Long-term Persistence of Immunity to Hepatitis B in Adults Vaccinated 20 to 30 Years Ago With Engerix-B
Phase: PHASE4
Conditions: Hepatitis B Vaccine
Sponsor: GlaxoSmithKline

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PPD 
, 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
 
 
 
Primary Study 
vaccine/product and 
number 
eTrack study number and 
Abbreviated Title 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l'Institut 89 
1330 Rixensart, Belgium 
 
GlaxoSmithKline (GSK) Biologicals’ hepatitis B 
vaccine, Engerix™-B (103860) 
 
116811 (HBV-322) 
 
EudraCT number 
2015-004099-31 
 
Date of protocol 
Final Version 1: 02 February 2016 
 
Title 
Long-term persistence of immunity to hepatitis B in 
adults vaccinated 20 to 30 years ago with Engerix™-B 
(103860). 
 
Detailed Title 
A phase IV, open-label, non-randomised, multicentre 
study to assess the long-term persistence of immunity 
to hepatitis B in adults vaccinated 20 to 30 years ago 
with 3 or 4 doses of GSK Biologicals’ hepatitis B 
vaccine, Engerix™-B. 
 
Co-ordinating author 
 
, Scientific Writer, Contractor for 
GSK Biologicals 
 
Contributing authors 
• 
 
, Vice President, Head of 
Clinical Research and Development 
• 
, Director, Senior, 
Clinical Research and Development Lead 
• 
, Lead Statistician 
• 
, Project Statistician 
• 
, Study Delivery Lead 
• 
, Study Delivery Manager 
• 
, Vaccine Supply Coordinator, Aprova, for 
GSK Biologicals 
• 
Clinical Safety Representative 
• 
, Study Data Manager Tata Consultancy 
Services, for GSK Biologicals 
• 
, CLS Project Manager 

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PPD 
PPD 
PPD 
PPD 
eTrack study number and 
Abbreviated Title 
116811 (HBV-322) 
 
EudraCT number 
2015-004099-31 
Detailed Title 
A phase IV, open-label, non-randomised, multicentre 
study to assess the long-term persistence of immunity 
to hepatitis B in adults vaccinated 20 to 30 years ago 
with 3 or 4 doses of GSK Biologicals’ hepatitis B 
vaccine, Engerix™-B. 
Contributing authors 
(cont.) 
• 
, Project Data Manager 
• 
, Manager, Global Regulatory Affairs 
• 
, Clinical R&D Representative 
• 
, Global Patent Representative 
GSK Biologicals’ Protocol DS v 14.1.1 
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or 
use of this information is prohibited. 

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Protocol Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
116811 (HBV-322) 
 
EudraCT number 
2015-004099-31 
 
Date of protocol 
Final Version 1: 02 February 2016 
 
Detailed Title 
A phase IV, open-label, non-randomised, multicentre 
study to assess the long-term persistence of immunity 
to hepatitis B in adults vaccinated 20 to 30 years ago 
with 3 or 4 doses of GSK Biologicals’ hepatitis B 
vaccine, Engerix™-B. 
 
Sponsor signatory 
Dominique Descamps, 
Vice President, Head of Clinical Research and 
Development 
GlaxoSmithKline Vaccines 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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I agree: 
Protocol Investigator Agreement 
 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccines and other study-related duties and 
functions as described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 
• 
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 
• 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements. 
 
Hence I: 
 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 

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eTrack study number and 
Abbreviated Title 
116811 (HBV-322) 
 
EudraCT number 
2015-004099-31 
Date of protocol 
Final Version 1: 02 February 2016 
Detailed Title 
A phase IV, open-label, non-randomised, multicentre 
study to assess the long-term persistence of immunity 
to hepatitis B in adults vaccinated 20 to 30 years ago 
with 3 or 4 doses of GSK Biologicals’ hepatitis B 
vaccine, Engerix™-B. 
Investigator name 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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1. Sponsor 
Sponsor Information 
 
GlaxoSmithKline Biologicals 
Rue de l'Institut 89 
1330 Rixensart, Belgium 
 
2. Sponsor Medical Expert for the Study 
 
Refer to the local study contact information document. 
 
3. Sponsor Study Monitor 
 
Refer to the local study contact information document. 
 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 7.4.2. 

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SYNOPSIS 
Detailed Title 
A phase IV, open-label, non-randomised, multicentre study to 
assess the long-term persistence of immunity to hepatitis B in 
adults vaccinated 20 to 30 years ago with 3 or 4 doses of GSK 
Biologicals’ hepatitis B vaccine, Engerix™-B. 
 
Indication 
Immunisation against infection caused by all known subtypes 
of hepatitis B virus. 
 
Rationale for the 
study and study 
design 
• 
Rationale for the study 
Studies conducted in different populations have shown long- 
term persistence and immune memory induced by Engerix-B 
against hepatitis B, extending up to 20 years after primary 
vaccination in infants [Poovorawan, 2010; Van Damme, 2010; 
Poovorawan, 2012; Poovorawan, 2013], and up to 15 years 
after vaccination of 8-10 year old children [Gilca, 2013]. 
 
This study will assess the persistence of immunity 20 to 30 
years after primary vaccination of healthy adults, aged 
between 18-40 years, with Engerix-B. 
 
• 
Rationale for the study design 
This study will assess the long-term protection against HBV 
infection in adult subjects vaccinated with three or four doses 
(2+1 or 3+1 schedule) of Engerix-B 20 to 30 years ago by 
measuring the circulating antibodies against hepatitis B 
surface antigen (anti-HBs), by checking for occult infection 
(presence of antibodies against hepatitis B core antigen [anti- 
HBc]), by evaluating the anamnestic response to a challenge 
dose of the vaccine, and by testing for T and memory B cell 
activation. 
 
Long-term protection against HBV infection after 
immunisation relies primarily on the ability of the immune 
system to mount an anamnestic response when exposed to 
HBV [European Consensus Group on Hepatitis B Immunity, 
2000; WHO, 2010]. The strongest assessment for persistence 
of immunity to hepatitis B in this study will be from the 
evaluation of anamnestic response in vaccinated individuals. 
 
Subjects who received three or four doses of Engerix-B 
vaccine as adults 20 to 30 years ago will be enrolled. 
Stratification of age will be carried out in order to ensure that 
the age of enrolled subjects is balanced across the 
participating countries. Hence, equal number of subjects will 
be enrolled into the two strata: 40-50 years and 51-60 years of 

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age in all of the participating countries. 
Since all of the subjects will have previously received 
vaccination with Engerix-B, they will be assessed for antibody 
persistence and long-term immunity, and will receive a single 
challenge dose of Engerix-B. The study will be non- 
randomised and open-label. 
Objectives 
Primary 
 
• 
To assess the persistence of immunity to hepatitis B in 
terms of anti-HBs anamnestic response to an Engerix-B 
challenge dose, in adult subjects vaccinated with three or 
four doses of Engerix-B 20 to 30 years ago. 
Secondary 
 
• 
To assess the persistence of immunity to hepatitis B in 
terms of Geometric Mean Concentrations (GMCs), 
seropositivity rates, seroprotection rates, and percentage 
of subjects with anti-HBs antibody concentrations  100 
mIU/ml, before or after the Engerix-B challenge dose, in 
subjects vaccinated with three or four doses of Engerix-B 
20 to 30 years ago. 
• 
To assess the persistence of immunity to hepatitis B in 
terms of T cell and memory B cell mediated immune 
responses specific to hepatitis B surface antigen, before 
and after the Engerix-B challenge dose, in adult subjects 
vaccinated with three or four doses of Engerix-B 20 to 30 
years ago. 
• 
To evaluate the safety and reactogenicity of Engerix-B 
challenge dose in terms of solicited symptoms, 
unsolicited symptoms and serious adverse events (SAEs). 
Study design 
• 
Experimental design: Phase IV, open-label, non- 
randomised, multi-centric, multi-country study with a 
single group. 
• 
Duration of the study: Approximately one month per 
subject, starting from the administration of the challenge 
dose. 
 Epoch 001: Primary starting at Visit 1 (Day 0) and 
ending at Visit 3 (Day 30). 
Study group: 
 
LTFU: Subjects who received 3 or 4 doses of 
Engerix-B 20 to 30 years ago. 

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Synopsis Table 1 
Study group and epoch foreseen in the study 
 
Study Group 
Number of subjects 
Age (Min/Max)* 
Epoch 
Epoch 001 
LTFU 
Approximately 100 
40 years – 60 years 
x 
*Age at visit 1 
 
Synopsis Table 2 
Study group and treatment foreseen in the study 
 
Treatment Name 
Vaccine Name 
Study Group 
LTFU 
Engerix-B 
HBV 
x 
• 
Control: uncontrolled. 
• 
Vaccination schedule: A single dose of Engerix-B will be 
administered to all subjects at Visit 1 (Day 0). 
• 
Treatment allocation: Non-randomised. 
• 
Blinding: Open label. 
 
Synopsis Table 3 
Blinding of study epoch 
 
Study Epoch 
Blinding 
Epoch 001 
open 
 
• 
Sampling schedule: Blood samples will be taken from all 
subjects in order to evaluate the immunogenicity endpoints. 
The following blood samples will be taken at each study 
visit (Visit 1, Visit 2 and Visit 3): 
 
Three heparinised tubes of whole blood, of 
approximately 9 ml each, will be sampled for the 
assessment of memory B cells and T cells. 
 
One tube of approximately 5 ml of blood will be taken, 
from which approximately 1.7 ml of serum will be 
extracted for the measurement of antibodies. 
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF). 
Number of subjects Approximately 100 adults between 40-60 years of age will be 
enrolled in the study. 

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Endpoints 
Primary 
 
• 
Persistence of immunity to hepatitis B in adult subjects 
vaccinated with three or four doses of Engerix-B 20 to 30 
years ago. 
 
Percentage of adult subjects with an anamnestic 
response 7 days and 30 days after the challenge dose. 
Secondary 
• 
Persistence of immunity to hepatitis B in adult subjects 
vaccinated with three or four doses of Engerix-B 20 to 30 
years ago. 
 
Percentage of adult subjects with anti-HBs antibody 
concentrations  6.2 mIU/ml,  10 mIU/ml and   
100 mIU/ml, at the pre-challenge dose time-point and 
Day 7 and Day 30 post-challenge dose time-points. 
 
Anti-HBs antibody concentrations, at the pre-challenge 
dose time-point and Day 7 and Day 30 post-challenge 
dose time-points. 
 
Hepatitis B specific memory B cell-mediated immune 
responses (frequency of HBs-specific memory B cells) 
at the pre-challenge dose time-point and Day 7 and 
Day 30 post-challenge dose time-points. 
 
