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

Persistence of Antibodies After Full Vaccination Course With GSK Biologicals' Menitorix or MenC Conjugate Vaccine, Co-administered With DTPa or DTPa/Hib Containing Vaccine and Pneumococcal Conjugate Vaccine, in Children up to 6 Years of Age

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.

Study Overview

• Status: Completed
• Conditions: Neisseria Meningitidis; Haemophilus Influenzae Type b
• Intervention / Treatment: Biological: Pneumococcal conjugate vaccine GSK1024850A; Biological: MeningitecTM; Biological: InfanrixTM hexa; Biological: InfanrixTM IPV/Hib; Biological: NeisVac-CTM; Biological: MenitorixTM; Biological: InfanrixTM penta; Biological: InfanrixTM IPV; Biological: PrevenarTM

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.

• Study Type: Interventional
• Enrollment (Actual): 582
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14197
    • GSK Investigational Site
  • Berlin, Germany, 13355
    • GSK Investigational Site
  • Baden-Wuerttemberg
    • Bad Saulgau, Baden-Wuerttemberg, Germany, 88348
      • GSK Investigational Site
    • Bretten, Baden-Wuerttemberg, Germany, 75015
      • GSK Investigational Site
    • Ettenheim, Baden-Wuerttemberg, Germany, 77955
      • GSK Investigational Site
    • Karlsruhe, Baden-Wuerttemberg, Germany, 76189
      • GSK Investigational Site
    • Kehl, Baden-Wuerttemberg, Germany, 77694
      • GSK Investigational Site
    • Mannheim, Baden-Wuerttemberg, Germany, 68163
      • GSK Investigational Site
    • Oberstenfeld, Baden-Wuerttemberg, Germany, 71720
      • GSK Investigational Site
    • Schwaebisch-Hall, Baden-Wuerttemberg, Germany, 74523
      • GSK Investigational Site
    • Tettnang, Baden-Wuerttemberg, Germany, 88069
      • GSK Investigational Site
  • Bayern
    • Muenchen, Bayern, Germany, 81735
      • GSK Investigational Site
    • Muenchen, Bayern, Germany, 81675
      • GSK Investigational Site
    • Noerdlingen, Bayern, Germany, 86720
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Hille, Nordrhein-Westfalen, Germany, 32479
      • GSK Investigational Site
    • Loehne, Nordrhein-Westfalen, Germany, 32584
      • GSK Investigational Site
    • Muenster, Nordrhein-Westfalen, Germany, 48163
      • GSK Investigational Site
    • Porta Westfalica, Nordrhein-Westfalen, Germany, 32457
      • GSK Investigational Site
  • Rheinland-Pfalz
    • Frankenthal, Rheinland-Pfalz, Germany, 67227
      • GSK Investigational Site
    • Trier, Rheinland-Pfalz, Germany, 54290
      • GSK Investigational Site
  • Sachsen
    • Doebeln, Sachsen, Germany, 04720
      • GSK Investigational Site
  • Thueringen
    • Lobenstein, Thueringen, Germany, 07356
      • GSK Investigational Site
    • Weimar, Thueringen, Germany, 99425
      • GSK Investigational Site
• Poland
  • Debica, Poland, 39-200
    • GSK Investigational Site
  • Krakow, Poland
    • GSK Investigational Site
  • Siemianowice Slaskie, Poland, 41-103
    • GSK Investigational Site
• Spain
  • Madrid, Spain, 28040
    • GSK Investigational Site
  • Móstoles/Madrid, Spain, 28935
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Synflorix-Meningitec Group; 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.	Biological: Pneumococcal conjugate vaccine GSK1024850A; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.; Biological: MeningitecTM; Intramuscular injection into the thigh as primary vaccination at 2 and 4 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study; Biological: InfanrixTM hexa; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age (all countries) and as booster dose at 11-18 months of age (Germany and Poland). No vaccine was administered during this long-term follow up study; Biological: InfanrixTM IPV/Hib; Intramuscular injection into the thigh as booster dose at 11-18 months of age (Spain). No vaccine was administered during this long-term follow up study
Experimental: Synflorix-NeisVac-C Group; 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.	Biological: Pneumococcal conjugate vaccine GSK1024850A; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.; Biological: InfanrixTM hexa; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age (all countries) and as booster dose at 11-18 months of age (Germany and Poland). No vaccine was administered during this long-term follow up study; Biological: InfanrixTM IPV/Hib; Intramuscular injection into the thigh as booster dose at 11-18 months of age (Spain). No vaccine was administered during this long-term follow up study; Biological: NeisVac-CTM; Intramuscular injection into the thigh as primary vaccination at 2 and 4 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study
Experimental: Synflorix-Menitorix Group; 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.	Biological: Pneumococcal conjugate vaccine GSK1024850A; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.; Biological: MenitorixTM; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.; Biological: InfanrixTM penta; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age (all countries) and as booster dose at 11-18 months of age (Germany and Poland). No vaccine was administered during this long-term follow up study; Biological: InfanrixTM IPV; Intramuscular injection into the thigh as booster dose at 11-18 months of age (Spain). No vaccine was administered during this long-term follow up study
