A Dose Ranging Safety and Immunogenicity Study of GlaxoSmithKline (GSK) Biologicals' GSK1557484A Vaccine in Children 6 to Less Than 36 Months of Age

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and immunogenicity of different formulations of GSK Biologicals' influenza candidate vaccine GSK1557484A, in children 6-35 months of age.

Detailed Description
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Safety and immunogenicity of different formulations administered as a 2-dose schedule in children 6-35 months of age will be evaluated. In addition, the quality of the 2-dose priming will be assessed through the anamnestic response elicited by an antigen challenge (unadjuvanted H5N1) administered 12 months later. The persistence of the immune response approximately 12 months (Day 385) after dose 2 will also be evaluated. Subjects from each group will be enrolled into the CMI sub-cohort comprising of approximately 100 subjects. Within the participating country(ies), these subjects will be enrolled in only selected/qualified sites.

Official Title
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An Observer-blind, Dose Ranging Safety and Immunogenicity Study of GSK Biologicals' GSK1557484A Vaccine in Children 6 to Less Than 36 Months of Age

Conditions
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Influenza

Intervention / Treatment
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* Biological: Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A).


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject's parent(s)/ Legally Acceptable Representative(s) [LAR(s)] who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Male or female children 6 months to less than 36 months old at the time of the first vaccination. Children who are not 36 months old as of Day 0, the day of first vaccine dose under this protocol, can be enrolled. Written informed consent obtained from the parent(s)/legally acceptable representative(s) [LAR(s)] of the subject prior to performance of any study specific procedure. Healthy subjects as established by medical history and standard physical examination before entering into the study. Born full-term to be confirmed by interview with parent/LAR or available medical records. Exclusion Criteria: Child in care. Medical history of physician-confirmed infection with an H5N1 virus. Previous vaccination at any time with an H5N1 vaccine. Concurrently participating in another clinical study, or use of an investigational or a non-registered vaccine, pharmaceutical product, or device within 30 days preceding the first dose of study vaccine, or planned use during the study period. Presence in the parent(s) / LAR(s) of evidence of substance abuse or of neurological or psychiatric diagnoses which, even if stable, are deemed by the investigator to render the parent(s)/LAR(s) unable/unlikely to provide accurate safety reports. Acute disease and/or fever at the time of enrolment. Administration of immunoglobulins, any blood products, or long-acting immune-modifying drugs during the period starting 3 months before the first dose of study vaccine, or planned administration during the study period. History of any neurological disorders or seizures, or Guillain-Barré Syndrome. Diagnosed with excessive daytime sleepiness or narcolepsy; or history of narcolepsy in a subject's parent or sibling. Administration of an inactive vaccine within 14 days or of a live attenuated vaccine within 30 days before the first vaccination. Planned administration of any vaccine not foreseen by the study protocol between Day 0 and Day 42 or planned administration of an inactive vaccine within 14 days or of a live attenuated vaccine within 30 days before through 30 days after the booster vaccination. Note: routine vaccinations may be provided on Day 42 after all study assessments have been performed. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine; a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine. Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine. For corticosteroids, this will mean a dose of prednisone or equivalent of > 2 mg/kg/day of body weight or ≥ 20 mg/day (for persons who weigh ≥ 10 kg). Inhaled and topical steroids are allowed. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Family history of congenital or hereditary immunodeficiency. Major congenital defects. Any condition which, in the opinion of the investigator, prevents the subject from participating in the study.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 35 Months