Hepatitis B specific T cell-mediated immune responses 
(frequency of HBs-specific CD4 T-lymphocytes) at the 
pre-challenge dose time-point and Day 7 and Day 30 
post-challenge dose time-points. 
• 
Solicited local and general symptoms. 
 
Occurrence of solicited local symptoms during the 4- 
day (Days 0-3) follow-up period after the challenge 
dose. 
 
Occurrence of solicited general symptoms during the 
4-day (Days 0-3) follow-up period after the challenge 
dose. 
• 
Unsolicited adverse events. 
 
Occurrence of unsolicited symptoms during the 31-day 
(Days 0-30) follow-up period after the challenge dose. 
• 
Serious adverse events. 
 
Occurrence of SAEs after the challenge dose, up to the 
study end. 

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TABLE OF CONTENTS 
 
PAGE 
 
SPONSOR INFORMATION ............................................................................................ 6 
SYNOPSIS ...................................................................................................................... 7 
LIST OF ABBREVIATIONS ........................................................................................... 17 
GLOSSARY OF TERMS ............................................................................................... 19 
TRADEMARKS ............................................................................................................. 22 
1. 
INTRODUCTION .................................................................................................... 23 
1.1. 
Background ................................................................................................ 23 
1.2. 
Rationale for the study and study design .................................................... 23 
1.2.1. 
Rationale for the study ................................................................. 23 
1.2.2. 
Rationale for the study design ...................................................... 23 
1.3. 
Benefit: Risk Assessment ........................................................................... 24 
1.3.1. 
Risk Assessment ......................................................................... 24 
1.3.2. 
Benefit Assessment ..................................................................... 25 
1.3.3. 
Overall Benefit: Risk Conclusion .................................................. 25 
2. 
OBJECTIVES ......................................................................................................... 25 
2.1. 
Primary objective ........................................................................................ 25 
2.2. 
Secondary objectives .................................................................................. 25 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 26 
4. 
STUDY COHORT ................................................................................................... 27 
4.1. 
Number of subjects/centres ........................................................................ 27 
4.2. 
Inclusion criteria for enrolment .................................................................... 28 
4.3. 
Exclusion criteria for enrolment ................................................................... 28 
5. 
CONDUCT OF THE STUDY .................................................................................. 30 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process .......................................................................................... 30 
5.2. 
Subject identification and randomisation of treatment ................................. 31 
5.2.1. 
Subject identification .................................................................... 31 
5.2.2. 
Randomisation of treatment ......................................................... 31 
5.2.2.1. 
Randomisation of supplies .......................................... 31 
5.2.2.2. 
Treatment allocation to the subject ............................. 31 
5.2.2.2.1. 
Study group and treatment 
number allocation ................................... 31 
5.3. 
Method of blinding ...................................................................................... 32 
5.4. 
General study aspects ................................................................................ 32 
5.5. 
Outline of study procedures ........................................................................ 32 
5.6. 
Detailed description of study procedures .................................................... 34 
5.6.1. 
Informed consent ......................................................................... 34 
5.6.2. 
Collect demographic data ............................................................ 34 
5.6.3. 
Medical history ............................................................................. 34 

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5.6.4. 
Hepatitis B vaccination history ..................................................... 34 
5.6.5. 
Physical examination ................................................................... 34 
5.6.6. 
Check inclusion and exclusion criteria .......................................... 35 
5.6.7. 
Record height and weight ............................................................ 35 
5.6.8. 
Check contraindications to vaccination......................................... 35 
5.6.9. 
Pre-vaccination urine pregnancy test ........................................... 35 
5.6.10. 
Assess pre-vaccination body temperature .................................... 35 
5.6.11. 
Treatment number allocation........................................................ 35 
5.6.12. 
Sampling ...................................................................................... 35 
5.6.12.1. Blood sampling for antibody determination and 
CMI response. ............................................................ 36 
5.6.13. 
Study Vaccine administration and observation of subjects 
following administration ................................................................ 36 
5.6.14. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ..................................................... 36 
5.6.15. 
Recording of solicited AEs and non-serious AEs .......................... 36 
5.6.16. 
Medically attended visit ................................................................ 37 
5.6.17. 
Return of diary cards and diary card transcription by 
investigator .................................................................................. 37 
5.6.18. 
Recording of AEs, SAEs, and pregnancies .................................. 37 
5.6.19. 
Study conclusion .......................................................................... 37 
5.7. 
Biological sample handling and analysis ..................................................... 37 
5.7.1. 
Use of specified study materials ................................................... 38 
5.7.2. 
Biological samples ....................................................................... 38 
5.7.3. 
Laboratory assays........................................................................ 39 
5.7.4. 
Biological samples evaluation ...................................................... 40 
5.7.4.1. 
Immunological read-outs ............................................ 40 
5.7.5. 
Immunological correlates of protection ......................................... 40 
6. 
STUDY VACCINE AND ADMINISTRATION ........................................................... 41 
6.1. 
Description of study vaccine ........................................................................ 41 
6.2. 
Storage and handling of study vaccine ........................................................ 41 
6.3. 
Dosage and administration of study vaccine ............................................... 42 
6.4. 
Replacement of unusable vaccine doses .................................................... 42 
6.5. 
Contraindications to vaccination .................................................................. 42 
6.5.1. 
Absolute contraindications ........................................................... 42 
6.5.2. 
Temporary contraindications ........................................................ 43 
6.6. 
Warnings and precautions .......................................................................... 43 
6.7. 
Concomitant medications/products and concomitant vaccinations .............. 43 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 43 
6.7.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses ........................ 44 
6.8. 
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses ......................................................................... 44 
7. 
SAFETY ................................................................................................................. 45 
7.1. 
Safety definitions ........................................................................................ 45 
7.1.1. 
Definition of an adverse event ...................................................... 45 
7.1.2. 
Definition of a serious adverse event ........................................... 46 
7.1.3. 
Solicited adverse events .............................................................. 47 
7.1.3.1. 
Solicited local (injection-site) adverse events .............. 47 

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7.1.3.2. 
Solicited general adverse events ................................ 47 
7.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 47 
7.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ........................................................................................... 48 
7.2.1. 
Pregnancy ................................................................................... 48 
7.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ......................................................................................... 49 
7.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 49 
7.3.2. 
Post-Study adverse events and serious adverse events .............. 50 
7.3.3. 
Evaluation of adverse events and serious adverse events ........... 51 
7.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 51 
7.3.3.2. 
Assessment of adverse events ................................... 51 
7.3.3.2.1. 
Assessment of intensity .......................... 51 
7.3.3.2.2. 
Assessment of causality ......................... 53 
7.3.3.3. 
Assessment of outcomes ............................................ 54 
7.3.3.4. 
Medically attended visits ............................................. 55 
7.4. 
Reporting of serious adverse events, pregnancies, and other events .......... 55 
7.4.1. 
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals ............................................ 55 
7.4.2. 
Contact information for reporting serious adverse events, 
pregnancies ................................................................................. 56 
7.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................... 56 
7.4.3.1. 
Back-up system in case the electronic reporting 
system does not work ................................................. 56 
7.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ................................................................................... 56 
7.4.5. 
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF .......................................... 57 
7.4.6. 
Regulatory   reporting   requirements   for   serious   adverse 
events .......................................................................................... 57 
7.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies ................................................................................................ 57 
7.5.1. 
Follow-up of adverse events and serious adverse events ............ 57 
7.5.1.1. 
Follow-up during the study .......................................... 57 
7.5.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 58 
7.5.2. 
Follow-up of pregnancies ............................................................. 58 
7.6. 
Treatment of adverse events ....................................................................... 58 
7.7. 
Subject card ................................................................................................ 58 
8. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 59 
8.1. 
Subject completion ...................................................................................... 59 
8.2. 
Subject withdrawal ...................................................................................... 59 
8.2.1. 
Subject withdrawal from the study ................................................ 59 
9. 
STATISTICAL METHODS ...................................................................................... 60 
9.1. 
Primary endpoint ......................................................................................... 60 

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9.2. 
Secondary endpoints .................................................................................. 60 
9.3. 
Determination of sample size ...................................................................... 61 
9.4. 
Cohorts for Analyses ................................................................................... 62 
9.4.1. 
Total vaccinated cohort ................................................................ 62 
9.4.2. 
According-to-protocol    cohort    for    analysis     of 
immunogenicity ............................................................................ 62 
9.5. 
Derived and transformed data ..................................................................... 62 
9.6. 
Analysis of demographics ........................................................................... 63 
9.7. 
Analysis of immunogenicity ......................................................................... 64 
9.8. 
Exploratory Analysis: .................................................................................. 65 
9.9. 
Analysis of safety ........................................................................................ 65 
9.10. Interpretation of analyses ............................................................................ 65 
9.11. Conduct of analyses ................................................................................... 65 
9.11.1. 
Sequence of analyses .................................................................. 66 
9.11.2. 
Statistical considerations for interim analyses .............................. 66 
10. ADMINISTRATIVE MATTERS ............................................................................... 66 
10.1. Electronic Case Report Form instructions ................................................... 66 
10.2. Study Monitoring by GSK Biologicals .......................................................... 66 
10.3. Record retention ......................................................................................... 67 
10.4. Quality assurance ....................................................................................... 68 
10.5. Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................ 68 
10.6. Provision of study results to investigators .................................................... 68 
11. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 68 
12. REFERENCES ....................................................................................................... 69 

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LIST OF TABLES 
 
PAGE 
 
Table 1 
Study group and epoch foreseen in the study ......................................... 26 
Table 2 
Study group and treatment foreseen in the study ................................... 27 
Table 3 
Blinding of study epoch .......................................................................... 27 
Table 4 
Number of subjects required for enrolment ............................................. 31 
Table 5 
List of study procedures ......................................................................... 33 
Table 6 
Intervals between study visits ................................................................. 34 
Table 7 
Biological samples ................................................................................. 39 
Table 8 
Humoral Immunity (Antibody determination) ........................................... 39 
Table 9 
Cell-Mediated Immunity (CMI) ................................................................ 39 
Table 10 
Immunological read-outs ........................................................................ 40 
Table 11 
Study vaccine ......................................................................................... 41 
Table 12 
Dosage and administration ..................................................................... 42 
Table 13 
Solicited local adverse events ................................................................ 47 
Table 14 
Solicited general adverse events ............................................................ 47 
Table 15 
Reporting periods for collecting safety information ................................. 50 
Table 16 
Intensity scales for solicited symptoms in adults (40-60 years) ............... 52 
Table 17 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ................................................. 55 
Table 18 
Exact two-sided 95% CI for a sample size of 80 evaluable 
subjects according to the anamnestic response to the challenge 
dose of Engerix-B ................................................................................... 61 
Table 19 
Reference values ................................................................................... 62 
Table 20 
GSK Biologicals’ laboratories ................................................................. 71 
Table 21 
Outsourced laboratories ......................................................................... 71 

