Development of Read-outs in Healthy, Hepatitis B Virus Naive Adults Vaccinated With the Hepatitis B Surface Antigen (HBsAg) in Combination With a GlaxoSmithKline (GSK) Biologicals' Adjuvant System

GlaxoSmithKline81 enrolled

Overview

This study aims to develop innovative immunological read-outs and new technologies in order to further characterise the early immune response and its kinetics as well as the adaptive immune responses to adjuvanted vaccines. This study will also evaluate the reactogenicity in healthy, hepatitis B virus naive adults vaccinated with the hepatitis B surface antigen in combination with a GSK Biologicals' Adjuvant System.

This study will be conducted in 2 steps with 2 study groups in each step. The entire study period for Step 1 is from Day -30 to Day 210 (240 days) The entire study period for Step 2 is from Day 0 to Day 180 for Group C and from Day 0 to Day 330 for Group D. Subjects will be blinded up to Day 60 in Step 1 and will be unblinded at the end of their Day 60 visit. Step 2 will be conducted in an open-label manner.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

SINGLE

Enrollment

Conditions

Hepatitis B

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol * A male or female between, and including, 18 and 45 years of age at the time of first study product administration * Written informed consent obtained from the subject * Healthy subjects, in the opinion of the investigator, as established by medical history, clinical examination, and clinical laboratory assessment with no active disease that could interfere with the study endpoints, before entering into the study * Body Mass Index (BMI) between 18.5 and 30 kg/m2 * Female subjects of non-childbearing potential may be enrolled in the study \- Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause. * Female subjects of childbearing potential may be enrolled in the study, if the subject: * has practiced adequate contraception for 30 days prior to first study product administration and * has a negative pregnancy test on the day of placebo administration/ vaccination, and * has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the study. Exclusion Criteria: * Known history of HBV infection. * Previous vaccination against hepatitis B. * Positive for anti-hepatitis B surface (HBs) antibodies, anti-hepatitis B core (HBc) antibodies, HBsAg, HCV antibodies and/or HIV. * Any previous administration of vaccine components. * Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the first study product administration, or planned use during the study period. * No significant dietary restrictions or life-threatening food allergies. * Regular use of non steroidal anti-inflammatory drugs within 1 month prior to first study product administration. * Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within 6 months prior to the first study product administration.. Inhaled and topical steroids are allowed. * Planned administration / administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first study product administration and during the entire study period (both Steps), with the exception of the influenza vaccine (pandemic or seasonal) which can be administered \> 21 days preceding or \> 21 days following each placebo/vaccine administration. * Administration of immunoglobulins and/or any blood products within the last 3 months preceding the first study product administration or planned administration during the study period. * Any confirmed or suspected immunosuppressive or immunodeficient condition, including HIV based on screening evaluations and on medical history and physical examination. * History of or current bleeding or coagulation disorder. * Any known or clinical signs of anaemia or any clinical condition (including vascular disorder) that would preclude frequent blood drawings. * Poor venous access as assessed at screening by the investigator. * Blood loss, including blood donation, of more than 300 mL within 90 days before the first study product administration. * History of or current autoimmune or other immune-mediated disease. * Any haematological or biochemical level out of normal range before entering into the study, as follows: * Haemoglobin level \< lower normal limit (LNL). * Platelet counts out of normal range. * Alanine aminotransferase \[ALT\] \> upper normal limit (UNL). * Aspartate aminotransferase \[AST\] \> UNL. * Creatinine \> UNL. * c-reactive protein \[CRP\] \> UNL. * Creatine phosphokinase \[CPK\] \> UNL without any plausible explanation for this abnormality (such as sport activity). In case of haematological and/or biochemical value out of range for parameters mentioned here above, one re-testing of out of range value may be performed. * Any acute or chronic, clinically significant disease, as determined by medical history, physical examination or laboratory screening tests. * Known or suspected reaction or hypersensitivity likely to be exacerbated by any component of the vaccines. * Acute disease and/or fever at the time of enrolment. * Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator. * Fever is defined as temperature ≥ 37.5°C for oral route. * Pregnant or lactating female. * Recent history of chronic alcohol consumption and/or drug abuse. * Other conditions that the principal investigator judges may interfere with study findings.

