Safety and Immunogenicity of the Zoster Vaccine GSK1437173A in Elderly Subjects

Study Overview
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Brief Summary
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Based on the results of a previous clinical PhaseI/II study, GSK1437173A is the lead GSK candidate Herpes Zoster (HZ) vaccine to prevent episodes of HZ (shingles). This phase II study will be subdivided into a primary study (108494) and three extension studies (108516, 108518 & 108520), consisting of one additional visit each at months 12, 24 and 36, respectively, from the first visit of the Zoster-003 primary study onwards. The aim of the primary 108494 study is to evaluate the immunogenicity & safety of different dosages of the GSK1437173A vaccine in healthy elderly population. The study population will be stratified by age. The primary objective of this trial is to select the best dosage of GSK1437173A. The aim of the extension studies is to evaluate the persistence of the immune response induced by the candidate HZ vaccine during a long term period. No new subjects will be enrolled during the extension phases of the study.

Detailed Description
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The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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A Phase II, Single-blind, Randomized, Controlled, Multicentre Vaccination Study to Evaluate the Safety and Immune Response of the GSK Biologicals Zoster Vaccine, gE/AS01B, and to Compare 3 Doses of gE With AS01B Adjuvant in Healthy Elderly Subjects, Aged 60 to 69 Years and 70 Years and Above.

Conditions
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Herpes Zoster

Intervention / Treatment
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* Biological: Herpes Zoster vaccine GSK1437173A Low Dose
* Biological: Herpes Zoster vaccine GSK1437173A Medium Dose
* Biological: Herpes Zoster vaccine GSK1437173A High Dose
* Biological: Herpes Zoster vaccine GSK1437173A Modified
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they can and will comply with the requirements of the protocol. A male or female aged 60 years or older at the time of the first vaccination. Written informed consent obtained from the subject 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 injection with study vaccine, or planned use during the study period. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs during the study period, except inhaled and topical steroids are allowed. Administration or planned administration of a vaccine not foreseen by the study protocol within 2 weeks of the first study vaccine injection, with the exception of the influenza vaccine, which can be administered 1 week preceding or 1 month after the first study vaccine injection. Previous vaccination against HZ. History of herpes zoster (Shingles). Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Acute disease at the time of enrolment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by subject's medical history or physical examination as assessed by the investigator. Administration of immunoglobulins and/or any blood products within the 3 months preceding the first injection of study vaccine or planned administration during the study period. History of or current drug and/or alcohol abuse.

Ages Eligible for Study
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Minimum Age: 60 Years