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LIST OF APPENDICES 
 
PAGE 
 
APPENDIX A CLINICAL LABORATORIES .................................................................. 71 

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LIST OF ABBREVIATIONS 
 
AE: 
Adverse Event 
Ag: 
Antigen 
Anti-HBc: 
Antibodies against Hepatitis B core antigen 
Anti-HBs: 
Antibodies against Hepatitis B surface antigen 
ATP: 
According-To-Protocol 
BMI 
Body Mass Index 
CFC: 
Cytokine Flow Cytometry 
CI: 
Confidence Interval 
CLIA: 
ChemiLuminescence ImmunoAssay 
CLS 
Clinical Laboratory Sciences 
CMI: 
Cell Mediated Immunity 
eCRF: 
Electronic Case Report Form 
ELISPOT: 
Enzyme-Linked Immunosorbent Spot 
eTDF: 
Electronic Temperature excursion Decision Form 
GMC: 
Geometric Mean Concentration 
GSK: 
GlaxoSmithKline 
HBsAg: 
Hepatitis B surface antigen 
HBV: 
Hepatitis B virus 
IU/ml: 
International Units per millilitre 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonisation 
IEC: 
Independent Ethics Committee 
IRB: 
Institutional Review Board 
MedDRA: 
Medical Dictionary for Regulatory Activities 

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PBMC: 
Peripheral Blood Mononuclear Cell 
SAE: 
Serious Adverse Event 
SBIR: 
Randomisation System on Internet 
SDV: 
Source Document Verification 
SPM: 
Study Procedures Manual 
 

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GLOSSARY OF TERMS 
Adequate contraception: 
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example: 
• 
abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle, 
• 
oral contraceptives, either combined or progestogen 
alone, 
• 
injectable progestogen, 
• 
implants of etenogestrel or levonorgestrel, 
• 
estrogenic vaginal ring, 
• 
percutaneous contraceptive patches, 
• 
intrauterine device or intrauterine system, 
• 
current tubal ligation, 
• 
male partner sterilisation prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject, 
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history. 
• 
a contraceptive method with failure rate of more than 
1% per year but still considered as acceptable birth 
control method. 
• 
male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), 
• 
male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, when this 
is their preferred and usual lifestyle. 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. 
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 

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finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Epoch: 
An epoch is a self-contained set of consecutive time- 
points or a single time-point from a single protocol. Self- 
contained means that data collected for all subjects at all 
time-points within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are primary 
vaccinations, boosters, yearly immunogenicity follow- 
ups, and surveillance periods for efficacy or safety. 
eTrack: 
GSK’s tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 6.7.2 and 9.4 for details on criteria for 
evaluability). 
Immunological correlate 
of protection: 
 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent. 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Menopause: 
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years. 
Primary completion 
date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated. 
Randomisation: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 

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Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 
Treatment number: 
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation. 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 

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TRADEMARKS 
The following trademark is used in the present protocol. 
 
Note: In the body of the protocol (including the synopsis), the names of the vaccine will 
be written without the superscript symbol ™ or ® and in italics. 
 
Trademarks of the GlaxoSmithKline 
group of companies 
Engerix™-B 
Generic description 
Hepatitis B vaccine 

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1. 
INTRODUCTION 
 
1.1. 
Background 
Hepatitis B is a life threatening liver infection caused by the Hepatitis B virus (HBV). An 
estimated 240 million people are chronically infected with HBV and around 780,000 
people die yearly due to HBV [Lozano, 2012]. 
In 2012, the European Centre for Disease Prevention and Control (ECDC) estimated a 
hepatitis B incidence of 3.5 per 100,000 population [ECDC, 2012] in 29 countries. 
Vaccination against hepatitis B is effective in preventing HBV infection. Universal infant 
vaccination was recommended by WHO in 1992 and more than 183 countries currently 
vaccinate infants against hepatitis B as part of their vaccination schedules [WHO, 2015]. 
GSK Biologicals’ hepatitis B vaccine (Engerix-B) has a strongly documented safety and 
immunogenicity profile both in monitored clinical trials and under field conditions [Van 
Damme, 2010]. 
 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
 
Studies conducted in different populations have shown long-term persistence and 
immune memory induced by Engerix-B against hepatitis B, extending up to 20 years after 
primary vaccination in infants [Poovorawan, 2010; Van Damme, 2010; Poovorawan, 
2012; Poovorawan, 2013], and up to 15 years after vaccination of 8-10 year old children 
[Gilca, 2013]. 
This study will assess the persistence of immunity 20 to 30 years after primary 
vaccination of healthy adults, aged between 18-40 years, with Engerix-B. 
 
1.2.2. 
Rationale for the study design 
 
This study will assess the long-term protection against HBV infection in adult subjects 
vaccinated with three or four doses (2+1 or 3+1 schedule) of Engerix-B 20 to 30 years 
ago by measuring the circulating antibodies against hepatitis B surface antigen (anti- 
HBs), by checking for occult infection (presence of antibodies against hepatitis B core 
antigen [anti-HBc]), by evaluating the anamnestic response to a challenge dose of the 
vaccine, and by testing for T and memory B cell activation. 
 
Long-term protection against HBV infection after immunisation relies primarily on the 
ability of the immune system to mount an anamnestic response when exposed to HBV 
[European Consensus Group on Hepatitis B Immunity, 2000; WHO, 2010]. The strongest 
assessment for persistence of immunity to hepatitis B in this study will be from the 
evaluation of anamnestic response in vaccinated individuals. 

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Subjects who received three or four doses of Engerix-B vaccine as adults 20 to 30 years 
ago will be enrolled. Stratification of age will be carried out in order to ensure that the 
age of enrolled subjects is balanced across the participating countries. Hence, equal 
number of subjects will be enrolled into the two strata: 40-50 years and 51-60 years of 
age in all of the participating countries. 
Since all subjects will have previously received vaccination with Engerix-B, they will be 
assessed for antibody persistence and long-term immunity and will receive a single 
challenge dose of Engerix-B. The study will be non-randomised and open-label. 
 
1.3. 
Benefit: Risk Assessment 
Engerix-B has demonstrated a good safety profile in the clinical studies performed to 
date. Please refer to the Prescribing Information for information regarding the summary 
of potential risks and benefits of Engerix-B. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
 
1.3.1. 
Risk Assessment 
 
Based on substantial data available from clinical and non-clinical experience, the safety 
profile of Engerix B has been established. The vaccine is well tolerated in all age groups 
and has been safely administered in schedules of 2+1 and 3+1 doses, including subjects 
with chronic medical conditions such as end-stage renal disease. 
 
Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational study vaccine/product: Engerix-B 
Hypersensitivity 
Spontaneous data/ hypersensitivity 
after administration of hepatitis B 
containing vaccines or to any 
component of the vaccine 
Subjects will be observed for at 
least 30 minutes after vaccine 
administration, with medical 
attention available in case of 
anaphylaxis reactions. 
Adequate human data on use during 
pregnancy/lactation and adequate 
animal reproduction studies are not 
available 
The effect of the vaccine on foetal 
development has not been 
assessed. 
Pregnant subjects will not be 
included in this study (see Section 
4.2). Female subjects of 
childbearing potential are to have a 
urine pregnancy test prior to the 
study vaccine administration and 
will not be vaccinated if the test is 
positive (see Section 4.2 and 4.3). 
Study Procedures 
Syncope 
Spontaneous Syncope (fainting) 
can occur following, or even 
before, any vaccination as a 
psychogenic response to the 
needle injection. 
Section 6.6 highlights that 
procedures should be in place to 
avoid injuries from falls following 
syncope. In addition, subjects 
should be observed for 30 minutes 
after administration of the vaccine. 

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1.3.2. 
Benefit Assessment 
 
By taking part in this study, the subject will know if he/she still has circulating antibodies 
20 to 30 years after vaccination which is information that is not routinely available. 
 
This study will provide detailed immunogenicity information about the antibody 
persistence and immune memory after primary vaccination with Engerix-B 20 to 30 years 
ago. This would also present an opportunity to facilitate better protection against the 
disease, in the future. 
 
The subject will also benefit from an additional vaccine dose, which is currently not 
routinely offered, and which may help to keep him/her protected against hepatitis B even 
longer. 
 
1.3.3. 
Overall Benefit: Risk Conclusion 
 
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential or identified risks identified in association with Engerix-B are 
justified by the potential benefits that may be afforded to subjects receiving the vaccine 
for immunisation against hepatitis B infection. 
 
2. 
OBJECTIVES 
 
2.1. 
Primary objective 
• 
To assess the persistence of immunity to hepatitis B in terms of anti-HBs anamnestic 
response to an Engerix-B challenge dose, in adult subjects vaccinated with three or 
four doses of Engerix-B 20 to 30 years ago. 
Refer to Section 9.1 for the definition of the primary endpoint. 
 
2.2. 
Secondary objectives 
• 
To assess the persistence of immunity to hepatitis B in terms of Geometric Mean 
Concentrations (GMCs), seropositivity rates, seroprotection rates, and percentage of 
subjects with anti-HBs antibody concentrations  100 mIU/ml, before or after the 
Engerix-B challenge dose, in subjects vaccinated with three or four doses of Engerix- 
B 20 to 30 years ago. 
• 
To assess the persistence of immunity to hepatitis B in terms of T cell and memory B 
cell mediated immune responses specific to hepatitis B surface antigen, before and 
after the Engerix-B challenge dose, in adult subjects vaccinated with three or four 
doses of Engerix-B 20 to 30 years ago. 
• 
To evaluate the safety and reactogenicity of Engerix-B challenge dose in terms of 
solicited symptoms, unsolicited symptoms and serious adverse events (SAEs). 
Refer to Section 9.2 for the definition of the secondary endpoints. 

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3. 
STUDY DESIGN OVERVIEW 
 
 
 
n = Total number of subjects, PRE = Blood sample to be collected before vaccination, PD7 = Blood sample to be 
collected 7 days after vaccination, PD30 = Blood sample to be collected 30 days after vaccination. 
 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 5.5), are essential and required for 
study conduct. 
 
• 
Experimental design: Phase IV, open-label, non-randomised, multi-centric, multi- 
country study with a single group. 
• 
Duration of the study: Approximately one month per subject, starting from the 
administration of the challenge dose. 
 Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 3 (Day 30). 
• 
Study group: 
 LTFU: Subjects who received 3 or 4 doses of Engerix-B 20 to 30 years ago. 
 