Outcomes

Primary Outcomes

Concentrations of Cytokines and Chemokines - Step 1

Cytokines and chemokines analysed were E-selectin, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-18, IL-2, IL-3, IL-4, IL-5, IL-6, IL-6r, IL-7, IL-8, IFN-γ-inducible protein (IP-10), monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-4, monokine induced by IFN-γ (MIG), macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta, MIP3-alpha, MPIF-1, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta. Concentrations are presented as median, expressed in picogram/milliliter (pg/mL), as measured by Multiplex in plasma.

Time frame: At Day -30 prior to placebo administration

Cytokines and Chemokines Concentrations - Step 1

Time frame: Post-placebo at Day -30 plus 1.5 Hours

Concentrations of Cytokines and Chemokines in Step 1

Time frame: Post-placebo at Day -30 plus 3 Hours

Concentrations of Cytokines and Chemokines During Step 1

Time frame: Post-placebo at Day -30 plus 6 Hours

Concentrations of Cytokines/Chemokines - Step 1

Time frame: Post-placebo at Day -30 plus 9 Hours

Concentrations of Cytokines/Chemokines in Step 1

Time frame: Post-placebo at Day -30 plus 12 Hours

Concentrations of Cytokines/Chemokines During Step 1

Time frame: Post-placebo at Day -30 plus 18 Hours

Cytokines and Chemokines Concentrations in Step 1

Time frame: Post-placebo at Day -29

Cytokines and Chemokines Concetrations During Step 1

Time frame: Post-placebo at Day -28

Cytokines/Chemokines Concentrations in Step 1

Time frame: Post-placebo at Day -27

Cytokines and Chemokines Concentrations During Step 1

Time frame: Post-placebo at Day -23

Concentrations of Cytokines and Chemokines - Study Step 1

Time frame: Pre-dose1 at Day 0

Concentrations of Cytokines and Chemokines in Step 1 of Study

Time frame: Post-dose1 at Day 0 plus 1.5 Hours

Concentrations of Cytokines and Chemokines During Step 1 of Study

Time frame: Post-dose1 at Day 0 plus 6 Hours

Cytokines and Chemokines Concentrations - Study Step 1

Time frame: Post-dose1 at Day 0 plus 12 Hours

Cytokines and Chemokines Concentrations in Step 1 of Study

Time frame: Post-dose1 at Day 0 plus 18 Hours

Cytokines and Chemokines Concentrations During Step 1 of Study

Time frame: Post-dose1 at Day 1

Cytokines/Chemokines Concentrations - Study Step 1

Time frame: Post-dose1 at Day 2

Cytokines/Chemokines Concentrations in Step 1 of Study

Time frame: Post-dose1 at Day 7

Cytokines/Chemokines Concentrations During Step 1 of Study

Time frame: Post-dose1 at Day 30

Plasma Concentrations of Cytokines and Chemokines - Step 1

Time frame: Post-dose 2 at Day 30 plus 1.5 Hours

Plasma Concentrations of Cytokines and Chemokines - Study Step 1

Time frame: Post-dose 2 at Day 30 plus 3 Hours

Plasma Concentrations of Cytokines and Chemokines in Step 1 of Study

Time frame: Post-dose 2 at Day 30 plus 6 hours

Plasma Concentrations of Cytokines and Chemokines During Step 1 of Study

Time frame: Post-dose 2 at Day 30 plus 9 Hours

Plasma Concentrations of Cytokines/Chemokines During Step 1 of Study

Time frame: Post-dose 2 at Day 30 plus 12 Hours

Plasma Concentrations of Cytokines/Chemokines - Step 1 of Study

Time frame: Post-dose 2 at Day 30 plus 18 Hours

Plasma Concentrations of Cytokines/Chemokines in Step 1 of Study

Time frame: Post-dose 2 at Day 31

Concentrations of Plasma Cytokines and Chemokines - Step 1

Time frame: Post-dose 2 at Day 32

Concentrations of Plasma Cytokines and Chemokines in Step 1

Time frame: Post-dose 2 at Day 33

Concentrations of Plasma Cytokines and Chemokines During Step 1

Time frame: Post-dose 2 at Day 37

Concentrations of Cytokines and Chemokines - Step 2

Time frame: Pre-dose 1 at Day 0

Cytokines and Chemokines Concentrations - Step 2

Time frame: Post-dose 1 at Day 1

Concentrations of Cytokines and Chemokines During Step 2

Time frame: Post-dose 1 at Day 30

Concentrations of Cytokines and Chemokines in Step 2

