Dose Ranging Study of Combined Haemophilus Influenzae Type B-Meningococcal Serogroups CY (Hib-MenCY-TT) Vaccine

Study Overview
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Brief Summary
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This study evaluated the safety and immunogenicity of 3 formulations of Hib-MenCY-TT vaccine compared to 2 control groups receiving licensed meningococcal serogroup C conjugate vaccine and/or licensed Hib conjugate vaccine administered at 2, 4, and 6 months of age. Antibody persistence and immune responses to polysaccharide vaccine boosters were additionally assessed at 11 to 14 months of age.

Official Title
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A Phase II, Open (Partially Double-blind), Randomised, Controlled, Multicentre, Primary Vaccination Study to Evaluate the Immunogenicity (Including Immune Memory), Reactogenicity and Safety of Three Different Formulations of the GSK Biologicals' Combined Haemophilus Influenzae Type B-meningococcal Serogroups CY Conjugate Vaccine Given Concomitantly With Infanrix® Penta and Prevenar®, Versus ActHIB® and Meningitec® Given Concomitantly With Infanrix® Penta and Versus ActHIB® Given Concomitantly With Infanrix® Penta and Prevenar® in Infants According to a 2-4-6 Month Schedule.

Conditions
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Haemophilus Influenzae Type b, Neisseria Meningitidis

Intervention / Treatment
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* Biological: Hib-MenCY-TT vaccine (MenHibrix)
* Biological: Meningitec®
* Biological: ActHIB®
* Biological: Infanrix® Penta
* Biological: Prevenar®
* Biological: Mencevax® ACWY
* Biological: PRP (Polyribosyl Ribitol Phosphate)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A male or female between, and including, 6 and 12 weeks (42-90 days) 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. Vaccinated against hepatitis B at birth. Born after a gestation period of 36 - 42 weeks. Exclusion criteria: Use of any investigational or non-registered 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 of immunosuppressants or other immune-modifying drugs since birth Any chronic drug therapy to be continued during the study period. Planned administration/ administration of a vaccine not foreseen by the study protocol within one month of the first dose of vaccine(s). Previous vaccination against diphtheria, tetanus, pertussis, polio, N. meningitidis of serogroups C and Y, Haemophilus influenzae type b or Streptococcus pneumoniae. History of or known exposure to diphtheria, tetanus, pertussis, polio, or invasive diseases due to N. meningitidis of serogroups C and Y, Haemophilus influenzae type b or Streptococcus pneumoniae. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection. A family history of congenital or hereditary immunodeficiency. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines. 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.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MenHibrix Formulation 1 Group<br>Subjects were primed with MenHibrix formulation 1 co-administered with Infanrix Penta and Prevenar according to a 2-4-6 months of age schedule, and received a polysaccharide challenge dose (1/5th dose of MenACWY polysaccharide vaccine co-administered with 10 µg dose of plain PRP) at 12 months of age. | Biological: Hib-MenCY-TT vaccine (MenHibrix)<br>* Three doses were administered intramuscularly (IM) in left thigh at Months 0,2 and 4 respectively<br>Biological: Infanrix® Penta<br>* Three doses were administered IM in right upper thigh at Months 0,2 and 4 respectively.<br>* Other names: DTPa-HBV-IPV vaccine;Biological: Prevenar®<br>* Three doses were administered IM in right lower thigh at Months 0,2 and 4 respectively.<br>Biological: Mencevax® ACWY<br>* One fifth of one dose was administered IM in deltoid region of right arm at Month 10 as booster.<br>Biological: PRP (Polyribosyl Ribitol Phosphate)<br>* One dose was administered IM in deltoid region of left arm at Month 10 as booster.<br>|