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: H5N1 Formulation 1 Group<br>Subjects received 2 primary doses (adjuvanted) at Days 0 and 21 of H5N1 vaccine Formulation 1 and a booster dose (unadjuvanted) at Day 385 of H5N1 vaccine (GSK1557484A). All doses were administered intramuscularly (IM) in anterolateral thigh. | Biological: Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A).<br>* All subjects will receive intramuscularly a two-dose primary series (adjuvanted) at a 21 day interval, and a booster dose (unadjuvanted) at Day 385 of GSK1557484A vaccine.<br>|
| Experimental: H5N1 Formulation 2 Group<br>Subjects received 2 primary doses (adjuvanted) at Days 0 and 21 of H5N1 vaccine Formulation 2 and a booster dose (unadjuvanted) at Day 385 of H5N1 vaccine (GSK1557484A). All doses were administered IM in anterolateral thigh. | Biological: Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A).<br>* All subjects will receive intramuscularly a two-dose primary series (adjuvanted) at a 21 day interval, and a booster dose (unadjuvanted) at Day 385 of GSK1557484A vaccine.<br>|
| Experimental: H5N1 Formulation 3 Group<br>Subjects received 2 primary doses (adjuvanted) at Days 0 and 21 of H5N1 vaccine Formulation 3 and a booster dose (unadjuvanted) at Day 385 of H5N1 vaccine (GSK1557484A). All doses were administered IM in anterolateral thigh. | Biological: Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A).<br>* All subjects will receive intramuscularly a two-dose primary series (adjuvanted) at a 21 day interval, and a booster dose (unadjuvanted) at Day 385 of GSK1557484A vaccine.<br>|
| Experimental: H5N1 Formulation 4 Group<br>Subjects received 2 primary doses (adjuvanted) at Days 0 and 21 of H5N1 vaccine Formulation 4 and a booster dose (unadjuvanted) at Day 385 of H5N1 vaccine (GSK1557484A). All doses were administered IM in anterolateral thigh. | Biological: Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A).<br>* All subjects will receive intramuscularly a two-dose primary series (adjuvanted) at a 21 day interval, and a booster dose (unadjuvanted) at Day 385 of GSK1557484A vaccine.<br>|
| Experimental: H5N1 Formulation 5 Group<br>Subjects received 2 primary doses (adjuvanted) at Days 0 and 21 of H5N1 vaccine Formulation 5 and a booster dose (unadjuvanted) at Day 385 of H5N1 vaccine (GSK1557484A). All doses were administered IM in anterolateral thigh. | Biological: Influenza A (H5N1) Virus monovalent vaccine (GSK1557484A).<br>* All subjects will receive intramuscularly a two-dose primary series (adjuvanted) at a 21 day interval, and a booster dose (unadjuvanted) at Day 385 of GSK1557484A vaccine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral Immune Response for A/Indonesia/05/2005 (H5N1) Strain in Terms of Vaccine-homologous Haemagglutination Inhibition (HI) Antibody Titers Following Primary Vaccination | The HI antibody titres were expressed in terms of immunogenicity indices for each group. Immunogenicity index (DGMT) = If the LL of the 95% CI for GMT group ratio is less than 0.25 then DGMT =0. If the LL of the 95% CI for GMT group ratio is greater than 1 then DGMT =1. | At Day 42 | 
| Humoral Immune Response for A/Indonesia/05/2005 (H5N1) Strain in Terms of Vaccine-homologous Microneutralization (MN) Antibody Titers Following Primary Vaccination | The MN antibody titres were expressed in terms of immunogenicity indices for each group. Immunogenicity index (DGMT) = If the LL of the 95% CI for GMT group ratio is less than 0.25 then DGMT =0. If the LL of the 95% CI for GMT group ratio is greater than 1 then DGMT =1. | At Day 42 | 
| Evaluation of Fever Index for A/Indonesia/05/2005 (H5N1) Strain in Terms of Vaccine-homologous Haemagglutination Inhibition (HI) Antibody Titers Following Primary Vaccination. | Fever index was defined as the average temperature for each vaccine group. Fever index (DR) = The average temperature measurement for each vaccine group. Fever index from Days 0-2 after each dose Any temperature < 38°C (100.4 F) was assigned a value of 0. Any temperature > 40.5°C was assigned a value of 40.5. DR correspond to 243 minus the sum of recorded temperature values for 3 days after (dose 1 and dose 2)/243. | During the 3-day follow-up period (i.e. on the day of vaccination and 2 subsequent days) after Dose 1 and Dose 2. | 
| Evaluation of Fever Index for A/Indonesia/05/2005 (H5N1) Strain in Terms of Vaccine-homologous Microneutralization (MN) Antibody Titers Following Primary Vaccination. | Fever index was defined as the average temperature for each vaccine group. Fever index (DR)= The average temperature measurement for each vaccine group. Fever index from Days 0-2 after each dose Any temperature < 38°C (100.4 F) was assigned a value of 0. Any temperature > 40.5°C was assigned a value of 40.5. DR correspond to 243 minus the sum of recorded temperature values for 3 days after (dose 1 and dose 2)/243. | During the 3-day follow-up period (i.e. on the day of vaccination and 2 subsequent days) after Dose 1 and Dose 2. | 
