary vaccination at 2, 4 and 6 months of age and a booster vaccination at 12 to 15 months of age. All subjects will have 3 blood samples taken. Half of the subjects of each group will have a blood sample taken just prior to the administration of the third dose of the primary vaccination and the other half of the subjects of each group will have a blood sample taken at one month after the third vaccine dose of the primary vaccination phase. In addition, all subjects of all groups will have a blood sample taken before and 42 days after administration of the booster dose.

Official Title
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A Multicentre Primary & Booster Vaccination Study of GSK Biologicals' Hib-MenCY-TT Conjugate Vaccine vs ActHIB® & MenC Conjugate Licensed Vaccine When Given According to the 2-4-6 Month Schedule to Healthy Infants With Booster Dose at 12 to 15 Months

Conditions
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Neisseria Meningitidis, Haemophilus Influenzae Type b

Intervention / Treatment
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* Biological: MenHibrix (Hib-MenCY-TT)
* Biological: Infanrix® Penta
* Biological: Prevenar®
* Biological: ActHIB®
* Biological: Meningitec®
* Biological: M-M-R®II
* Biological: Varivax®
* Biological: PedvaxHIB®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects for whom the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study. 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. Free of obvious health problems as established by medical history and clinical examination before entering into the study. Born after a gestation period between 36 and 42 weeks. 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 vaccine(s). Previous vaccination against Neisseria meningitidis, Haemophilus influenzae type b, diphtheria, tetanus, pertussis, poliovirus, and/or Streptococcus pneumoniae; more than one previous dose of hepatitis B vaccine. Vaccination with hepatitis B at birth is accepted (although not mandatory). Influenza vaccination is allowed 30 days after administration of the third vaccine dose to 30 days preceding the booster dose. History of Neisseria meningitidis, Haemophilus influenzae type b, diphtheria, tetanus, pertussis, hepatitis B, poliovirus, Streptococcus pneumoniae and/or varicella invasive disease. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s), including dry natural latex rubber, tetanus toxoid, diphtheria toxoid, neomycin, polymyxin. Major congenital defects or serious chronic illness. History of any neurologic disorders or seizures. Acute disease at the time of enrolment. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. Additional specific criteria for the booster part of the study History of or previous vaccination against measles, mumps, rubella or varicella. Previous booster vaccination with Hib or meningococcal serogroup C vaccine since the last visit of the primary phase.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 12 Weeks

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MenHibrix Group<br>Subjects primed in study 102370 with 3 doses of MenHibrix, Infanrix Penta and Prevenar vaccines and receiving a fourth dose of MenHibrix co-administered with M-M-RII and Varivax vaccines in study 102371. | Biological: MenHibrix (Hib-MenCY-TT)<br>* One intramuscular dose at 2, 4 and 6 months of age ( group A) and one intramuscular dose at 12 to 15 months of age (groups A and B)<br>Biological: Infanrix® Penta<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: Prevenar®<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: M-M-R®II<br>* One subcutaneous dose at 12-15 months of age<br>Biological: Varivax®<br>* One subcutaneous dose at 12 to 15 months of age<br>|
| Active Comparator: ActHIB + Meningitec Group<br>Subjects primed in study 102370 with 3 doses of ActHIB, Infanrix Penta, Prevenar and Meningitec vaccines and receiving a dose of MenHibrix co-administered with M-M-RII and Varivax vaccines in study 102371. | Biological: MenHibrix (Hib-MenCY-TT)<br>* One intramuscular dose at 2, 4 and 6 months of age ( group A) and one intramuscular dose at 12 to 15 months of age (groups A and B)<br>Biological: Infanrix® Penta<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: Prevenar®<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: ActHIB®<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: Meningitec®<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: M-M-R®II<br>* One subcutaneous dose at 12-15 months of age<br>Biological: Varivax®<br>* One subcutaneous dose at 12 to 15 months of age<br>|
