A Phase I/IIa, Open-label, Randomised, Controlled, Multi-country, Dose-escalation Study to Assess the Safety and Immunogenicity of AS37 in Combination With the Hepatitis B Surface Antigen (HBsAg), According to a 0-1 Month Schedule, in Healthy, HBs naïve, Adults Aged 18-45 Years
Phase: PHASE1
Conditions: Hepatitis B
Sponsor: GlaxoSmithKline

Protocol Amendment 4
Study ID:  215301
Official Title of Study: A Phase 1/2a, open-label, randomized, controlled, 
multicountry, dose-escalation study to assess the safety and immunogenicity of 
AS37 in combination with the Hepatitis B surface antigen (HBsAg), according to a 
0-1-month schedule, in healthy, HBs-naïve, adults aged 18-45 years
NCT number: NCT05561673
Date of Document: 17-Sep-2024
Note: The typo appears in the following sections of the Protocol document - 1.1 
(Synopsis), 3 (Objectives), and 9.3.1 (Primary Endpoints Analyses).  The phrase 
currently reads “absolute values and changes”, but it should be “absolute values of 
changes”.

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CLINICAL STUDY PROTOCOL  
Primary study intervention 
and number 
GSK’s Hepatitis B surface antigen (HBsAg) 
adjuvanted with GSK’s AS37 Adjuvant System 
(GSK2231392A) 
Other study interventions 
• 
GSK’s Hepatitis B vaccine adjuvanted with 
aluminum hydroxide (Engerix-B, SKF103860) 
• 
GSK’s Hepatitis B vaccine adjuvanted with 
GSK’s AS04 Adjuvant System (Fendrix) 
• 
GSK’s HBsAg candidate vaccine adjuvanted 
with GSK’s AS03 Adjuvant System 
(GSK2231392A) 
Study identifier and 
abbreviated title 
215301 (EARLY-CLINRES-017) 
EudraCT number 
2021-005629-25 
Date of protocol 
Final: 25 April 2022 
Date of protocol amendment 
Amendment 1 Final: 10 August 2022 
Amendment 2 Final: 01 March 2023 
Amendment 3 Final: 17 November 2023 
Amendment 4 Final: 17 Sep 2024  
Title 
A Phase 1/2a, open-label, randomized, controlled, 
multi-country, dose-escalation study to assess the 
safety and immunogenicity of AS37 in combination 
with the Hepatitis B surface antigen (HBsAg), 
according to a 0-1-month schedule, in healthy, 
HBs-naïve, adults aged 18-45 years 
Brief title 
A study on the safety and immune response of AS37 
together with Hepatitis B antigen in adults aged 
18-45 years 
Sponsor 
GlaxoSmithKline Biologicals SA 
Rue de l'Institut 89 
1330 Rixensart 
Belgium 
Sponsor signatory 
Bach-Yen Nguyen, MD 
Vice-President, Head of Therapeutic Cluster, 
Vaccines Clinical Sciences 

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Medical monitor name and contact information can be found in the local study 
contact information document. 
Based on GlaxoSmithKline Biologicals SA Protocol WS v17.2 
©2024 GSK group of companies or its licensor. Trademarks are property of their 
respective owners. 

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Protocol Amendment 4 Sponsor Signatory Approval  
Study identifier and 
abbreviated title 
215301 (EARLY-CLINRES-017) 
EudraCT number 
2021-005629-25 
Date of protocol 
Final: 25 April 2022 
Date of protocol amendment 
Amendment 1 Final: 10 August 2022 
Amendment 2 Final: 01 March 2023 
Amendment 3 Final: 17 November 2023 
Amendment 4 Final: 17 Sep 2024 
Title  
A Phase 1/2a, open-label, randomized, controlled, 
multi-country, dose-escalation study to assess the 
safety and immunogenicity of AS37 in combination 
with the Hepatitis B surface antigen (HBsAg), 
according to a 0-1-month schedule, in healthy, 
HBs-naïve, adults aged 18-45 years 
Sponsor signatory 
Bach-Yen Nguyen, MD 
Vice-President, Head of Therapeutic Cluster, 
Vaccines Clinical Sciences 
Signature 
 
 
 
Date 
 
Note: Not applicable if an alternative signature process (e.g., electronic signature or 
email approval) is used to get the sponsor approval. 

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Protocol Amendment 4 Investigator Agreement  
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, GCP and all applicable regulatory 
requirements. 
• 
That I will comply with the terms of the site agreement. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To cooperate with representative(s) of GSK in the monitoring and data management 
processes of the study with respect to data entry and resolution of queries about the 
data. 