| Mean Geometric Increase (MGI) for Vaccine Homologous and Heterologous HI Antibody Titers Against Each of the Four Vaccine Influenza Strains. | MGI was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer (Day 392) to the pre-vaccination (Day 385) reciprocal HI titer for the vaccine virus. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam/1194/2004 H5N1 (heterologous), Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous) and Flu A/gyrfalcon/Washington/41088-6/2014 H5N8 (heterologous). | At Day 392 (relative to Day 385) post booster vaccination | 
| Mean Geometric Increase (MGI) for Vaccine Homologous and Heterologous MN Antibody Titers Against Each of the 3 Vaccine Influenza Strains. | MGI was defined as the geometric mean of the within-subject ratios of the post-vaccination (Day 392) reciprocal MN titer to the pre-vaccination (Day 385) reciprocal MN titer for the vaccine virus. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam /1194/2004 H5N (heterologous) and Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous). | At Day 392 (relative to Day 385) post booster vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroconverted Subjects for HI Antibodies Against Each of the 4 Vaccine Influenza Strains. | Seroconversion rate (SCR) was defined as the proportion of subjects who have either a pre-vaccination reciprocal HI titer less than (<) 10 and a post-vaccination reciprocal titer greater than or equal to (≥) 40, or a pre-vaccination reciprocal HI titer ≥ 10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam/1194/2004 H5N1 (heterologous), Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous) and Flu A/gyrfalcon/Washington/41088-6/2014 H5N8 (heterologous). | At Days 42, 385 and 392 | 
| Number of Subjects Who Were Seroprotected for HI Antibodies Against Each of the 4 Vaccine Influenza Strains. | Seroprotection rate (SPR) was defined as the proportion of subjects with H5N1 reciprocal HI titers ≥ 40 against the tested vaccine virus The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam/1194/2004 H5N1 (heterologous), Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous) and Flu A/gyrfalcon/Washington/41088-6/2014 H5N8 (heterologous). | At Days 0, 42, 385, 392 | 
| Geometric Mean Titers (GMTs) for Humoral Immune Response in Terms of HI Antibodies Against Vaccine-homologous/Heterologous Antigens | GMTs were defined as the geometric mean antibody titres calculated on all subjects post the primary immunization (at Day 0, 42, 385) and 7 days post booster dose (at Day 392). The aggregate variables were calculated for each group. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam/1194/2004 H5N1 (heterologous), Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous) and Flu A/gyrfalcon/Washington/41088-6/2014 H5N8 (heterologous). | At Days 0, 42 and 385 (post the primary immunization), at Day 392 (7 days post booster dose) | 
| Mean Geometric Increase (MGI) for Haemagglutination Inhibition (HI) Antibody Titer Against Each of the 4 Vaccine Influenza Strains | MGI was defined as the geometric mean of the within-subject ratios of the post-vaccination (Day 42) reciprocal HI titer to the pre-vaccination (Day 0) reciprocal HI titer for the vaccine virus. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam/1194/2004 H5N1 (heterologous), Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous) and Flu A/gyrfalcon/Washington/41088-6/2014 H5N8 (heterologous). | At Day 42 (relative to Day 0), at Day 385 (relative to Day 0) and at Day 392 (relative to Day 0) | 
| Mean Geometric Increase (MGI) for MN Antibodies Against the 3 Vaccine Influenza Strains. | MGI was defined as the geometric mean of the within-subject ratios of the post-vaccination (Day 385) reciprocal MN titer to the pre-vaccination (Day 0) reciprocal MN titer for the vaccine virus. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam /1194/2004 H5N (heterologous) and Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous). | At Day 385 (relative to Day 0) | 
| Humoral Immune Response for A/Indonesia/05/2005 (H5N1) Strain in Terms of MN Antibodies Against Vaccine-homologous/Heterologous Antigens | MN antibody titers were expressed as Geometric Mean Titers (GMTs). The cut-off of the assay was the seropositivity cut-off of ≥ 1:28. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam /1194/2004 H5N (heterologous) and Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous). | At Days 0, 42, 385 and Day 392 | 