| Experimental: MenHibrix Formulation 2 Group<br>Subjects were primed with MenHibrix formulation 2 co-administered with Infanrix Penta and Prevenar according to a 2-4-6 months of age schedule, and received a polysaccharide challenge dose (1/5th dose of MenACWY polysaccharide vaccine co-administered with 10 µg dose of plain PRP) at 12 months of age. | Biological: Hib-MenCY-TT vaccine (MenHibrix)<br>* Three doses were administered intramuscularly (IM) in left thigh at Months 0,2 and 4 respectively<br>Biological: Infanrix® Penta<br>* Three doses were administered IM in right upper thigh at Months 0,2 and 4 respectively.<br>* Other names: DTPa-HBV-IPV vaccine;Biological: Prevenar®<br>* Three doses were administered IM in right lower thigh at Months 0,2 and 4 respectively.<br>Biological: Mencevax® ACWY<br>* One fifth of one dose was administered IM in deltoid region of right arm at Month 10 as booster.<br>Biological: PRP (Polyribosyl Ribitol Phosphate)<br>* One dose was administered IM in deltoid region of left arm at Month 10 as booster.<br>|
| Experimental: MenHibrix Formulation 3 Group<br>Subjects were primed with MenHibrix formulation 3 co-administered with Infanrix Penta and Prevenar according to a 2-4-6 months of age schedule, and received a polysaccharide challenge dose (1/5th dose of MenACWY polysaccharide vaccine co-administered with 10 µg dose of plain PRP) at 12 months of age. | Biological: Hib-MenCY-TT vaccine (MenHibrix)<br>* Three doses were administered intramuscularly (IM) in left thigh at Months 0,2 and 4 respectively<br>Biological: Infanrix® Penta<br>* Three doses were administered IM in right upper thigh at Months 0,2 and 4 respectively.<br>* Other names: DTPa-HBV-IPV vaccine;Biological: Prevenar®<br>* Three doses were administered IM in right lower thigh at Months 0,2 and 4 respectively.<br>Biological: Mencevax® ACWY<br>* One fifth of one dose was administered IM in deltoid region of right arm at Month 10 as booster.<br>Biological: PRP (Polyribosyl Ribitol Phosphate)<br>* One dose was administered IM in deltoid region of left arm at Month 10 as booster.<br>|
| Active Comparator: Menjugate Group<br>Subjects were primed with Menjugate co-administered with Infanrix Penta and ActiHIB according to a 2-4-6 months of age schedule, and received a polysaccharide challenge dose (1/5th dose of MenACWY polysaccharide vaccine co-administered with 10 µg dose of plain PRP) at 12 months of age. | Biological: Meningitec®<br>* Three doses were administered IM in right lower thigh at Months 0,2 and 4.<br>Biological: ActHIB®<br>* Three doses were administered IM in left thigh at Months 0,2 and 4.<br>Biological: Infanrix® Penta<br>* Three doses were administered IM in right upper thigh at Months 0,2 and 4 respectively.<br>* Other names: DTPa-HBV-IPV vaccine;Biological: Mencevax® ACWY<br>* One fifth of one dose was administered IM in deltoid region of right arm at Month 10 as booster.<br>Biological: PRP (Polyribosyl Ribitol Phosphate)<br>* One dose was administered IM in deltoid region of left arm at Month 10 as booster.<br>|
| Active Comparator: ActHIB Group<br>Subjects were primed with ActHIB co-administered with Infanrix Penta and Prevenar according to a 2-4-6 months of age schedule, and received a polysaccharide challenge dose (1/5th dose of MenACWY polysaccharide vaccine co-administered with 10 µg dose of plain PRP) at 12 months of age. | Biological: ActHIB®<br>* Three doses were administered IM in left thigh at Months 0,2 and 4.<br>Biological: Infanrix® Penta<br>* Three doses were administered IM in right upper thigh at Months 0,2 and 4 respectively.<br>* Other names: DTPa-HBV-IPV vaccine;Biological: Prevenar®<br>* Three doses were administered IM in right lower thigh at Months 0,2 and 4 respectively.<br>Biological: Mencevax® ACWY<br>* One fifth of one dose was administered IM in deltoid region of right arm at Month 10 as booster.<br>Biological: PRP (Polyribosyl Ribitol Phosphate)<br>* One dose was administered IM in deltoid region of left arm at Month 10 as booster.<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) Antibody Concentrations Greater Than or Equal to 1 Milligram Per Milliliter | The cut-off concentration assessed was 1 milligram per milliliter (mg/mL). | One month after primary vaccination (Month 5) | 
| Number of Subjects With Serum Bactericidal Activity Using Baby Rabbit Complement (rSBA)- Neisseria Meningitidis Serogroup C (MenC) Titers Greater Than or Equal to 1:8 | The cut-off titer assessed was a dilution of 1:8. Titers were expressed as the reciprocal of the dilution resulting in 50 percent inhibition. | One month after primary vaccination (Month 5) | 