Active Comparator: Prevenar-Menitorix Group; 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.	Biological: Pneumococcal conjugate vaccine GSK1024850A; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.; Biological: MenitorixTM; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.; Biological: InfanrixTM penta; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age (all countries) and as booster dose at 11-18 months of age (Germany and Poland). No vaccine was administered during this long-term follow up study; Biological: InfanrixTM IPV; Intramuscular injection into the thigh as booster dose at 11-18 months of age (Spain). No vaccine was administered during this long-term follow up study; Biological: PrevenarTM; Intramuscular injection into the thigh as primary vaccination at 2, 4 and 6 months of age and as booster dose at 11-18 months of age. No vaccine was administered during this long-term follow up study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Titers Using Rabbit Complement (rSBA-MenC) Equal to or Above Cut-off Value	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.	At 3 years of age
Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Titers Using Rabbit Complement (rSBA-MenC) Equal to or Above Cut-off Value	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.	At 6 years of age
Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Titers Using Rabbit Complement (rSBA-MenC) Equal to or Above Cut-off Value	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.	At 4 years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With an rSBA-MenC Titer Equal to or Above Cut-off Value	The cut-off value was defined as a titer equal to or above 1:128.	At 3 years of age
rSBA-MenC Titers	Titers are given as Geometric Mean Titers (GMTs).	At 3 years of age
Number of Subjects With Anti-polyribosyl-ribitol Phosphate (Anti-PRP) Antibody Concentrations Equal to or Above Cut-off Values	The cut-off values were defined as a concentration equal to or above 0.15 microgram per milliliter (μg/mL) and equal to or above 1.0 μg/mL.	At 3 years of age
Anti-PRP Concentrations	Concentrations were defined as Geometric Mean Concentrations (GMCs) in μg/mL,	At 3 years of age
Antibody Concentrations Against Vaccine Pneumococcal Serotypes	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.	At 3 years of age
Number of Subjects With Opsonophagocytic Activity	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 titre of 8.	At 3 years of age
Concentration of Antibodies Against Protein D	Concentrations were expressed as GMCs in enzyme-linked immunosorbent-assay (ELISA) units per milliliter (EL.U/mL).	At 3 years of age
Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values	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.	At 3 years of age
Anti-HBs Antibody Concentrations	Concentrations were expressed as GMCs in mIU/mL.	At 3 years of age
Number of Subjects With Serious Adverse Events (SAEs)	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.	From last study contact of the study (NCT00463437) at 17-24 months of age until 3 years of age
rSBA-MenC Titers	Titers are given as Geometric Mean Titers (GMTs).	At 4 years of age
Number of Subjects With an rSBA-MenC Titer Equal to or Above Cut-off Value	rSBA-MenC antibody cut-off value assessed was equal to or above 1:128.	At 4 years of age
Number of Subjects With Anti-polyribosyl-ribitol Phosphate (Anti-PRP) Antibody Concentrations Equal to or Above Cut-off Values	The cut-off values were defined as a concentration equal to or above 0.15 microgram per milliliter (μg/mL) and equal to or above 1.0 μg/mL.	At 4 years of age
Anti-PRP Concentrations	Concentrations were defined as Geometric Mean Concentrations (GMCs) in μg/mL	At 4 years of age
Antibody Concentrations Against Vaccine Pneumococcal Serotypes	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.	At 4 years of age
Number of Subjects With Opsonophagocytic Activity	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.	At 4 years of age
Concentration of Antibodies Against Protein D	Concentrations were expressed as GMCs in enzyme-linked immunosorbent-assay (ELISA) units per milliliter (EL.U/mL).	At 4 years of age
Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values	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.	At 4 years of age
Anti-HBs Antibody Concentrations	Concentrations were expressed as GMCs in mIU/mL.	At 4 years of age
Number of Subjects With Serious Adverse Events (SAEs)	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.	From last study contact of the study (NCT00463437) at 17-24 months of age until 4 years of age
Number of Subjects With rSBA-MenC Titer Equal to or Above Cut-off Value	rSBA-MenC antibody cut-off value assessed was equal to or above 1:128.	At 6 years of age
rSBA-MenC Titers	Titers are given as Geometric Mean Titers (GMTs).	At 6 years of age
Number of Subjects With Anti-polyribosyl-ribitol Phosphate (Anti-PRP) Antibody Concentrations Equal to or Above Cut-off Values	The cut-off values were defined as a concentration ≥ 0.15 microgram per milliliter (μg/mL) and ≥ 1.0 μg/mL.	At 6 years of age
Anti-PRP Concentrations	Concentrations were defined as Geometric Mean Concentrations (GMCs) in μg/mL	At 6 years of age
Antibody Concentrations Against Vaccine Pneumococcal Serotypes	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.	At 6 years of age
Concentration of Antibodies Against Protein D	Concentrations were expressed as GMCs in enzyme-linked immunosorbent-assay (ELISA) units per milliliter (EL.U/mL).	At 6 years of age
Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values as Measured by ELISA.	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.	At 3 and 4 years of age
Anti-HBs Antibody Concentrations as Measured by ELISA	Concentrations were expressed as GMCs in mIU/mL.	At 3 and 4 years of age
Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations Equal to or Above Cut-off Values	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.	At 3, 4 and 6 years of age
Anti-HBs Antibody Concentrations	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).	At 3, 4 and 6 years of age
Number of Subjects With Serious Adverse Events (SAEs)	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.	From last study contact of the study (NCT00463437) at 17-24 months of age until 6 years of age