The study group and epoch foreseen in the study are provided in Table 1. 
 
Table 1 
Study group and epoch foreseen in the study 
 
Study group 
Number of subjects 
Age (Min/Max)‡ 
Epoch 
Epoch 001 
LTFU 
Approximately 100 
40 years - 60 years 
x 
‡ Age at vaccination. 
 
The study group and treatment foreseen in the study are provided in Table 2. 

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Table 2 
Study group and treatment foreseen in the study 
 
Treatment name 
Vaccine name 
Study Group 
LTFU 
Engerix-B 
HBV 
x 
 
• 
Control: uncontrolled. 
• 
Vaccination schedule: A single dose of Engerix-B will be administered to all subjects 
at Visit 1 (Day 0). 
• 
Treatment allocation: Non-randomised. 
• 
Blinding: Open-label. 
 
Table 3 
Blinding of study epoch 
 
Study Epoch 
Blinding 
Epoch 001 
open-label 
 
• 
Sampling schedule: Blood samples will be taken from all subjects in order to 
evaluate the immunogenicity endpoints. The following blood samples will be taken 
at each study visit (Visit 1 [PRE], Visit 2 [PD7] and Visit 3 [PD30]): 
 
Three heparinised tubes of whole blood, of approximately 9 ml each, will be 
sampled for the assessment of memory B cells and T cells. 
 
One tube of approximately 5 ml of blood will be taken, from which 
approximately 1.7 ml of serum will be extracted for the measurement of 
antibodies. 
• 
Type of study: self-contained 
• 
Data collection: electronic Case Report Form (eCRF). 
4. 
STUDY COHORT 
 
4.1. 
Number of subjects/centres 
Approximately 100 adults between 40-60 years of age will be enrolled in study. 
Overview of the recruitment plan 
• 
The study will be conducted at multiple centres in Canada and Europe. 
• 
Enrolment will be stopped when approximately 100 eligible subjects have been 
enrolled in all participating countries. 
• 
Recruitment of subjects into the study will be tracked using the randomisation 
system on Internet (SBIR). 
• 
Recruitment will be monitored by the site monitor. 

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4.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
 
All subjects must satisfy ALL the following criteria at study entry: 
 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for follow-up 
visits). 
• 
A male or female between, and including, 40 and 60 years of age (from and 
including the 40th birthday up to, but excluding, the 61st birthday) at the time of the 
vaccination. 
• 
Written informed consent obtained from the subject. 
• 
Documented evidence of previous vaccination with three or four consecutive doses 
of Engerix-B administered in adulthood (i.e. at least 18 years of age) with 
 
the last dose received 4 to 12 months after the previous one, 
 
no subsequent booster dose ever received later, and 
 
the last dose received 20 to 30 years before enrolment. 
• 
Female subjects of non-childbearing potential may be enrolled in the study. 
 
Non-childbearing potential is defined as pre-menarche, hysterectomy, 
ovariectomy or post-menopause. 
Please refer to the glossary of terms for the definition of menopause. 
• 
Female subjects of childbearing potential may be enrolled in the study, if the subject: 
 
has practiced adequate contraception for 30 days prior to vaccination, and 
 
has a negative pregnancy test on the day of vaccination, and 
 
has agreed to continue adequate contraception during the entire treatment period 
and for one month after vaccination. 
Please refer to the glossary of terms for the definition of adequate contraception. 
 
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 

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The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the dose of study vaccine, or 
planned use during the study period. 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within six months prior to 
the vaccine dose. For corticosteroids, this will mean prednisone  20 mg/day, or 
equivalent. Inhaled and topical steroids are allowed. 
• 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
• 
Previous hepatitis B booster vaccination since completion of the primary vaccination 
series with three or four doses of Engerix-B. 
• 
Planned administration of a vaccine not foreseen by the study protocol within 30 
days preceding the dose of study vaccine, or planned administration during the study 
period, with the exception of seasonal influenza vaccine. 
• 
Any medical condition that in the judgment of the investigator places the subject at 
undue risk by participating in the study. 
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device). 
• 
History of hepatitis B disease or episode of jaundice with unknown etiology. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
• 
Major congenital defects or serious chronic illness (including insulin-dependent 
diabetes). 
• 
Acute disease and/or fever at the time of enrolment. 
 
Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or 
 38.0°C on rectal route. 
 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator. 
• 
Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the dose of study vaccine, or planned administration during 
the study period. 
• 
Drug and/ or alcohol abuse within the last 5 years. 

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5. 
CONDUCT OF THE STUDY 
 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
 
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
 
Conduct of the study includes, but is not limited to, the following: 
 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject informed consent. 
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
 
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject prior to participation in the study. 
 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF. 
 
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. 

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5.2. 
Subject identification and randomisation of treatment 
 
5.2.1. 
Subject identification 
 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre. 
 
5.2.2. 
Randomisation of treatment 
 
5.2.2.1. 
Randomisation of supplies 
 
The randomisation of supplies will be performed at GSK Biologicals, using MATerial 
EXcellence (MATEX), a program developed for use in Statistical Analysis System 
(SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to the study 
centres /warehouse(s). 
 
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation of supplies will be prepared. 
 
5.2.2.2. 
Treatment allocation to the subject 
 
The treatment numbers will be allocated by dose. 
 
5.2.2.2.1. 
Study group and treatment number allocation 
 
The enrolment will be performed to ensure equal distribution of approximately 100 
subjects across the two age strata (40 to 50 years and 51-60 years). Therefore, the 
expected distribution of subjects is as shown in Table 4. 
 
Table 4 
Number of subjects required for enrolment 
 
Age Stratum 
Vaccine 
N 
40-50 years 
Engerix B 
50 
51-60 years 
Engerix B 
50 
N = number of subjects to be enrolled 
 
Allocation of a treatment number to the subject at the investigator site will be performed 
using a randomisation system on internet (SBIR). 
 
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the study staff in charge of the vaccine administration will 
access SBIR. Upon providing the age (40 to 50 years and 51 to 60 years) and the subject 
identification number, the randomisation system will determine the age group and will 
provide the treatment number to be used for the dose. 

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The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 
 
Note that as soon as the target number of approximately 50 subjects in a specific age 
group has been reached, the enrolment will be frozen for this age group. 
 
5.3. 
Method of blinding 
This is an open-label study as all the subjects will receive a single challenge dose of 
Engerix-B. 
 
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample. 
 
5.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
 
5.5. 
Outline of study procedures 
The list of study procedures are provided in Table 5. 

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Table 5 
List of study procedures 
 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Time-points 
Day 0 
Day 7 
Day 30 
Sampling time-points 
PRE 
PD7 
PD30 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Collect demographic data 
● 
Medical history 
● 
Hepatitis B vaccination history† 
● 
Physical examination* 
● 
O 
O 
Measure/record height and weight 
● 
Check contraindications to vaccination 
O 
Pre-vaccination urine pregnancy test for female subjects of 
child bearing potential 
● 
Pre-vaccination body temperature measurement 
● 
Treatment number allocation 
O 
Blood sampling for antibody determination (~5 ml) 
● 
● 
● 
Blood sampling for CMI response (~27 ml) 
● 
● 
● 
Vaccine administration 
● 
Observation of the subjects for at least 30 minutes after 
vaccine administration 
O 
Record any concomitant medication/vaccination 
● 
● 
● 
Record any intercurrent medical conditions 
● 
● 
Distribution of diary cards 
O 
Recording of solicited adverse events (Days 0–3) by 
subjects 
● 
Recording of non-serious adverse events (Days 0-30) post- 
vaccination, by investigator or subjects 
● 
● 
● 
Medically attended visits 
● 
● 
Return of diary cards 
O 
O 
Diary card transcription by investigator‡ 
● 
● 
Recording of serious adverse events (SAEs) 
● 
● 
● 
Recording of SAEs related to study participation or to a 
concurrent GSK medication/vaccine 
● 
● 
● 
Recording of pregnancies and pregnancy outcomes 
● 
● 
● 
Study Conclusion 
● 
PRE = Blood sample to be collected before vaccination, PD7 = Blood sample to be collected 7 days after vaccination, 
PD30 = Blood sample to be collected 30 days after vaccination 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
O is used to indicate a study procedure that does not require documentation in the individual eCRF. 
* Physical examination after the vaccination visit, will be performed only if the subject indicates during questioning that 
there might be some underlying pathology(ies) or if deemed necessary by the Investigator or delegate. 
† Documentation regarding previous hepatitis B vaccination should be checked for subjects. 
‡ Diary card will be returned to the subject to continue recording adverse events until the last Visit. 
 
The intervals to be considered within the study are provided in Table 6. 

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Table 6 
Intervals between study visits 
 
Interval 
Optimal length of interval 
Allowed interval1 
Visit 1 Visit 2 
7 days 
5 days - 12 days 
Visit 1 Visit 3 
30 days 
21 days - 48 days 
1 Subjects will not be eligible for inclusion in the ATP cohort for analysis of immunogenicity if they make the study visit 
outside this interval. 
 
5.6. 
Detailed description of study procedures 
 
5.6.1. 
Informed consent 
 
The signed/witnessed/thumb printed informed consent of the subject/subject’s LAR(s) 
must be obtained before study participation. Refer to Section 5.1 for the requirements on 
how to obtain informed consent. 
 
5.6.2. 
Collect demographic data 
 
Demographic data such as age in years at challenge dose, gender, geographic ancestry, 
height, weight and body mass index (BMI) will be recorded in the subject’s eCRF at Visit 
1. 
 
5.6.3. 
Medical history 
 
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the study vaccination in the eCRF. 
 
5.6.4. 
Hepatitis B vaccination history 
 
Review the subject’s hepatitis B vaccination history and record the actual date of 
vaccination and brand of vaccine. This information should be recorded in the eCRF. 
 
5.6.5. 
Physical examination 
 
Perform a physical examination of the subject, including assessment of body temperature 
and resting vital signs: systolic/diastolic blood pressure, heart rate and respiratory rate 
after at least 10 minutes of rest. Collected information needs to be recorded in the eCRF. 
 
Physical examination at each study visit subsequent to the vaccination visit will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the Investigator or delegate. 
 
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 

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5.6.6. 
Check inclusion and exclusion criteria 
 
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
 
5.6.7. 
Record height and weight 
 
Height and weight of the subjects will be recorded at Visit 1. 
 
5.6.8. 
Check contraindications to vaccination 
 
Contraindications, warnings and precautions to vaccination must be checked at the 
vaccination visit. Refer to Sections 6.5 for more details. 
 
5.6.9. 
Pre-vaccination urine pregnancy test 
 
Female subjects of childbearing potential are to have a urine pregnancy test prior to study 
vaccine administration. The study vaccine may only be administered if the pregnancy test 
is negative. 
 