| Number of Subjects With Serum Bactericidal Activity Using Baby Rabbit Complement (rSBA)- Neisseria Meningitidis Serogroup Y (MenY) Titers Greater Than or Equal to 1:8 | The cut-off titer assessed was a dilution of 1:8. Titers were expressed as the reciprocal of the dilution resulting in 50 percent inhibition. | One month after primary vaccination (Month 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Serum Bactericidal Activity Using Baby Rabbit Complement (rSBA)- Neisseria Meningitidis Serogroup C (MenC) Titers Greater Than or Equal to 1:8 | The cut-off titer assessed was a dilution of 1:8. Titers were expressed as the reciprocal of the dilution resulting in 50 percent inhibition. | Prior to vaccination (Day 0), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Serum Bactericidal Activity Using Baby Rabbit Complement (rSBA)- Neisseria Meningitidis Serogroup C (MenC) Titers | Titers were presented as geometric mean titers (GMTs) expressed as the reciprocal of the dilution resulting in 50 percent inhibition. | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Number of Subjects With rSBA-MenY Titers Greater Than or Equal to 1:8 | The cut-off titer assessed was a dilution of 1:8. Titers were expressed as the reciprocal of the dilution resulting in 50 percent inhibition. | Prior to vaccination (Day 0), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Serum Bactericidal Activity Using Baby Rabbit Complement (rSBA)- Neisseria Meningitidis Serogroup Y (MenY) Titers | Titers were presented as geometric mean titers (GMTs) expressed as the reciprocal of the dilution resulting in 50 percent inhibition. | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Number of Subjects With Anti-polysaccharide C (PSC) Antibody Concentration Greater Than or Equal to 30 Micrograms Per Milliliter (µg/mL) | The cut-off concentration assessed was 30 micrograms per milliliter (µg/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Anti-polysaccharide C (PSC) Antibody Concentration | Titers are presented as Geometric Mean Titers (GMTs) expressed as micrograms per milliliter (µg/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Number of Subjects With Anti-polysaccharide Y (PSY) Antibody Concentration Greater Than or Equal to 30 Micrograms Per Milliliter (µg/mL) | The cut-off concentration assessed was 30 micrograms per milliliter (µg/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Anti-polysaccharide Y (PSY) Antibody Concentration | Titers are presented as Geometric Mean Titers (GMTs) expressed as micrograms per milliliter (µg/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Number of Subjects With Anti-PRP Antibody Concentration Greater Than or Equal to Pre-defined Cut-off Values | The cut-off concentrations assessed were 0.15 micrograms per milliliter (µg/mL) and 1 µg/mL. | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Anti-PRP Antibody Concentration | Concentrations are presented as GMCs and expressed as µg/mL. | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5), before administration of the polysaccharide challenge dose (Month 10) and one month after administration of the polysaccharide challenge dose (Month 11) | 
| Number of Subjects Seroprotected for Anti-diphtheria Antibodies | Seroprotection is defined as anti-diphtheria toxoid antibody concentration greater than or equal to 0.1 International Units per Milliliter (IU/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti-diphtheria Antibody Concentrations | Concentrations are presented as GMCs and expressed as International Units per Milliliter (IU/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Seroprotected for Anti-tetanus Antibodies | Seroprotection is defined as anti-tetanus toxoid antibody concentration greater than or equal to 0.1 International Units per Milliliter (IU/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti-tetanus Antibody Concentrations | Concentrations are presented as GMCs and expressed as International Units per Milliliter (IU/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Seroseropositive for Anti-filamentus Haemagglutinin (FHA) Antibodies | Seropositivity is defined as anti-FHA antibody concentration greater than or equal to 5 Enzyme-Linked Immunosorbent Assay (ELISA) Units per Milliliter (EL.U/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti- FHA Antibody Concentrations | Concentrations are presented as GMCs and expressed as Enzyme-Linked Immunosorbent Assay (ELISA) Units per Milliliter (EL.U/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Seroseropositive for Anti-pertactin (PRN) Antibodies | Seropositivity is defined as anti-PRN antibody concentration greater than or equal to 5 Enzyme-Linked Immunosorbent Assay (ELISA) Units