Persistence of Antibodies at 3, 4 and 6 Years of Age After Vaccination With Meningococcal, Pneumococcal and Hib Vaccines

Phase 3

Completed

Conditions: Neisseria Meningitidis
Haemophilus Influenzae Type b

Interventions: Biological: Pneumococcal conjugate vaccine GSK1024850A
Biological: MenitorixTM
Biological: MeningitecTM
Biological: NeisVac-CTM
Biological: InfanrixTM penta
Biological: InfanrixTM hexa
Biological: PrevenarTM
Biological: InfanrixTM IPV/Hib
Biological: InfanrixTM IPV

Registration Number: NCT00891176

Lead Sponsor: GlaxoSmithKline

Brief Summary: This protocol posting deals with objectives \& outcome measures of an extension phase when subjects are aged 3, 4 and 6 years of age. The objectives \& outcome measures of the primary phase are presented in a separate protocol posting (NCT number = NCT00334334). The objectives \& outcome measures of the booster phase are presented in a separate protocol posting (NCT number = NCT00463437).

The purpose of this study is to evaluate the persistence of pneumococcal, meningococcal serogroup C, Hib and Hepatits B antibodies after booster vaccination, when the subjects are aged 3, 4 and 6 years. No vaccine will be administered during this persistence phase of the study.

Detailed Description: This multicenter study is open. No vaccine will be administered during this persistence phase of the study. The subjects were randomized in the primary vaccination study 107005 and will not be further randomized in this study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 582

Inclusion Criteria

Subjects who 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, 36 and 40 months of age at the time of Visit 1; between, and including, 48 and 52 months of age at the time of Visit 2; and between, and including, 72 and 76 months of age at the time of Visit 3.
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.
Subjects who previously participated in the primary and booster studies, who received a full vaccination course with the vaccines corresponding to their group during the primary and booster studies and who were part, in the booster study, of the blood sampling subset.

Exclusion Criteria

Use of any investigational or non-registered product (drug or vaccine) within 30 days preceding the first blood sampling.
Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.
Administration of any additional meningococcal serogroup C, Hib, hepatitis B and pneumococcal vaccine since the end of the booster study
History of meningococcal serogroup C, Haemophilus influenzae type b, hepatitis B and invasive pneumococcal diseases since the end of booster study.
Any confirmed or suspected immunosuppressive or immunodeficient condition since the end of booster study, based on medical history and physical examination (no laboratory testing required).
Administration of immunoglobulins and/or any blood products within the three months preceding the first blood sampling.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Synflorix-Meningitec Group	Pneumococcal conjugate vaccine GSK1024850A	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age 2 primary doses of Meningitec intramuscularly into the lower left thigh at 2 and 4 months of age. 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Meningitec at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Synflorix-Meningitec Group	MeningitecTM	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age 2 primary doses of Meningitec intramuscularly into the lower left thigh at 2 and 4 months of age. 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Meningitec at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Synflorix-Menitorix Group	InfanrixTM penta	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Synflorix-NeisVac-C Group	Pneumococcal conjugate vaccine GSK1024850A	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 2 primary doses of Neis-Vac-C intramuscularly into the lower left thigh at 2 and 4 months of age and 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Neis-Vac-C at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Synflorix-NeisVac-C Group	NeisVac-CTM	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 2 primary doses of Neis-Vac-C intramuscularly into the lower left thigh at 2 and 4 months of age and 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Neis-Vac-C at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Prevenar-Menitorix Group	InfanrixTM IPV	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Prevenar intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Synflorix-NeisVac-C Group	InfanrixTM hexa	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 2 primary doses of Neis-Vac-C intramuscularly into the lower left thigh at 2 and 4 months of age and 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Neis-Vac-C at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Synflorix-NeisVac-C Group	InfanrixTM IPV/Hib	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 2 primary doses of Neis-Vac-C intramuscularly into the lower left thigh at 2 and 4 months of age and 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Neis-Vac-C at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Synflorix-Menitorix Group	Pneumococcal conjugate vaccine GSK1024850A	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Synflorix-Menitorix Group	InfanrixTM IPV	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Prevenar-Menitorix Group	Pneumococcal conjugate vaccine GSK1024850A	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Prevenar intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Synflorix-Meningitec Group	InfanrixTM hexa	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age 2 primary doses of Meningitec intramuscularly into the lower left thigh at 2 and 4 months of age. 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Meningitec at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Synflorix-Meningitec Group	InfanrixTM IPV/Hib	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age 2 primary doses of Meningitec intramuscularly into the lower left thigh at 2 and 4 months of age. 3 primary doses of Infanrix hexa intramuscularly into the upper left thigh at 2, 4 and 6 months of age. (In Poland subjects were offered a third dose of Meningitec at 7 months of age to comply with national recommendations). During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV/Hib was given instead of Infanrix hexa.
Prevenar-Menitorix Group	MenitorixTM	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Prevenar intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Synflorix-Menitorix Group	MenitorixTM	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Synflorix intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Prevenar-Menitorix Group	PrevenarTM	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Prevenar intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.
Prevenar-Menitorix Group	InfanrixTM penta	Subjects who received concomitantly in the primary study (NCT00334334): 3 primary doses of Prevenar intramuscularly into the right thigh at 2, 4 and 6 months of age, 3 primary doses of Menitorix intramuscularly into the lower left thigh at 2, 4 and 6 months of age and 3 primary doses of Infanrix penta intramuscularly into the upper left thigh at 2, 4 and 6 months of age. During the booster study (NCT00463437) subjects received the same vaccines as during the primary study at 11-18 months of age, with the exception of Spain, where Infanrix IPV was given instead of Infanrix penta.