Note: The urine pregnancy test must be performed even if the subject is menstruating at 
the time of the study visit. 
 
5.6.10. 
Assess pre-vaccination body temperature 
 
The axillary or oral body temperature of all subjects needs to be measured prior to study 
vaccine administration. The preferred routes for recording temperature in this study will 
be axillary or oral. If the subject has fever [fever is defined as temperature  37.5°C for 
oral, axillary or tympanic route or  38.0°C on rectal route] on the day of vaccination, the 
vaccination visit will be rescheduled within the allowed interval for this visit (refer 
Table 6). 
 
5.6.11. 
Treatment number allocation 
 
Treatment number allocation will be performed as described in Section 5.2.2. The 
number of each administered treatment must be recorded in the eCRF. 
 
5.6.12. 
Sampling 
 
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. 

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5.6.12.1. 
Blood sampling for antibody determination and CMI response. 
 
Blood samples will be taken during all study visits as specified in Section 5.5; List of 
Study Procedures. 
 
• 
A volume of approximately 5 ml of whole blood (to provide at least 1.7 ml of serum) 
should be drawn from all subjects for analysis of humoral immune response at each 
visit (PRE, PD7 and PD30). After centrifugation, serum samples should be kept at 
-20°C or below until shipment. Refer to the SPM for more details on sample storage 
conditions. 
• 
A volume of approximately 27 ml of whole blood should be drawn from all subjects 
for analysis of cell-mediated immune (CMI) response at each visit (PRE, PD7 and 
PD 30). The blood should be stored at the investigator’s site at room temperature and 
it must not be centrifuged. Samples will be shipped/transferred at room temperature 
(15 to 25°C) to the designated laboratory for cell separation to be performed within 
24 hours of blood collection. Refer to the SPM for more details on sample storage 
conditions. 
 
5.6.13. 
Study Vaccine administration and observation of subjects 
following administration 
 
• 
After completing all prerequisite procedures prior to vaccination, the study vaccine 
will be administered intramuscularly (IM) in the deltoid, preferably of the non- 
dominant arm (refer to Section 6.3 for detailed description of the vaccine 
administration procedure). If the investigator or delegate determines that the 
subject’s health on the day of administration temporarily precludes vaccine 
administration, the visit will be rescheduled within the allowed interval for this visit 
(refer to Table 6). 
• 
The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccine, with appropriate medical treatment readily available in 
case of anaphylaxis. 
 
5.6.14. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7. 
Intercurrent medical conditions must also be checked and recorded in the eCRF as 
described in Section 6.8. 
 
5.6.15. 
Recording of solicited AEs and non-serious AEs 
 
• 
At Visit 1, the diary card will be provided to the subject. The subject will record 
body (preferred routes are axillary or oral) temperature and any solicited 
local/general AEs (i.e. on the day of vaccination and during the next 3 days) or any 
unsolicited AEs (i.e. on the day of vaccination and during the next 30 days) 

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occurring after vaccination. The subject will be instructed to return the completed 
diary card to the investigator at the next study visit. 
 
5.6.16. 
Medically attended visit 
 
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/she received medical attention defined as hospitalisation, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF. 
 
5.6.17. 
Return of diary cards and diary card transcription by investigator 
 
• 
Collect and verify completed diary cards during discussion with the subject at Visit 2 
and Visit 3. 
• 
Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure. The investigator or delegate will transcribe the 
collected information into the eCRF in English. 
 
5.6.18. 
Recording of AEs, SAEs, and pregnancies 
 
• 
Refer to Section 7.3 for procedures for the investigator to record AEs, SAEs, and 
pregnancies. Refer to Section 7.4 for guidelines and how to report SAE and 
pregnancy reports to GSK Biologicals. Refer to section 7.5.2 for guidelines on how 
to report pregnancy outcomes to GSK Biologicals. 
• 
The subjects will be instructed to contact the investigator immediately should the 
subjects manifest any signs or symptoms they perceive as serious. 
 
5.6.19. 
Study conclusion 
 
The investigator will: 
 
• 
review data collected to ensure accuracy and completeness 
• 
complete the Study Conclusion screen in the eCRF. 
5.7. 
Biological sample handling and analysis 
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment). 
 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
 
• 
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 

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methods, as well as making sure that new tests are comparable to previous methods 
and work reliably. 
• 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed, will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research. 
 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
 
Any sample testing will be done in line with the consent of the individual subject. 
 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
 
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed. 
 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
 
5.7.1. 
Use of specified study materials 
 
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 9.4 for the definition of 
cohorts to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM. 
 
5.7.2. 
Biological samples 
 
The type and quantity of biological samples that will be collected for analysis has been 
provided in Table 7. 

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Table 7 
Biological samples 
 
Sample type 
Quantity 
Unit 
Time-point 
Blood sample for antibody 
determination 
Approximately 5 
ml 
PRE (Visit 1), PD7 (Visit 2), PD30 (Visit 3) 
Blood sample for CMI 
Approximately 
27 
ml 
PRE (Visit 1), PD7 (Visit 2), PD30 (Visit 3) 
PRE = Blood sample to be collected before vaccination 
PD7 = Blood sample to be collected 7 days after vaccination 
PD30 = Blood sample to be collected 30 days after vaccination. 
 
5.7.3. 
Laboratory assays 
 
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analysis. 
 
Serological assays for the determination of antibodies against HBV will be performed by 
ELISA at a GSK Biologicals’ laboratory or in a laboratory designated by GSK 
Biologicals using standardised and validated procedures (refer to Table 8 and Table 9). 
 
Table 8 
Humoral Immunity (Antibody determination) 
 
System 
Component 
Method 
Kit / Manufacturer 
Unit 
Cut-off 
Laboratory 
* 
SER 
Hepatitis B 
Virus.Core Ab 
CLIA 
Immulite (Siemens 
Healthcare) 
No unit 
N/A 
CEVAC 
SER 
Hepatitis B 
Virus.Surface Ab 
CLIA 
ADVIA Centaur anti- 
HBs2 (Siemens 
Healthcare) 
mIU/ml 
6.2 
GSK 
Biologicals** 
*Refer to APPENDIX A for the laboratory addresses. 
SER = Serum 
CLIA = ChemiLuminescence ImmunoAssay 
N/A = Not Applicable 
CEVAC = Centre for Vaccinology, University of Gent 
**GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
 
Table 9 
Cell-Mediated Immunity (CMI) 
 
System 
Component 
Challenge 
Method 
Unit 
Laboratory* 
PBMC 
memory B-cells 
HBV03 
ELIB 
SFC/10E6 
SFC IgG 
GSK 
Biologicals** 
PBMC 
Cells CD4.CD40L(+)+Interleukin- 
2(-)+Tumor Necrosis Factor 
alpha(-)+Interferon gamma(-) 
HBV02 
CFC 
Events/10E6 
cells 
GSK 
Biologicals** 
*Refer to APPENDIX A for the laboratory addresses. 
PBMC = Peripheral Blood Mononuclear Cell 
ELIB = B cell Enzyme-linked Immunosorbent Spot 
SFC/10E6 SFC IgG = Frequency of specific memory B cells per million of memory B cells 
Events/10E6 cells = frequency of specific CD4+ T Cells per million of CD4+ T cells 
CFC = Cytokine Flow Cytometry 

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**GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium. Alternatively, the 
testing may be outsourced to a laboratory designated by GSK Biologicals using standardised and validated 
procedures. 
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory- 
independent Quality Department. 
 
5.7.4. 
Biological samples evaluation 
 
5.7.4.1. 
Immunological read-outs 
The immunological read-outs are provided in Table 10. 
Table 10 
Immunological read-outs 
 
Blood sampling time-point 
No. subjects 
Component 
Components priority rank 
Type of contact 
and time-point 
Sampling time- 
point 
Visit 1 (Day 0) 
PRE 
ALL 
Anti-HBs* 
1 
ALL 
Anti-HBc* 
2 
ALL 
Memory B cells 
1 
ALL 
T cells 
2 
Visit 2 (Day 7) 
PD7 
ALL 
Anti-HBs* 
1 
ALL 
Memory B cells 
1 
ALL 
T cells 
2 
Visit 3 (Day 30) 
PD30 
ALL 
Anti-HBs* 
1 
ALL 
Memory B cells 
1 
ALL 
T cells 
2 
* The results of these testings might potentially impact the subject medical care. 
PRE = Blood sample to be collected before vaccination, PD7 = Blood sample to be collected 7 days after vaccination, 
PD30 = Blood sample to be collected 30 days after vaccination. 
Anti-HBs = Antibodies against hepatitis B surface antigen 
Anti-HBc = Antibodies against hepatitis B core antigen 
 
In case of insufficient blood sample volume to perform assays for all components, the 
samples will be analysed according to priority ranking provided in Table 10. 
 
5.7.5. 
Immunological correlates of protection 
 
An anti-HBs antibody concentration  10 mIU/ml defines seroprotection [Centers for 
Disease Control and Prevention, 1991; WHO, 1988]. 
 
The immunological assay results will be communicated to the investigator when 
available, for the data collected up to Visit 3. 
 
The investigator is encouraged to share the immunological assay results for non- 
responders with the study subjects. 
 
For subjects identified as non-responders, it remains the responsibility of the study 
investigator in charge of the subject’s clinical management to determine the medical need 

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for re-vaccination, and to re-vaccinate the subjects according to local recommendations 
and practices. 
 
For subjects for whom an occult infection is identified, it is the responsibility of the study 
investigator in charge of the subject’s clinical management to determine the medical care 
of the subjects according to local recommendation. 
 
6. 
STUDY VACCINE AND ADMINISTRATION 
 
6.1. 
Description of study vaccine 
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained. 
 
The vaccines are labelled and packed according to applicable regulatory requirements. 
 
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics. 
 
The details of the study vaccine are presented in Table 11. 
 
Table 11 
Study vaccine 
 
Treatment 
name 
Vaccine name 
Formulation 
Presentation 
Volume to be 
administered 
Number of 
doses 
Engerix-B 
HBV 
HBsAg=20 µg; 
Al(OH)₃=500µg Al3+ 
The vaccine is 
presented as a 
suspension for 
injection in vials 
or prefilled 
syringes. 
1 ml 
1 
HBsAg: Hepatitis B surface antigen. 
 
6.2. 
Storage and handling of study vaccine 
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorised study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine. 
 
Temperature excursions must be reported in degree Celsius. 
 
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 

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The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor. 
 
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion. 
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take. 
 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccine. 
 