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1437173A _LD Group<br>Healthy male or female subjects aged 60 years or older, who received 2 doses of herpes zoster subunit vaccine (GSK1437173A) low dose (LD) formulation, according to a 0, 2-month schedule. The vaccine was administrated by intramuscular injection (IM) in the upper deltoid site of the left arm. | Biological: Herpes Zoster vaccine GSK1437173A Low Dose<br>* Single or two-dose intramuscular injection.<br>|
| Experimental: GSK1437173A _MD Group<br>Healthy male or female subjects aged 60 years or older, who received 2 doses of herpes zoster subunit vaccine (GSK1437173A) medium dose (MD) formulation, according to a 0, 2-month schedule. The vaccine was administrated by (IM) in the upper deltoid site of the left arm. | Biological: Herpes Zoster vaccine GSK1437173A Medium Dose<br>* Single or two-dose intramuscular injection.<br>|
| Experimental: GSK1437173A _HD Group<br>Healthy male or female subjects aged 60 years or older, who received 2 doses of herpes zoster subunit vaccine (GSK1437173A) high dose (HD) formulation, according to a 0, 2-month schedule. The vaccine was administrated by (IM) in the upper deltoid site of the left arm. | Biological: Herpes Zoster vaccine GSK1437173A High Dose<br>* Single or two-dose intramuscular injection.<br>|
| Placebo Comparator: Placebo + GSK1437173A _HD Group<br>Healthy male or female subjects aged 60 years or older, who received a 1st dose of saline solution and a 2nd dose of GSK1437173A high dose (HD) formulation, according to a 0, 2-month schedule. The vaccine was administrated by (IM) in the upper deltoid site of the left arm. | Biological: Herpes Zoster vaccine GSK1437173A High Dose<br>* Single or two-dose intramuscular injection.<br>Biological: Placebo<br>* Single intramuscular injection<br>|
| Active Comparator: GSK1437173A_MODIFIED GROUP<br>Healthy male or female subjects aged 60 years or older, who received 2 doses of GSK1437173A modified formulation vaccine reconstituted with saline solution, according to a 0, 2-month schedule. The vaccine was administrated by (IM) in the upper deltoid site of the left arm. | Biological: Herpes Zoster vaccine GSK1437173A Modified<br>* Single or two-dose intramuscular injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Glycoprotein E (gE)-Specific Cluster of Differentiation (CD4) T-cells Expressing at Least Two Different Activation Markers | Among the activation markers expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS) in subjects aged 70 or higher (≥). | One month after the second vaccination (Month 3) | 
| Frequency Odds Ratio of gE-specific CD4 T-cells Expressing at Least Two Different Activation Markers | Among the activation markers expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS) in subjects ≥ 70 years old. The odds-ratios are calculated using the the frequency of CD4 secreting cytokines, upon in vitro stimulation with the specific antigen, at the numerator and the frequency of the CD4 secreting cytokines with the medium only (background level) at the denominator. The odds-ratios represent the fold-change in the specific response compared to the background level. | One month after the second vaccination (Month 3) | 
| Frequency of gE-specific CD4 T-cells Expressing at Least Two Different Activation Markers | Among the activation markers expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS) in subjects ≥ 70 years old. | One month after the second vaccination (Month 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of gE-specific CD4 T-cells Expressing at Least Two Different Activation Markers | Among the activation markers expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS) in subjects 60 to 69 years (60-69y) and ≥ 70 years (+70y) old. | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD4 T-cells Expressing IFN-γ and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or tumour necrosis factor-alpha [TNF-α] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD4 T-cells Expressing IL-2 and at Least Another Activation Marker | Among other activation markers expressed were interferon-gamma [IFN-γ] or tumour necrosis factor-alpha [TNF-α] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD4 T-cells Expressing TNF-α and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or interferon-gamma [IFN-γ] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD4 T-cells Expressing CD40L and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or interferon-gamma [IFN-γ] or tumour necrosis factor-alpha [TNF-α] . Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD8 T-cells Expressing at Least Two Different Activation Markers | Among the activation markers expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD8 T-cells Expressing IFN-γ and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or tumour necrosis factor-alpha [TNF-α] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD8 T-cells Expressing IL-2 and at Least Another Activation Marker | Among other activation markers expressed were interferon-gamma [IFN-γ] or tumour necrosis factor-alpha [TNF-α] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD8 T-cells Expressing TNF-α and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or interferon-gamma [IFN-γ] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD8 T-cells Expressing CD40L and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or interferon-gamma [IFN-γ] or tumour necrosis factor-alpha [TNF-α]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Anti-gE Specific Antibody Concentrations | Concentrations were presented as geometric mean concentrations (GMCs) and expressed in enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Anti-varicella Zoster Virus (VZV) Specific Antibody Concentrations | Concentrations were presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL), as assessed by ELISA. | At pre-vaccination (Day 0), one month after the first vaccination (Month 2) and second vaccination (Month 3) | 