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Titers Using Rabbit Complement (rSBA-MenC) Equal to or Above Cut-off Value	At 4 years of age	rSBA-MenC antibody cut-off value assessed was equal to or above 1:8. The rSBA-MenC assay was performed at the Public Health England (PHE) laboratory at 6 years of age while the GSK laboratory was used for testing at 3 and 4 years of age.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects With an rSBA-MenC Titer Equal to or Above Cut-off Value	At 4 years of age	rSBA-MenC antibody cut-off value assessed was equal to or above 1:128.
rSBA-MenC Titers	At 6 years of age	Titers are given as Geometric Mean Titers (GMTs).
Number of Subjects With Anti-polyribosyl-ribitol Phosphate (Anti-PRP) Antibody Concentrations Equal to or Above Cut-off Values	At 6 years of age	The cut-off values were defined as a concentration ≥ 0.15 microgram per milliliter (μg/mL) and ≥ 1.0 μg/mL.
Anti-PRP Concentrations	At 6 years of age	Concentrations were defined as Geometric Mean Concentrations (GMCs) in μg/mL
Antibody Concentrations Against Vaccine Pneumococcal Serotypes	At 6 years of age	Antibody concentrations were expressed as GMCs in μg/mL. Vaccine pneumococcal serotypes assessed included 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F.
Number of Subjects With Opsonophagocytic Activity	At 4 years of age	Opsonophagocytic activity was measured by a killing-assay. The results were presented as the dilution of serum (opsonic titer) able to sustain 50% killing of live pneumococci under the assay conditions. The cut-off of the assay was an opsonic titer of 8.
Concentration of Antibodies Against Protein D	At 6 years of age	Concentrations were expressed as GMCs in enzyme-linked immunosorbent-assay (ELISA) units per milliliter (EL.U/mL).
Number of Subjects With rSBA-MenC Titer Equal to or Above Cut-off Value	At 6 years of age	rSBA-MenC antibody cut-off value assessed was equal to or above 1:128.
Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values	At 3, 4 and 6 years of age	Cut-off values assessed were defined as equal to or above (≥) 6.2 milli-international units per milliliter (mIU/mL), 10 mIU/mL and 100 mIU/mL. Note: A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL) when tested by Enzyme-Linked Immunosorbent Assay (ELISA). The tables show both the results obtained by ELISA as well as updated results following complete retesting and reanalysis by a Chemiluminescence immunoassay (CLIA). Anti-HBs seroprotection was redefined as CLIA concentration above 10 mIU/mL.
Number of Subjects With Serious Adverse Events (SAEs)	From last study contact of the study (NCT00463437) at 17-24 months of age until 6 years of age	SAEs assessed include 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. Related = SAE assessed by the investigator as being related to the study procedures.
Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values as Measured by ELISA.	At 3 and 4 years of age	Cut-off values assessed were defined as equal to or above 10 milli-international units per milliliter (mIU/mL) or equal to or above 100 mIU/mL.
Anti-HBs Antibody Concentrations	At 3, 4 and 6 years of age	Concentrations were expressed as GMCs in mIU/mL. Note: A decrease in the specificity of the anti-HB ELISA assay had been observed in some studies for low levels of antibody (10-100 mIU/mL) when tested by ELISA. The tables show both the results obtained by ELISA as well as updated results following complete retesting and reanalysis by a Chemiluminescence immunoassay (CLIA).
Anti-HBs Antibody Concentrations as Measured by ELISA	At 3 and 4 years of age	Concentrations were expressed as GMCs in mIU/mL.