6.3. 
Dosage and administration of study vaccine 
All subjects will receive a single dose of Engerix-B. 
In order to ensure proper intramuscular (IM) injection of the study vaccine, a needle of at 
least 1 inch (2.54 cm) length, 25 gauge will be used [Centers for Disease Control and 
Prevention, 2002]. IM injections should be administered at a 90-degree angle into the 
deltoid region, preferably in the non-dominant arm. 
 
The details of dosage and administration of study vaccine are presented in Table 12. 
 
Table 12 
Dosage and administration 
 
Type of contact 
and time-point 
Volume to 
be     
administered 
Study 
group 
Treatment name 
Route1 
Site 
Side 
Visit 1 (Day 0) 
1 ml 
LTFU 
Engerix-B 
IM 
Deltoid 
Non-dominant 
1Intramuscular (IM) 
 
6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 50% additional vaccine doses will be 
supplied to replace those that are unusable. 
 
6.5. 
Contraindications to vaccination 
 
6.5.1. 
Absolute contraindications 
 
Engerix-B should not be administered to subjects with known hypersensitivity to any 
component of the vaccine, or to subjects having shown signs of hypersensitivity after 
previous Engerix-B administration. Since this is a single-dose study, the contraindications 
are included in the exclusion criteria (See Section 4.3). 

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6.5.2. 
Temporary contraindications 
 
The following events constitute temporary contraindications to administration of 
Engerix-B at that point in time. If any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol (see Section 5.5), or the subject may be withdrawn at the 
discretion of the investigator (see Section 7.5). 
 
• 
Acute disease and/or fever at the time of vaccination. 
 
Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or 
 38.0°C for rectal route. The preferred route for recording temperature in this 
study will be axillary or oral. 
 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered the vaccine. 
 
6.6. 
Warnings and precautions 
As with all injectable vaccines, appropriate medical treatment and supervision should 
always be readily available in case of a rare anaphylactic reaction following the 
administration of the study vaccine. 
Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic 
response to the needle injection. It is important that procedures are in place to avoid 
injury from faints. 
Refer to the approved product label/package insert for more information. 
 
6.7. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator should question the subject about any 
medications/products taken and vaccinations received by the subject. 
 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF. 
 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting 30 days before and following the dose of 
study vaccine (Day 0 to Day 30). 
• 
Any concomitant vaccination administered in the period starting 30 days before the 
dose of study vaccine and ending at the last study visit (Day 0 to Day 30). 
• 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 

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An anti-pyretic is considered to be prophylactic when it is given in the absence of 
fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal 
route]. 
• 
Any concomitant medications/products/vaccines listed in Section 6.7.2. 
• 
Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report. 
 
6.7.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses 
 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 9.4 for cohorts to be analysed. 
 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting 30 days before and following the dose of 
study vaccine. 
• 
Any concomitant vaccination administered in the period starting 30 days before the 
dose of study vaccine and ending at the last study visit. 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) during the study period. For corticosteroids, this will mean 
prednisone  20 mg/day or equivalent. Inhaled and topical steroids are allowed. 
• 
Immunoglobulins and/or any blood products administered from 3 months before the 
dose of study vaccine and during the study period. 
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab). 
 
6.8. 
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses 
At each study visit subsequent to the vaccination visit, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF. 
 
• 
Subjects who are anti-HBc positive. 
• 
Occurrence of a condition that has the capability of altering the subject’s immune 
response. 
• 
Any confirmed or suspected immunosuppressive or immunodeficiency condition 
based on medical history and physical examination (no laboratory tests required). 

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7. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol. 
 
Each subject will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious. 
 
7.1. 
Safety definitions 
 
7.1.1. 
Definition of an adverse event 
 
An AE is 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. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
 
Examples of an AE include: 
 
• 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• 
New conditions detected or diagnosed after investigational vaccine administration 
even though they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs, symptoms temporally associated with vaccine administration. 
• 
Significant failure of expected pharmacological or biological action. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen). 

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AEs to be recorded as endpoints (solicited AEs) are described in Section 7.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
 
Examples of an AE DO NOT include: 
 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF. 
 
7.1.2. 
Definition of a serious adverse event 
 
A SAE is any untoward medical occurrence that: 
 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation, 
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
d. Results in disability/incapacity, OR 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 

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Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
 
7.1.3. 
Solicited adverse events 
 
7.1.3.1. 
Solicited local (injection-site) adverse events 
 
The following local (injection-site) AEs will be solicited (Table 13): 
 
Table 13 
Solicited local adverse events 
 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
 
7.1.3.2. 
Solicited general adverse events 
 
The following general AEs will be solicited (Table 14): 
 
Table 14 
Solicited general adverse events 
 
Fatigue 
Fever 
Gastrointestinal symptoms † 
Headache 
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain. 
 
Note: Temperature will be preferably recorded in the evening. Should additional 
temperature measurements be performed at other times of day, the highest temperature 
will be recorded in the eCRF. 
 
7.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. vital signs, etc.) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 7.1.1 and 7.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. 

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The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
 
7.2. 
Events or outcomes not qualifying as adverse events or 
serious adverse events 
 
7.2.1. 
Pregnancy 
 
Female subjects who become pregnant after the vaccination may continue the study at the 
discretion of the investigator. 
 
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE. 
Note: The pregnancy itself should always be recorded on an electronic pregnancy report. 
 
The following should always be considered as SAE and will be reported as described in 
Sections 7.4.1 and 7.4.3: 
 
• 
Spontaneous pregnancy loss, including: 
 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
 
ectopic and molar pregnancy 
 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognised that national 
regulations might be different. 
• 
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 
• 
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion. 
 
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the investigational vaccine will be reported 
to GSK Biologicals as described in Section 7.4.3. While the investigator is not obligated 
to actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting. 

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7.3. 
Detecting and recording adverse events, serious adverse 
events and pregnancies 
 
7.3.1. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
 
All AEs following the administration of the dose of study vaccine (Day 0 to Day 30) 
must be recorded into the appropriate section of the eCRF, irrespective of intensity or 
whether or not they are considered vaccination related. 
 
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccine and will end 30 days following administration of the dose of study vaccine for 
each subject. See Section 7.4 for instructions on reporting of SAEs. 
 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the receipt of study vaccine. 
 
SAEs that are related to the investigational vaccine will be collected and recorded from 
the time of the receipt of study vaccine until the subject is discharged from the study. 
 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study. 
 
The time period for collecting and recording pregnancies will begin at the receipt of study 
vaccine and will end 30 days following administration of the dose of study vaccine. See 
section 7.4 for instructions on reporting of pregnancies. 
 
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 15. 

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Table 15 
Reporting periods for collecting safety information 
 
Event 
ICF 
sign 
off* 
Visit 1 
Vaccination 
4 d 
(Days 0-3) 
post-vaccination 
Visit 2 
Visit 3 
31 d (Days 0-30) 
post-vaccination 
Study Conclusion 
D0 
D7 
D30 
Solicited local and 
general AEs 
Unsolicited AEs 
AEs/SAEs leading 
to withdrawal from 
the study 
SAEs related to 
the investigational 
vaccine 
SAEs related to 
study participation 
or concurrent 
GSK 
medication/vaccin 
e 
Pregnancies 
* i.e. consent obtained. D: Day. 
 
7.3.2. 
Post-Study adverse events and serious adverse events 
 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 15. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccine, the investigator will promptly 
notify the Study Contact for Reporting SAEs. 

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7.3.3. 
Evaluation of adverse events and serious adverse events 
 
7.3.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
 
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as: 
 
‘Have you felt different in any way since receiving the vaccine or since the previous visit? 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the subject’s 
medical records to GSK Biologicals instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by GSK Biologicals. In this instance, all subject identifiers will be blinded on 
the copies of the medical records prior to submission to GSK Biologicals. 
 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
 
7.3.3.2. 
Assessment of adverse events 
 
7.3.3.2.1. 
Assessment of intensity 
 
The intensity of the following solicited AEs will be assessed as described (refer Table 
16): 

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Table 16 
Intensity scales for solicited symptoms in adults (40-60 years) 
 
Adults (40-60 years) 
Adverse Event 
Intensity grade 
Parameter 
Pain at injection site 
0 
None 
1 
Mild: Any pain neither interfering with nor preventing 
normal every day activities. 
2 
Moderate: Painful when limb is moved and interferes with 
every day activities. 
3 
Severe: Significant pain at rest. Prevents normal every 
day activities. 
Redness at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Fever* 
Record temperature in °C 
Headache 
0 
Normal 
1 
Mild: Headache that is easily tolerated 
2 
Moderate: Headache that interferes with normal activity 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
1 
Mild: Fatigue that is easily tolerated 
2 
Moderate: Fatigue that interferes with normal activity 
3 
Severe: Fatigue that prevents normal activity 
Gastrointestinal symptoms 
(nausea, vomiting, diarrhoea and/or 
abdominal pain) 
0 
Normal 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
2 
Moderate: Gastrointestinal symptoms that interfere with 
normal activity 
3 
Severe: Gastrointestinal symptoms that prevent normal 
activity 
*Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal route. The 
preferred route for recording temperature in this study will be axillary or oral. 
 
The maximum intensity of local injection site redness and swelling will be scored at GSK 
Biologicals as follows: 
 
0 
: 
Absent 
1 
: 
 20 mm 
2 
: 
> 20 mm and  50 mm 
3 
: 
> 50 mm 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 

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The intensity should be assigned to one of the following categories: 
 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities 
(for example, prevent attendance at work and would necessitate 
the administration of corrective therapy.) 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre- 
defined outcomes as described in Section 7.1.2. 
 
7.3.3.2.2. 
Assessment of causality 
 
The definitions for ‘NO’ and ‘YES’ have been written in such a way that all events that 
have been attributed a ‘NO’ can be pooled with events which in the primary vaccination 
study were determined to be ‘not related’ or ‘unlikely to be related’ to vaccination. Those 
events that are attributed a ‘YES’ can be pooled with those events that in the past were 
determined to have a ‘suspected’ or ‘probable’ relationship to vaccination in the primary 
vaccination study. 
 
The investigator is obligated to assess the relationship between investigational vaccine 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 
of the event to the investigational vaccine will be considered and investigated. The 
investigator will also consult the Prescribing Information for marketed products to 
determine his/her assessment. 
 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
 
In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual vaccine 
administered The investigator should, therefore, assess whether the AE could be causally 
related to vaccination rather than to the individual vaccines 

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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
 
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine? 
 
YES 
: 
There is a reasonable possibility that the vaccine contributed to the 
AE. 
NO 
: 
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine. There are other, more 
likely causes and administration of the study vaccine is not 
suspected to have contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 7.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
 
Possible contributing factors include: 
 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
 
7.3.3.3. 
Assessment of outcomes 
 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 

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7.3.3.4. 
Medically attended visits 
 
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/she received medical attention defined as hospitalisation, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF. 
 