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Tejedor JC, Brzostek J, Konior R, Grunert D, Kolhe D, Baine Y, Van Der Wielen M. Antibody Persistence in Young Children 5 Years after Vaccination with a Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C Conjugate Vaccine Coadministered with Diphtheria-Tetanus-Acellular Pertussis-Based and Pneumococcal Conjugate Vaccines. Clin Vaccine Immunol. 2016 Jul 5;23(7):555-63. doi: 10.1128/CVI.00057-16. Print 2016 Jul.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: May 14, 2009
• Primary Completion (Actual): November 21, 2012
• Study Completion (Actual): November 21, 2012

Study Registration Dates

• First Submitted: April 30, 2009
• First Submitted That Met QC Criteria: April 30, 2009
• First Posted (Estimate): May 1, 2009

Study Record Updates

• Last Update Posted (Actual): February 15, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2017
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Antibody persistence; Pneumococcal vaccine; Conjugate vaccines; Meningococcal serogroup C vaccine; Haemophilus Influenzae type b vaccine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunologic Factors; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: 112830

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Statistical Analysis Plan
   Information identifier: 112830
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Dataset Specification
   Information identifier: 112830
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Individual Participant Data Set
   Information identifier: 112830
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Informed Consent Form
   Information identifier: 112830
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Study Protocol
   Information identifier: 112830
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: 112830
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register