| Vaccine Response Rate (VRR) for Homologous and Heterologous MN Antibodies Against Each of the 3 Vaccine Influenza Strains. | VRR for MN was defined as the incidence rate of subjects with at least a 4-fold increase in post vaccination reciprocal titer relative to pre vaccination titers. The vaccine strains assessed were Flu A/Indonesia/5/2005 H5N1 (homologous), Flu A/Vietnam /1194/2004 H5N (heterologous) and Flu A/duck/Bangladesh/19097/2013 H5N1 (heterologous). | At Day 42, Day 385 (relative to Day 0), Day 392 (relative to Day 0) and D 392 (relative to Day 385) | 
| Cell Mediated Immunity (CMI) in Terms of T-cell Markers Related to Flu A/Indonesia/05/2005 Antigen. | Antigen-specific CD4+/CD8+ T Cells identified as CD4/CD8+ were analysed for T cells expressing two or more of the following immune markers: CD40 Ligand, Interleukin (IL)-2, Tumor Necrosis Factor alpha (TNF-a), Interferon-gamma (IFN-g). The frequency was presented as number of cytokine-producing CD4+/CD8+ cells per million CD4+/CD8+ cells repsectively. All doubles = T cell expressing at least 2 cytokines. | At Days 0, 42, 385 and 392 | 
| Number of Subjects Reporting Solicited Local Symptoms | Solicited local AEs assessed were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = cried when limb is moved/spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | During the 7-day follow-up period (i.e. on the day of vaccination and 6 subsequent days) after any vaccine dose | 
| Duration of Solicited Local Symptoms | Duration was defined as number of days with any grade of local symptoms. | During the 7-day follow-up period (i.e. on the day of vaccination and 6 subsequent days) after any vaccine dose | 
| Number of Subjects Reporting Solicited General Symptoms. | Assessed solicited general symptoms were fever (defined as temperature ≥ 38.0 degrees Celsius (°C) assessed by any route (oral, axillary, rectal)], irritability/fussiness, drowsiness and. loss of appetite. Any = occurrence of the symptom regardless of intensity grade. Grade 3 irritability/Fussiness and Drowsiness = Prevented normal activity, Grade3 Loss of appetite = Did not eat at all. Grade 3 fever = fever > 40.0 °C. Related = symptom assessed by the investigator as related to the vaccination | During the 7-day follow-up period (i.e. on the day of vaccination and 6 subsequent days) after any vaccine dose | 
| Duration of Solicited General Symptoms. | Duration was defined as number of days with any grade of general symptoms. | During the 7-day follow-up period (i.e. on the day of vaccination and 6 subsequent days) after any vaccine dose | 
| Number of Subjects Reporting Any Unsolicited Adverse Events (AEs) Post Primary Vaccination. | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any is defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevents normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | During the 21-day follow-up period (Day 0-Day 20) after each vaccine dose | 
| Number of Subjects Reporting Any Unsolicited Adverse Events (AEs) Post Booster Vaccination | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any is defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevents normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | During the 30-day (Day 385-Day 415) follow-up period after vaccination | 
| Number of Subjects Reporting Medically Attended Events (MAEs) | MAEs are adverse events with medically-attended visits that were not routine visits for physical examination or vaccination. Any MAE was defined as at least 1 MAE experienced. | During the entire study period (Day 0 to Day 415 approximately) | 
| Number of Subjects Reporting Potential Immune Mediated Diseases (pIMDs) | Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. Any pIMD = at least one pIMD experienced by the study subject. Related = pIMD assessed by the investigator to be causally related to the study vaccination. | During the entire study period (Day 0 to Day 415 approximately) | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | A serious adverse event was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination. | During the entire study period (Day 0 to Day 415 approximately) | 
| Number of Subjects Reporting Adverse Events of Special Interest (AESI) | AESI are a subset of adverse events defined in the Committee for Medicinal Products for Human Use (CHMP) Risk Management Plan for Pandemic Vaccines for safety monitoring. | During the entire study period (Day 0 to Day 415 approximately) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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H5N1, children, observer-blind, Influenza, dose-ranging