7.4. 
Reporting of serious adverse events, pregnancies, and 
other events 
 
7.4.1. 
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals 
 
SAEs that occur in the time period defined in Section 7.3 will be reported promptly to 
GSK within the timeframes described in Table 17, once the investigator determines that 
the event meets the protocol definition of a SAE. 
 
Pregnancies that occur in the time period defined in Section 7.3 will be reported promptly 
to GSK within the timeframes described in Table 17, once the investigator becomes 
aware of the pregnancy. 
 
The timeframes for submitting serious adverse event, pregnancy and other event reports 
to GSK Biologicals are presented in Table 17. 
 
Table 17 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals 
 
Type of 
Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours*‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Pregnancies 
2 weeks* 
electronic pregnancy 
report 
2 weeks* 
electronic pregnancy report 
* Timeframe allowed after receipt or awareness of the information. 
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE. 

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7.4.2. 
Contact information for reporting serious adverse events, 
pregnancies 
 
Study Contact for Reporting SAEs and pregnancies 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs and pregnancies 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: PPD 
or PPD 
 
Email address: PPD 
 
7.4.3. 
Completion and transmission of SAE reports to GSK Biologicals 
 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS. 
 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
 
7.4.3.1. 
Back-up system in case the electronic reporting system does not work 
 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
 
7.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals 
 
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS. 

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Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report. 
 
7.4.5. 
Updating of SAE and pregnancy information after removal of 
write access to the subject’s eCRF 
 
When additional SAE and pregnancy information is received after removal of the write 
access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 17. 
 
7.4.6. 
Regulatory reporting requirements for serious adverse events 
 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 7.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation. 
 
7.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
 
7.5.1. 
Follow-up of adverse events and serious adverse events 
 
7.5.1.1. 
Follow-up during the study 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 17). 
 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 

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All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the vaccination. 
 
7.5.1.2. 
Follow-up after the subject is discharged from the study 
 
The investigator will follow subjects: 
 
• 
with SAEs or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable. 
 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
 
7.5.2. 
Follow-up of pregnancies 
 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using electronic pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period doesn’t 
need to be longer than six to eight weeks after the estimated date of delivery. 
 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE. 
 
7.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7). 
 
7.7. 
Subject card 
Study subjects must be provided with the address and telephone number of the main 
contact for information about the clinical study. 
 
The investigator (or designate) must therefore provide a “subject card” to each subject. In 
an emergency situation this card serves to inform the responsible attending physician that 

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the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator. 
 
Subjects must be instructed to keep subject cards in their possession for the duration of 
the study. 
 
8. 
SUBJECT COMPLETION AND WITHDRAWAL 
 
8.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
 
8.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
 
8.2.1. 
Subject withdrawal from the study 
 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol. 
 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
 
Investigators will attempt to contact those subjects who do not return for scheduled visits 
or follow-up. To re-establish contact, the investigator will make 3 documented attempts 
(3 phone calls) followed by a certified letter to the last known address. 
 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
 
• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 

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• 
Other (specify). 
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF. 
 
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 7.5.1.2). 
 
9. 
STATISTICAL METHODS 
 
9.1. 
Primary endpoint 
• 
Persistence of immunity to hepatitis B in adult subjects vaccinated with three or four 
doses of Engerix-B 20 to 30 years ago. 
 
Percentage of adult subjects with an anamnestic response 7 days and 30 days 
after the challenge dose. 
Refer to Section 9.5 for the definition of anamnestic response. 
 
9.2. 
Secondary endpoints 
• 
Persistence of immunity to hepatitis B in adult subjects vaccinated with three or four 
doses of Engerix-B 20 to 30 years ago. 
 
Percentage of adult subjects with anti-HBs antibody concentrations  6.2 
mIU/ml,  10 mIU/ml and  100 mIU/ml, at the pre-challenge dose time-point 
and Day 7 and Day 30 post-challenge dose time-points. 
 
Anti-HBs antibody concentrations, at the pre-challenge dose time-point and Day 
7 and Day 30 post-challenge dose time-points. 
 
Hepatitis B specific memory B cell-mediated immune responses (frequency of 
HBs-specific memory B cells) at the pre-challenge dose time-point and Day 7 
and Day 30 post-challenge dose time-points. 
 
Hepatitis B specific T cell-mediated immune responses (frequency of HBs- 
specific CD4 T-lymphocytes) at the pre-challenge dose time-point and Day 7 
and Day 30 post-challenge dose time-points. 
• 
Solicited local and general symptoms. 
 
Occurrence of solicited local symptoms during the 4-day (Days 0-3) follow-up 
period after the challenge dose. 
 
Occurrence of solicited general symptoms during the 4-day (Days 0-3) follow- 
up period after the challenge dose. 

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• 
Unsolicited adverse events. 
 
Occurrence of unsolicited symptoms during the 31-day (Days 0-30) follow-up 
period after the challenge dose. 
• 
Serious adverse events. 
 
Occurrence of SAEs after the challenge dose, up to the study end. 
 
9.3. 
Determination of sample size 
The primary objective of the study is to assess the anamnestic response to a challenge 
dose of Engerix-B in adults subjects vaccinated 20 to 30 years ago with 3 or 4 doses of 
Engerix-B. Since the objectives of the study are descriptive, the sample size for this study 
was not estimated using any power based computations. Considering at least 20% of 
enrolled subjects would be non-evaluable at the time of the analysis (e.g. drop-outs, non- 
compliance with protocol, etc.), the approximate number of subjects to be enrolled in the 
study is 100. 
The precision achieved with a sample size of 80 evaluable subjects (after accounting for 
20% drop-outs from 100 enrolled subjects), for anamnestic response to the challenge dose 
of Engerix-B in terms of exact 95% confidence interval (CI) is presented in Table 18. 
 
Table 18 
Exact two-sided 95% CI for a sample size of 80 evaluable subjects 
according to the anamnestic response to the challenge dose of 
Engerix-B 
 
No. of subjects to be 
enrolled 
No. of evaluable subjects 
to be expected (N) 
considering 20% drop out 
rate 
Subjects who mounted an anamnestic response as 
defined in primary endpoint 
n 
% 
Exact 95% CI 
LL 
UL 
100 
80 
72 
90.0 
81.2 
95.6 
72 
91.0 
82.4 
96.3 
73 
92.0 
83.6 
97.0 
74 
93.0 
85.0 
97.5 
75 
94.0 
86.2 
98.2 
76 
95.0 
87.7 
98.6 
76 
96.0 
88.9 
99.2 
77 
97.0 
90.2 
99.6 
78 
98.0 
91.9 
99.9 
79 
99.0 
93.2 
100.0 
80 
100.0 
95.5 
100.0 
n = Number of subjects who mounted an anamnestic response. 
% = (n/N)*100; LL = Lower limit; UL = Upper limit 
Reference data: Please refer Table 19. 
 
The reference values for the sample size computation mentioned above have been 
presented in Table 19. 

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Table 19 
Reference values 
 
Study 
Country 
Population 
(Age in Years) 
N 
N ATP 
Anamnestic response 
% (CI) 
108984 (HBV-313) 
Thailand 
19-21 
76 
72 
95.8 (88.3,99.1) 
110071 (HBV-316 BST:115) 
Thailand 
19-20 
29 
29 
96.6 (82.2,99.9) 
110073 (HBV-317 BST: 143) 
(CLIA) 
Thailand 
19-20 
49 
43 
92.1 (78.6,98.3) 
110073 (HBV-317 BST: 143) 
(ELISA) 
Thailand 
19-20 
49 
43 
95.3 (84.2,99,4) 
N = number of subjects included in the Total vaccinated cohort 
N ATP=number of subjects included in the ATP cohort for immunogenicity 
Response defined as: 
For initially seronegative subjects, antibody concentration 10 mIU/ml one month after the post-challenge dose 
For initially seropositive subjects: antibody concentration at one month after the post-challenge dose  4 fold the pre- 
vaccination antibody concentration. 
 
9.4. 
Cohorts for Analyses 
The two cohorts defined for the purpose of analysis are: 
 
• 
Total vaccinated cohort, 
• 
ATP cohort for analysis of immunogenicity. 
9.4.1. 
Total vaccinated cohort 
 
The TVC will include all subjects who received the challenge dose. 
 
9.4.2. 
According-to-protocol cohort for analysis of immunogenicity 
 
The ATP cohort for analysis of immunogenicity will include all evaluable subjects 
(i.e. those meeting all eligibility criteria, complying with the procedures defined in the 
protocol, with no elimination criteria during the study) who have received the challenge 
dose and for whom data concerning immunogenicity endpoint measures at pre-challenge 
(Visit 1) and one month post-challenge (V3) are available. The interval between Visit 1 
and Visit 3, considered for inclusion of a subject in the ATP cohort for analysis of 
immunogenicity will be 21-48 days. 
 
9.5. 
Derived and transformed data 
• 
Seronegative subjects: 
 
Subjects with anti-HBs antibody concentration < 6.2 mIU/ml 
• 
Seropositive subjects: 
 
Subjects with anti-HBs antibody concentration ≥ 6.2 mIU/ml 
• 
Seroprotected subjects: 
 
Subjects with anti-HBs antibody concentration ≥ 10 mIU/ml 

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• 
Anamnestic response to the challenge dose is defined as: 
 
At least (i.e. ≥) 4-fold rise in one month post-vaccination anti-HBs antibody 
concentrations in previously seropositive subjects. 
 
In previously seronegative subjects, anti-HBs antibody concentrations 
≥10 mIU/ml at one month post-challenge dose time-point. 
• 
Amplitude of anamnestic response is the change in fold value from pre-challenge 
dose time-point to one month post-challenge dose. 
• 
GMC calculations are performed by taking the anti-log of the mean of the log10 
concentration transformations. GMC will be calculated on all subjects. Antibody 
concentrations below the cut-off of the assay will be given an arbitrary value of half 
the cut-off for the purpose of GMC calculation. 
• 
For a given subject and a given immunogenicity measurement, missing or non- 
evaluable measurements will not be replaced. Therefore, an analysis will exclude 
subjects with missing or non-evaluable measurements. 
Safety/Reactogenicity: 
For the analysis of solicited symptoms within 4 days (Days 0-3) post-challenge dose, 
missing or non-evaluable measurements will not be replaced. Therefore, the analysis of 
the solicited symptoms based on the TVC will include only subjects with documented 
safety data (i.e. symptom screen completed). 
More specifically, the following rules will be used: 
• 
Subjects who documented the absence of a solicited symptom after challenge dose 
will be considered not having that symptom after that dose. 
• 
Subjects who documented the presence of a solicited symptom and fully or partially 
recorded daily measurement over the solicited period will be included in the 
summaries at the challenge dose and classified according to their maximum observed 
daily recording over the solicited period. 
• 
Subjects who documented the presence of a solicited symptom after the challenge 
dose without having recorded any daily measurement will be assigned to the lowest 
intensity category at that dose (i.e. 37.5°C for fever or grade 1 for other symptoms). 
• 
Doses without symptom sheets documented will be excluded. 
• 
For the analysis of unsolicited adverse events/concomitant medication, all vaccinated 
subjects will be considered and subjects who did not report an event will be 
considered as subjects without an event. 
 