| Active Comparator: ActHIB/PedvaxHIB Group<br>Subjects primed in study 102370 with 3 doses of ActHIB, Infanrix Penta and Prevenar vaccines and receiving a dose of PedvaxHIB co-administered with M-M-RII and Varivax vaccines in study 102371. | Biological: Infanrix® Penta<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: Prevenar®<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: ActHIB®<br>* One intramuscular dose at 2, 4 and 6 months of age<br>Biological: M-M-R®II<br>* One subcutaneous dose at 12-15 months of age<br>Biological: Varivax®<br>* One subcutaneous dose at 12 to 15 months of age<br>Biological: PedvaxHIB®<br>* One intramuscular dose at 12 to 15 months of age<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-polyribosyl-ribitol-phosphate (Anti-PRP) Concentration Greater Than or Equal to 1.0 Microgram Per Milliliter (µg/mL) | The analysis was performed on blood samples taken from half of the subjects in the MenHibrix and ActHIB/PedvaxHib groups only. The other half of the subjects in these study groups donated a blood sample after the second vaccine dose for analysis of the corresponding secondary outcome measure. | One month after the 3-dose primary vaccination course | 
| Number of Subjects With Meningococcal Polysaccharide C Serum Bactericidal Activity/Assay Using Baby Rabbit Complement (rSBA-MenC) Titer Greater Than or Equal to 1:128 | The analysis was performed on blood samples taken from half of the subjects in the MenHibrix and ActHIB + Meningitec groups only. The other half of the subjects in these study groups donated a blood sample after the second vaccine dose for analysis of the corresponding secondary outcome measure. | One month after the 3-dose primary vaccination course | 
| Number of Subjects Seroconverted for Anti-measles Antibodies | The analysis was performed on blood samples taken from the subjects in the MenHibrix and ActHIB groups only. Anti-measles seroconversion is defined as the appearance of antibodies (i.e. concentration greater than or equal to the cut-off value of 150 milli-international units per milliliter (mIU/mL)) in the serum of subjects seronegative (below 150 mIU/mL) before vaccination. | 42 days after the fourth dose vaccination | 
| Number of Subjects Seroconverted for Anti-mumps Antibodies | The analysis was performed on blood samples taken from the subjects in the MenHibrix and ActHIB groups only. Anti-mumps seroconversion is defined as titer greater than or equal to 28 ED50 in subjects seronegative (<28 ED50) before vaccination. ED50 is defined as the reciprocal of the sample dilution in the neutralising assay reducing the number of viral plaques by fifty percent. | 42 days after the fourth dose vaccination | 
| Number of Subjects With an Anti-rubella Seroresponse | The analysis was performed on blood samples taken from the subjects in the MenHibrix and ActHIB groups only. Anti-rubella seroresponse is defined as post-vaccination concentration greater than or equal to 10 IU/mL (ELISA, Enzygnost) in subjects seronegative (concentration below 4 IU/mL) before vaccination. | 42 days after the fourth dose vaccination | 
| Number of Subjects Seroconverted for Anti-varicella Antibodies | The analysis was performed on blood samples taken from the subjects in the MenHibrix and ActHIB groups only. Anti-varicella seroconversion is defined as post-vaccination titers greater than or equal to 1:5, in subjects seronegative (titers below 1:5) before vaccination. | 42 days after the fourth dose vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With rSBA-MenC Titer Greater Than or Equal to Pre-defined Cut-off Values | The analyses for post-Dose 2 and post-Dose 3 data were performed on blood samples taken from the respective half of the subjects at both time points. The cut-off values assessed were titers 1:8 and 1:128. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| rSBA-MenC Titers | The analyses for post-Dose 2 and post-Dose 3 data were performed on blood samples taken from the respective half of the subjects at both time points. Titers are given as Geometric Mean Titers. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With rSBA-MenY Titer Greater Than or Equal to Pre-defined Cut-off Values | The analyses for post-Dose 2 and post-Dose 3 data were performed on blood samples taken from the respective half of the subjects at both time points. The cut-off values assessed were titers 1:8 and 1:128. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| rSBA-MenY Titers | The analyses for post-Dose 2 and post-Dose 3 data were performed on blood samples taken from the respective half of the subjects at both time points. Titers are given as Geometric Mean Titers. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With Meningococcal Polysaccharide C Serum Bactericidal Activity/Assay Using Human Complement (hSBA-MenC) Antibody Titer Greater Than or Equal to Pre-defined Cut-off Values | The analysis for was performed on the first 30% of the blood samples taken at each time point. The cut-off values assessed were titers 1:4 and 1:8. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| hSBA-MenC Titers | The analysis for was performed on the first 30% of the blood samples taken at each time point. Titers are given as Geometric Mean Titers. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With Meningococcal Polysaccharide Y Serum Bactericidal Activity/Assay Using Human Complement (hSBA-MenY) Antibody Titer Greater Than or Equal to Pre-defined Cut-off Values | The analysis for was performed on the first 30% of the blood samples taken at each time point. The cut-off values assessed were titers 1:4 and 1:8. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| hSBA-MenY Titers | The analysis for was performed on the first 30% of the blood samples taken at each time point. Titers are given as Geometric Mean Titers. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With Anti-Polysaccharide C (Anti-PSC) Antibody Concentration Greater Than or Equal to Pre-defined Cut-off Values | The analysis for post-Dose 2 and post-Dose 3 data was performed on blood samples taken from the respective half of the subjects at both time points. The cut-off values assessed were 0.3 µg/mL and 2 µg/mL. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Anti-PSC Concentrations | The analysis for post-Dose 2 and post-Dose 3 data was performed on blood samples taken from the respective half of the subjects at both time points. Concentrations are given as Geometric Mean Concentrations. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With Anti-Polysaccharide Y (Anti-PSY) Antibody Concentration Greater Than or Equal to Pre-defined Cut-off Values | The analysis for post-Dose 2 and post-Dose 3 data was performed on blood samples taken from the respective half of the subjects at both time points. The cut-off values assessed were 0.3 µg/mL and 2 µg/mL. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Anti-PSY Concentrations | The analysis for post-Dose 2 and post-Dose 3 data was performed on blood samples taken from the respective half of the subjects at both time points. Concentrations are given as Geometric Mean Concentrations. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With Anti-PRP Antibody Concentration Greater Than or Equal to Pre-defined Cut-off Values | The analysis for post-Dose 2 and post-Dose 3 data was performed on blood samples taken from the respective half of the subjects at both time points. The cut-off values assessed were 0.15 µg/mL and 1.0 µg/mL. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Anti-PRP Concentrations | The analysis for post-Dose 2 and post-Dose 3 data was performed on blood samples taken from the respective half of the subjects at both time points. Concentrations are given as Geometric Mean Concentrations. | After the second vaccine dose (post-dose 2), one month after the 3-dose primary vaccination course (post-dose 3), just prior to (pre-dose 4) and 42 days after the fourth dose (post-dose 4) | 
| Number of Subjects With Anti-measles Concentration Greater Than or Equal to 150 mIU/mL | The cut-off value assessed was 150 mIU/mL. | Just prior to the fourth dose and 42 days after the fourth dose | 
| Number of Subjects With Anti-mumps Titer Greater Than or Equal to 24 ED50 | ED50 is defined as the reciprocal of the sample dilution in the neutralising assay reducing the number of viral plaques by fifty percent. | Just prior to the fourth dose and 42 days after the fourth dose | 
| Number of Subjects With Anti-rubella Concentration Greater Than or Equal to 4 IU/mL | The cut-off value assessed was 4 IU/mL. | Just prior to the fourth dose and 42 days after the fourth dose | 
| Number of Subjects With Anti-varicella Titer Greater Than or Equal to 1:5 | The cut-off value assessed was a titer of 1:5. | Just prior to the fourth dose and 42 days after the fourth dose | 
| Number of Subjects With a Fourth Dose Response for hSBA-MenC | Fourth dose response for hSBA-MenC is defined as: •For initially seronegative subjects (i.e., subjects with pre fourth dose hSBA antibody titer below 1:4), post fourth dose hSBA antibody titer greater than or equal to 1:16; •For initially seropositive subjects (i.e., subjects with pre fourth dose antibody titer greater than or equal to 1:4), post fourth dose hSBA antibody titer greater than or equal to 1:128. | 42 days after the fourth dose | 
| Number of Subjects With a Fourth Dose Response for hSBA-MenY | Fourth dose response for hSBA-MenY defined as: •For initially seronegative subjects (i.e., pre fourth dose hSBA antibody titer < 1:4), post fourth dose hSBA antibody titer greater than or equal to (≥) 1:16; •For initially seropositive subjects with pre fourth dose hSBA antibody titer ≥ 1:4 and < 1:64, post fourth dose hSBA antibody titer at least 4-fold higher than the pre fourth dose hSBA antibody titer; •For initially seropositive subjects with pre fourth dose hSBA antibody titer ≥ 1:64, post fourth dose hSBA antibody titer at least 2-fold higher than the pre fourth dose hSBA antibody titer. | 42 days after the fourth dose | 
| Number of Subjects With Anti-measles Concentration Greater Than or Equal to Predefined Cut-off Values in Initially Seronegative Subjects | The pre-defined cut-off values were 150 mIU/mL and 200 mIU/mL. Initially seronegative subjects are defined as subjects with pre-vaccination anti-measles concentration below 150 mIU/mL. | 42 days after the fourth dose | 
| Anti-measles Concentrations in Initially Seronegative Subjects | Concentrations are presented as Geometric Mean Concentrations expressed as mIU/mL. Initially seronegative subjects are defined as subjects with pre-vaccination anti-measles concentration below 150 mIU/mL. | 42 days after the fourth dose | 