Time frame: Post-dose2 at Day 30 plus 6 Hours

Concentrations of Cytokines/Chemokines - Step 2

Time frame: Post-dose 2 at Day 31

Concentrations of Cytokines/Chemokines in Step 2

Time frame: Post-dose 2 at Day 37

Concentrations of Cytokines/Chemokines During Step 2

Time frame: Post-dose 2 at Day 180

Plasma Concentrations of Cytokines and Chemokines - Study Step 2

Time frame: Post-dose 3 at Day 180 plus 6 Hours

Plasma Concentrations of Cytokines and Chemokines in Step 2 of Study

Time frame: Post-dose 3 at Day 181

Plasma Concentrations of Cytokines and Chemokines During Step 2 of Study

Time frame: Post-dose 3 at Day 187

Secondary Outcomes

Anti-Hepatitis B Surface (Anti-HBs) Antibody Concentrations in Serum - Step 1

Anti-HBs antibody concentrations in serum were measured by Chemi Luminiscence Immuno Assay (CLIA). Concentrations were presented as geometric mean concentrations, in milli-International Units per milliliter (mIU/mL).

Time frame: At Day 0 (PRE) and Day 60 (D60) post-vaccination

Number of Subjects With Any and Grade 3 Solicited Local Symptoms - Step 1

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.

Time frame: During the 7-day (Days 0-6) post-placebo (PP) and post-vaccination period following each vaccine dose (D1 and D2) and across doses

Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms - Step 1

Assessed solicited general symptoms were fatigue, gastrointestinal symptoms \[nausea, vomiting, diarrhoea and /or abdominal pain\], headache, malaise, myalgia, shivering and temperature \[defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)\]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever \> 39.5 °C. Related = symptom assessed by the investigator as related to the vaccination

Time frame: During the 7-day (Days 0-6) post-placebo (PP) and post-vaccination period following each vaccine dose (D1 and D2) and across doses

Number of Subjects With Solicited Symptoms, as Assessed by the Investigator/Study Nurse - Step 1

Assessed solicited symptoms were fever \[defined as oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)\], pain, redness \[spreading beyond 20 millimeters (mm) of injection site\], induration \[spreading beyond 20 millimeters (mm) of injection site\], swelling \[spreading beyond 20 millimeters (mm) of injection site\] and muscle stiffness.

Time frame: Up to 4 days post-placebo/vaccine administration.

Number of Subjects With Any Unsolicited Adverse Events (AEs) - Step 1

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 out-side 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.

Number of Subjects With Serious Adverse Events (SAEs) - Step 1

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.

Time frame: From Day 0 up to Day 60 for the HBsAg/AS_1 Group and from Day 0 up to Day 210 for the Engerix-B_1 Group

Number of Subjects With Any Potential Immune-mediated Disorders (pIMDs) - Step 1

PIMD(s) 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.

Time frame: From Day 0 up to Day 60 for the HBsAg/AS_1 Group and from Day 0 up to Day 210 for the Engerix-B_1 Group

Number of Subjects With Any New Medical Conditions Requiring Medical Attention (MAEs) - Step 1

MAEs were defined as events for which the subject received medical attention defined as hospitalization, an emergency room visit, or a visit to or from medical personnel (medical doctor) for any reason. Any MAE(s) = Occurrence of any MAE(s) regardless of intensity grade or relation to vaccination. Analysis of intensity and relationship to vaccination of MAEs was not performed.

Time frame: From Day 0 up to Day 60 for the HBsAg/AS_1 Group and from Day 0 up to Day 210 for the Engerix-B_1 Group

Levels of Alanine Aminotransferase (ALT) in Blood Samples - Step 1

Biochemical laboratory parameters assessed included ALT levels. ALT concentrations were expressed in units per liter (U/L). ALT levels were assessed at different time points (plus 6, 12 and 18 hours - H6, H12, H18) on Day 0 and Day 30.