9.6. 
Analysis of demographics 
• 
The demographic characteristics (age in years at challenge dose, gender, geographic 
ancestry, height, weight and BMI) at Visit 1, cohort description and withdrawal 
status will be summarised using descriptive statistics. The same analysis will be 
performed stratified by age. The age stratification will be 40-50 and 51-60 years. 

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• 
Mean, median and standard deviation will be provided for continuous variables such 
as age. 
• 
Frequency tables will be generated for categorical variables such as gender, race and 
centre. 
 
9.7. 
Analysis of immunogenicity 
The primary analysis on the response to the challenge dose will be performed on the ATP 
cohort for analysis of immunogenicity. If the percentage of subjects excluded from the 
ATP cohort for immunogenicity is more than 5%, a second analysis based on the TVC 
will be performed to complement the ATP analysis of immunogenicity. The 
immunogenicity analysis based on the TVC will include subjects for whom 
immunogenicity data are available. All the immunogenicity analysis will be performed as 
a whole group and by age stratification. The age stratification will be 40-50 years and 51- 
60 years. 
 
The following analyses will be performed: 
 
• 
The percentage of subjects with anti-HBs antibody concentrations  6.2 mIU/ml, 
 10 mIU/ml,  100 mIU/ml,  1000 mIU/ml with exact 95% CIs will be calculated 
at the pre-challenge dose time-point, Day 7 and Day 30 post-challenge dose time- 
points. 
• 
The percentage of subjects who mount an anamnestic response to the challenge dose, 
one month after vaccination, will be tabulated with exact 95% CI as a whole and 
according to their seroprotection status at pre-challenge time-point (anti-HBs 
antibody concentrations  or  10 mIU/ml). 
• 
GMCs with 95% CI will be calculated for anti-HBs antibodies at the pre-challenge 
dose time-point, Day 7 and Day 30 post-challenge dose time-points. 
• 
The distribution of anti-HBs antibody concentrations will be displayed using reverse 
cumulative distribution curve (RCC) at the pre-challenge dose time-point and Day 30 
post-challenge dose time-point. 
• 
Relationship between pre-challenge dose time-point and Day 30 post-challenge dose 
time-point results will be presented by regression line graph. 
• 
CMI responses in terms of frequency of HBs-specific CD4+ T- lymphocytes and 
frequency of HBs-specific memory B cells at Day 0, Day 7 and Day 30 (for subjects 
who received a challenge dose) will be evaluated. 
• 
The percentage of subjects with anti-HBs concentrations ≥ 6.2 mIU/ml, ≥ 10 mIU/ml 
and  100 mIU/ml (with 95% CI) at the Day 7 and Day 30 post-challenge dose time- 
points will be tabulated in relation to their pre-challenge dose status (overall, 
< 10 mIU/ml and  10 mIU/ml). 
• 
The percentage of subjects (with 95% CI) who mount an anamnestic response will be 
calculated and in relation to their pre-challenge dose status (< 10 mIU/ml and 
≥ 10 mIU/ml). 

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9.8. 
Exploratory Analysis: 
• 
Correlation between the anti-HBs specific T and memory B cells (frequency of 
cytokine-positive CD4+ or T-lymphocytes and frequency of memory B cells) with 
the amplitude of anamnestic response one month after the challenge dose will be 
analysed by Pearson’s correlation coefficient. 
 
• 
Further logistic regression modelling will be used to assess the impact of prognosis 
factors like age, gender, geographic ancestry, BMI and pre-vaccination status 
(seroprotected or not) on the seroprotection rate after the challenge dose. Actual age 
and BMI at the time of screening will be considered in the model. 
 
9.9. 
Analysis of safety 
The primary analysis will be performed on the TVC. 
 
• 
The percentage of subjects who reported at least one local AE (solicited and 
unsolicited), with at least one general AE (solicited and unsolicited) and with any AE 
during the 4-day (Days 0-3) follow-up period after the vaccination will be tabulated 
with exact 95% CI. The same calculations will be performed for any Grade 3 
(solicited or unsolicited) symptoms and any symptoms requiring medical attention. 
• 
The percentage of subjects reporting each individual solicited symptom during the 4- 
day (Days 0-3) follow-up period with exact 95% CI, by type of AE; by severity (any 
Grade, Grade 3 only); by relationship to vaccination (any relationship, related only) 
will be tabulated. 
• 
The occurrence of fever will be tabulated per 0.5°C cumulative increments as well as 
the occurrence of Grade 3 fever (> 39.0 °C axillary temperature) with causal 
relationship to vaccination. 
• 
The percentage of subjects reporting at least one report of unsolicited AE classified 
by the Medical Dictionary for Regulatory Activities (MedDRA) and reported within 
the 31-day (Days 0-30) follow-up period after vaccination will be tabulated with 
exact 95% CI. The same tabulation will be performed for Grade 3 unsolicited AEs 
and for unsolicited AEs with a causal relationship to vaccination. 
• 
SAEs during the entire study period and withdrawals due to AEs and SAEs reported 
during the 31-day follow-up period after the challenge dose will be described in 
detail. 
 
9.10. 
Interpretation of analyses 
The analyses will be detailed in a descriptive manner. 
 
9.11. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 

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9.11.1. 
Sequence of analyses 
 
The demographic, immunogenicity and safety analyses of the antibodies and the 
challenge dose will be performed at the end of the study when all data are available. 
These analyses will be the basis of a Clinical Study Report and will be made available to 
the investigator. 
 
9.11.2. 
Statistical considerations for interim analyses 
 
Interim analyses are not planned for this study. 
 
10. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
 
10.1. 
Electronic Case Report Form instructions 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
 
10.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, the: 
 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 

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The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
 
For eCRF, the monitor freezes completed and approved screens at each visit. 
 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
 
10.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 

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10.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
 
10.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
 
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully disclosed. 
 
10.6. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually- 
agreeable location. 
 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
 
11. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable. 

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12. 
REFERENCES 
Centers for Disease Control and Prevention. Hepatitis B Virus: A Comprehensive 
Strategy for Eliminating Transmission in the United States Through Universal Childhood 
Vaccination: Recommendations of the Immunization Practices Advisory Committee 
(ACIP). MMWR. 1991; 40(RR-13): 1-19. 
 
Centers for Disease Control and Prevention. General recommendations on immunization: 
Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the 
American Academy of Family Physicians (AAFP). MMWR. 2002; 51(RR02); 1-36. 
 
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf 
 
EMA Guideline on the exposure to medicinal products during pregnancy: need for post- 
authorization data (Doc. Ref. EMEA/CHMP/313666/2005) ‘adopted at Community level 
in May 2006); 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g 
uideline/2009/11/WC500011303.pdf 
 
European Consensus Group on Hepatitis B Immunity. Are booster immunisations needed 
for lifelong hepatitis B immunity? Lancet. 2000; 355: 561-565. 
 
Gilca V, De Serres G, Boulianne N et al. Antibody persistence and the effect of a booster 
dose given 5, 10 or 15 years after vaccinating preadolescents with a recombinant hepatitis 
B vaccine. Vaccine. 2013;31(3):448-51. 
 
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, et al. 
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 
2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 
2012;380:2095-2128 
 
Poovorawan Y, Chongsrisawat V, Theamboonlers A, et al. Persistence of antibodies and 
immune memory to hepatitis B vaccine 20 years after infant vaccination in Thailand. 
Vaccine. 2010; 28(3):730-6. 
 
Poovorawan Y, Chongsrisawat V, Theamboonlers A, et al. Persistence and immune 
memory to hepatitis B vaccine 20 years after primary vaccination of Thai infants, born to 
HBsAg and HBeAg positive mothers. Hum Vaccin Immunother. 2012; 8(7):896-904 
 
Poovorawan Y, Chongsrisawat, Theamboonlers A, et al. Long-term anti-HBs antibody 
persistence following infant vaccination against hepatitis B and evaluation of anamnestic 
response: a 20-year follow-up study in Thailand. Hum Vaccin Immunother. 2013; 
9(8):1679-84. 

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The European Centre for Disease Prevention and Control (ECDC). 
(http://ecdc.europa.eu/en/healthtopics/hepatitis_B/Pages/index.aspx. Accessed August 
2015. 
 
Van Damme P, Moiseeva A, Marichev I, et al. Five years follow-up following two or 
three doses of a hepatitis B vaccine in adolescents aged 11-15 years: a randomised 
controlled study. BMC Infectious Diseases 2010; 10:357. 
 
WHO. Progress in the control of viral hepatitis: Memorandum from a WHO Meeting. 
Bull WHO. 1988; 66(4): 443–445. 
 
WHO. Hepatitis B vaccines: WHO position paper-recommendations. Vaccine. 2010; 
28(3):589-90. 
 
WHO. Immunization, Vaccines and Biologicals. 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index5.html. Accessed: 
August 2015. 

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APPENDIX A 
CLINICAL LABORATORIES 
Table 20 
GSK Biologicals’ laboratories 
 
Laboratory 
Address 
GSK Biologicals Global Vaccine 
Clinical Laboratory, Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Global Vaccine 
Clinical Laboratory, Wavre-Nord 
Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
 
Table 21 
Outsourced laboratories 
 
Laboratory 
Address 
CEVAC - University of Gent 
De Pintelaan, 185 Gent 
Belgium 

 
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116811 (HBV-322) 
Protocol Final Version 1 
Protocol Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
 
EudraCT number 
Date of protocol 
Detailed Title 
 
 
 
 
Sponsor signatory 
116811 (HBV-322) 
 
 
2015-004099-31 
 
Final Version 1: 02 February 2016 
 
A phase IV, open-label, non-randomised, multicentre 
study to assess the long-term persistence of immunity 
to hepatitis B in adults vaccinated 20 to 30 years ago 
with 3 or 4 doses of GSK Biologicals' hepatitis B 
vaccine, Engerix™-B. 
 
Dominique Descamps, 
Vice President, Head of Clinical Research and 
Development 
GlaxoSmithKline Vaccines 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
 
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