| Number of Subjects With Anti-rubella Concentration Greater Than or Equal to Predefined Cut-off Values in Initially Seronegative Subjects | The pre-defined cut-off values were 4 IU/mL and 10 IU/mL. Initially seronegative subjects are defined as subjects with pre-vaccination anti-measles concentration below 4 IU/mL. | 42 days after the fourth dose | 
| Anti-rubella Concentrations in Initially Seronegative Subjects | Concentrations are presented as Geometric Mean Concentrations expressed as IU/mL. Initially seronegative subjects are defined as subjects with pre-vaccination anti-rubella concentration below 4 IU/mL. | 42 days after the fourth dose | 
| Number of Subjects With Anti-mumps Titer Greater Than or Equal to 28 ED50 in Subjects With Anti-mumps Titer Below 28 ED50 Before Vaccination | ED50 is defined as the reciprocal of the sample dilution in the neutralising assay reducing the number of viral plaques by fifty percent. | 42 days after the fourth dose | 
| Number of Subjects With Anti-mumps Titer Greater Than or Equal to Predefined Cut-off Values in Initially Seronegative Subjects | The pre-defined cut-off values were 28 ED50 and 51 ED50. Initially seronegative subjects are defined as subjects with pre-vaccination anti-mumps titer below 24 ED50. | 42 days after the fourth dose | 
| Anti-mumps Titers in Initially Seronegative Subjects | Titers are presented as Geometric Mean Titers expressed as ED50, the reciprocal of the sample dilution in the neutralising assay reducing the number of viral plaques by fifty percent. Initially seronegative subjects are defined as subjects with pre-vaccination anti-mumps titer below 24 ED50. | 42 days after the fourth dose | 
| Number of Subjects With Anti-varicella Titer Greater Than or Equal to Predefined Cut-off Values in Initially Seronegative Subjects | The pre-defined cut-off values were 1:5 and 1:40. Initially seronegative subjects are defined as subjects with pre-vaccination anti-varicella titer below 1:5. | 42 days after the fourth dose | 
| Anti-varicella Titers in Initially Seronegative Subjects | Titers are presented as Geometric Mean Titers. Initially seronegative subjects are defined as subjects with pre-vaccination anti-varicella titer below 1:5. | 42 days after the fourth dose | 
| Number of Subjects Reporting Solicited Local and General Symptoms During the Primary Vaccination Phase | Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include drowsiness, fever (rectal temperature greater than or equal to 38 degrees Celcius), irritability and loss of appetite. | During a 4-day period (Day 0-3) after any vaccine dose in the primary vaccination phase | 
| Number of Subjects Reporting Solicited Local and General Symptoms During the Fourth Dose Vaccination Phase | Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include drowsiness, fever (rectal temperature greater than or equal to 38 degrees Celcius), irritability and loss of appetite. | During a 4-day period (Day 0-3) after the fourth dose vaccination phase | 
| Number of Subjects Reporting Unsolicited Adverse Events | Unsolicited adverse event covers any adverse event 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. | During the 31-day (Day 0-30) post-primary and post-fourth dose vaccination period | 
| Number of Subjects Reporting Specific Solicited General AEs Related to Measles, Mumps, Rubella Vaccine and Varicella Vaccine | Specific solicited general symptoms assessed include fever (temperature greater than or equal to 38 degrees Celcius), meningismus/ febrile convulsion, parotid / salivary gland swelling and rash. | During a 43-day (Day 0-42) after the fourth dose | 
| Number of Subjects Reporting Serious Adverse Events (SAEs), New Onset of Chronic Illnesses (NOCI), Rash, Emergency Room Visits (ER), Physician Office Visits (PO) During the Primary Vaccination Phase | SAEs: medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. NOCI: e.g. autoimmune disorders, asthma, type I diabetes and allergies. Types of rash: hives, idiopathic thrombocytopenic purpura and petechiae. ER and PO visits assessed were not related to well-child care, vaccination, injury or common acute illnesses such as upper respiratory tract infection, otitis media, pharyngitis and gastroenteritis. | From enrolment through the day preceding the fourth dose | 
| Number of Subjects Reporting Serious Adverse Events (SAEs), New Onset of Chronic Illnesses (NOCI), Rash, Emergency Room Visits (ER), Physician Office Visits (PO) During the Fourth Dose Vaccination Phase | SAEs: medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. NOCI: e.g. autoimmune disorders, asthma, type I diabetes and allergies. Types of rash: hives, idiopathic thrombocytopenic purpura and petechiae. ER and PO visits assessed were not related to well-child care, vaccination, injury or common acute illnesses such as upper respiratory tract infection, otitis media, pharyngitis and gastroenteritis. | From the day of administration of the fourth dose until the end of the extended safety follow-up period (last study contact at 18-21 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invasive Hib & N. meningitidis diseases