| Frequency of gE-specific CD4/CD8 T-cells Expressing at Least Two Different Activation Markers | Among the activation markers expressed were interleukin-2 [IL-2] and/or interferon-gamma [IFN-γ] and/or tumour necrosis factor-alpha [TNF-α] and/or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). Month 12, 24 and 36 CMI analyses on CD8+ T cells were not performed as no detectable CD8 T+ cell response was measured to any of the vaccine formulations in the primary (108494) study. | At Months 12, 24 and 36 | 
| Frequency of gE-specific CD4/CD8 T-cells Expressing IFN-γ and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or tumour necrosis factor-alpha [TNF-α] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). Month 12, 24 and 36 CMI analyses on CD8+ T cells were not performed as no detectable CD8 T+ cell response was measured to any of the vaccine formulations in the primary (108494) study. | At Months 12, 24 and 36 | 
| Frequency of gE-specific CD4/CD8 T-cells Expressing IL-2 and at Least Another Activation Marker | Among other activation markers expressed were interferon-gamma [IFN-γ] or tumour necrosis factor-alpha [TNF-α] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). Month 12, 24 and 36 CMI analyses on CD8+ T cells were not performed as no detectable CD8 T+ cell response was measured to any of the vaccine formulations in the primary (108494) study. | At Months 12, 24 and 36 | 
| Frequency of gE-specific CD4/CD8 T-cells Expressing TNFα and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or interferon-gamma [IFN-γ] or cluster of differentiation 40-ligand [CD40-L]. Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). Month 12, 24 and 36 CMI analyses on CD8+ T cells were not performed as no detectable CD8 T+ cell response was measured to any of the vaccine formulations in the primary (108494) study. | At Month 12, 24 and 36 | 
| Frequency of gE-specific CD4/CD8 T-cells Expressing CD40L and at Least Another Activation Marker | Among other activation markers expressed were interleukin-2 [IL-2] or interferon-gamma [IFN-γ] or tumour necrosis factor-alpha [TNF-α] . Analysis of cytokines expression was done by means of in vitro flow cytometry using intracellular cytokine staining (ICS). Month 12, 24 and 36 CMI analyses on CD8+ T cells were not performed as no detectable CD8 T+ cell response was measured to any of the vaccine formulations in the primary (108494) study. | At Month 12, 24 and 36 | 
| Anti-gE Specific Antibody Concentrations | Concentrations were presented as geometric mean concentrations (GMCs) and expressed in enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). | At Months 12, 24 and 36 | 
| Anti-varicella Zoster Virus (VZV) Specific Antibody Concentrations | Concentrations were presented as geometric mean concentrations (GMCs) and expressed in milli-international units per milliliter (mIU/mL). | At Months 12, 24 and 36 | 
| Frequency of VZV-specific Memory B-cells in a Subset of Subjects | Memory B cells specific to the gE antigen, as assessed by the enzyme-linked immunosorbent spot (ELISPOT) method, were expressed as a frequency of the specific memory B-cells per million memory B-cells. Results were tabulated for subjects aged 70 years and older. | At pre-vaccination (Day 0) and at Month 3 | 
| Number of Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were albumin [ALB], alanine aminotransferase [ALT], aspartate aminotransferase [AST], basophils [BAS], calcium [CAL], eosinophils [EOS], fibrinogen [FIB], haematocrit [HEM], hemoglobin [Hgb], leucocytes [LEU], lymphocytes [LYM], lactate dehydrogenate [LDH], monocytes [MON], neutrophils [NEU], partial thromboplastin time [PTPT], platelets [PLA], pro thrombin time [PTT], red blood cells [RBC], serum creatinine [SCREA], total protein [TP]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were - unknown, below, within and above. | At Day 0, Month 2 and Month 3 | 
| Number of German Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were albumin [ALB], calcium [CAL], fibrinogen [FIB], lactate dehydrogenase [LDH], partial thrombo-plastin time [PTPT], pro thrombin time [PTT], total protein [TP]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were - below, within, above and missing, as compared to the pre-vaccination status (below, within, above or missing). Values for electrophoresis (globulins and albumin/globulin ratio) were not displayed. | At one week post-vaccination 1 (Month 0) | 
| Number of German Subjects With Different Biochemical and Haematological Levels | Among biochemical and haematological parameters assessed were albumin [ALB], calcium [CAL], fibrinogen [FIB], lactate dehydrogenase [LDH], partial thrombo-plastin time [PTPT], pro thrombin time [PTT], total protein [TP]. Levels of haematological/biochemical parameters assessed in terms of normal laboratory values were - below, within, above and missing, as compared to the pre-vaccination status (below, within, above or missing). Values for electrophoresis (globulins and albumin/globulin ratio) were not displayed. | At one week post-vaccination 2 (Month 2) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) of injection site. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)], headache and myalgia. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Occurrence of Clinically Diagnosed Herpes Zoster (HZ) Episodes | Clinically diagnosed episodes included rash that was assessed by hives, idiopathic thrombocytopenic purpura, petechiae. | From Month 0 to Month 3 | 
| Number of Subjects With Occurrence of Clinically Diagnosed HZ Episodes | Clinically diagnosed episodes included rash that was assessed by hives, idiopathic thrombocytopenic purpura, petechiae. | From Month 3 up to Month 36 | 
| Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs) | 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 was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | During the 30-day (Days 0-29) post-vaccination period | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Month 0 to Month 3 | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Month 3 to Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK Biologicals, Herpes Zoster (HZ), Vaccine, Varicella Zoster Virus (VZV), Shingles