per Milliliter (EL.U/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti-PRN Antibody Concentrations | Concentrations are presented as GMCs and expressed as Enzyme-Linked Immunosorbent Assay (ELISA) Units per Milliliter (EL.U/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Seroseropositive for Anti-pertussis Toxoid (PT) Antibodies | Seropositivity is defined as anti-PT antibody concentration greater than or equal to 5 Enzyme-Linked Immunosorbent Assay (ELISA) Units per Milliliter (EL.U/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti- PT Antibody Concentrations | Concentrations are presented as GMCs and expressed as Enzyme-Linked Immunosorbent Assay (ELISA) Units per Milliliter (EL.U/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Seroprotected for Anti-hepatitis B (HBs) Antibodies | Seroprotection is defined as anti-HBs antibody concentration greater than or equal to 10 Milli-International Units per Milliliter (mIU/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti- HBs Antibody Concentrations | Concentrations are presented as GMCs and expressed as Milli-International Units per Milliliter (mIU/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Seroprotected for Anti-poliovirus Types 1, 2 and 3 Antibodies | Seroprotection is defined as anti-polio antibody titer greater than or equal to 1:8 dilution. | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti-poliovirus Types 1, 2 and 3 Antibody Titers | Titers are presented as GMTs and expressed in terms of the 50 % inhibitory dilution. | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects With Anti-pneumococcal Antibody Concentrations Greater Than or Equal to Pre-defined Cut-off Values | Pneumococcal antibodies assessed included anti-4, anti-6B, anti-9V, anti-14, anti-18C, anti-19F and anti-23F antibodies. The cut-off values assessed were 0.05 and 0.2 micrograms per milliliter (µg/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Anti-pneumococcal Antibody Concentrations | Pneumococcal antibodies assessed included anti-4, anti-6B, anti-9V, anti-14, anti-18C, anti-19F and anti-23F antibodies. Concentrations are presented as GMCs and expressed as micrograms per milliliter (µg/mL). | Prior to vaccination (Day 0), one month after the 3-dose primary vaccination course (Month 5) and before administration of the polysaccharide challenge dose (Month 10) | 
| Number of Subjects Reporting Solicited Local and General Symptoms During the Primary Vaccination Course | Solicited local symptoms assessed include pain, redness and swelling at the injection site. Solicited general symptoms assessed include drowsiness, irritability, loss of appetite and fever (rectal temperature greater than or equal to 38 degrees Celcius). | During the 8-Day (Day 0-7) follow-up period after any vaccine dose during the primary vaccination course | 
| Number of Subjects Reporting Solicited Local and General Symptoms After Administration of the Polysaccharide Challenge Dose | Solicited local symptoms assessed include pain, redness and swelling at the injection site. Solicited general symptoms assessed include drowsiness, irritability, loss of appetite and fever (rectal temperature greater than or equal to 38 degrees Celcius). | During the 8-Day (Day 0-7) follow-up period after the polysaccharide challenge dose | 
| Number of Subjects Reporting Unsolicited Adverse Events During the Primary Vaccination Course | 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) follow-up period after any vaccine dose during the primary vaccination course | 
| Number of Subjects Reporting Unsolicited Adverse Events After Administration of the Polysaccharide Challenge Dose | 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) follow-up period after administration of the polysaccharide challenge dose | 
| Number of Subjects Reporting Serious Adverse Events During the Primary Vaccination Course | Serious adverse events cover all 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. | Up to one month after the 3-dose primary vaccination course (Month 5) | 
| Number of Subjects Reporting Serious Adverse Events After Administration of the Polysaccharide Challenge Dose | Serious adverse events cover all 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. | Up to one month following administration of the polysaccharide challenge dose (Month 11) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invasive bacterial disease caused by Hib, Neisseria meningitidis serogroups C & Y