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Study identifier and 
abbreviated title 
215301 (EARLY-CLINRES-017) 
EudraCT number 
2021-005629-25 
Date of protocol 
Final: 25 April 2022 
Date of protocol amendment 
Amendment 1 Final: 10 August 2022 
Amendment 2 Final: 01 March 2023 
Amendment 3 Final: 17 November 2023 
Amendment 4 Final: 17 Sep 2024 
Title 
A Phase 1/2a, open-label, randomized, controlled, 
multi-country, dose-escalation study to assess the 
safety and immunogenicity of AS37 in combination 
with the Hepatitis B surface antigen (HBsAg), 
according to a 0-1-month schedule, in healthy, 
HBs-naïve, adults aged 18-45 years 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
name, function and title 
 
 
 
Signature 
 
 
 
Date of signature 
 
 
 
PPD

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SPONSOR INFORMATION  
1. Sponsor 
GSK 
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 Serious Adverse Events (SAEs) 
GSK central back-up study contact for reporting SAEs: refer to Section 8.4.3.1. 
Study contact for reporting SAEs: refer to the local study contact information 
document. 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 4 
17 Sep 2024 
Amendment 3 
17 November 2023 
Amendment 2 
01 March 2023 
Amendment 1 
10 August 2022 
Original Protocol 
25 April 2022 
Amendment 4 (17 Sep 2024) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it relates to changes in the conduct of assays addressing tertiary 
endpoints of the clinical study. 
Overall rationale for the current Amendment: 
Several factors are driving this amendment: i) the results obtained in the main analysis 
from immunogenicity data (secondary endpoints) collected from all participants 
post-Dose 2 (Day 61), ii) 
 
 
. Timelines for data 
availability are also impacting the content of the final analysis and clinical study report. 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RESPECTIVE 
RATIONALE: 
Section # and title 
Description of change 
Brief rationale 
Headers, title page, Protocol 
Amendment Summary of 
Changes (new) 
Headers and title page were 
updated with new document 
number, amendment 
information, and sponsor 
signatory name; Protocol 
Amendment Summary of 
Changes section was updated 
to include the rationale for this 
amendment; minor corrections 
and formatting adjustments 
were made to add clarification 
and/or remove discrepancies. 
Editorial changes have been 
implemented as needed. 
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Section # and title 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Added/updated subheadings 
to summarize details in the 
synopsis.  
To align with the latest 
protocol template. 
Section 3 Objectives and 
endpoints  
Updated the tertiary 
endpoints.  
Section 6.1.1 Medical devices  Added a section on medical 
devices.  
To align with the latest 
protocol template.  
Section 8.1 Immunogenicity 
assessments  
Updated the paragraph on 
sample collection for 
immunogenicity assessments.  
To align with the latest 
protocol template.  
Section 8.1.2 Laboratory 
assays 
Updated the methods of 
laboratory assays. 
 
 
Added a table on assays and 
subsets.  
Availability of alternative 
assays with higher 
throughput. 
 
To provide details of assays 
and number of participants in 
each assay.  
Section 8.6 
Pharmacodynamics  
Added a section on 
pharmacodynamics.  
To align with the latest 
protocol template.  
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Section # and title 
Description of change 
Brief rationale 
Section 10.1.1 Regulatory and 
ethical considerations 
Section 10.1.3 Informed 
consent process 
Section 10.1.4 Data protection 
Section 10.1.6 Dissemination 
of clinical study data 
Section 10.1.7 Data quality 
assurance 
Section 10.1.8 Source 
documents 
Section 10.1.10 Publication 
policy  
Updated the sections with 
latest template text. 
To align with the latest 
protocol template.  
Section 10.2.2 Protocol-
required immunogenicity 
assessments 
Updated the laboratory assay 
methods.  
To reflect change in assay 
selection.  
Section 10.3 Appendix 3: 
Adverse Events: definitions 
and procedures for recording, 
evaluating, follow-up, and 
reporting 
Updated the sections with 
latest template text.  
To align with the latest 
protocol template.  
Section 10.4 Appendix 4: 
Contraceptive guidance and 
collection of pregnancy 
information 
Updated the sections with 
latest template text.  
To align with the latest 
protocol template.  
Section 10.6 Appendix 6: 
Definition of medical device 
AE, adverse device effect 
(ADE), serious adverse device 
effect (SADE) and 
unanticipated SADE (USADE) 
Updated the sections with 
latest template text.  
To align with the latest 
protocol template.  
Section 10.9 Appendix 9: List 
of potential immune-mediated 
disorders, Table 27 List of 
pIMDs  
Updated the pIMD table.  
To align with the latest 
protocol template.  
 
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TABLE OF CONTENTS  
PAGE  
SPONSOR INFORMATION ............................................................................................ 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 7 
List of main changes in the protocol and their respective rationale: .......................... 7 
1. 
PROTOCOL SUMMARY ........................................................................................ 18 
1.1. 
Synopsis ..................................................................................................... 18 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedule of Activities (SoA) ........................................................................ 20 
2. 
INTRODUCTION .................................................................................................... 25 
2.1. 
Study rationale ............................................................................................ 25 
2.2. 
Background ................................................................................................ 26 
2.3. 
Benefit/Risk assessment ............................................................................. 26 
2.3.1. 
Risk assessment .......................................................................... 26 
2.3.2. 
Benefit assessment ..................................................................... 27 
2.3.3. 
Overall benefit/risk conclusion ..................................................... 28 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 28 
4. 
STUDY DESIGN .................................................................................................... 30 
4.1. 
Overall design ............................................................................................. 30 
4.2. 
Study groups .............................................................................................. 32 
4.2.1. 
Overview of the recruitment plan ................................................. 32 
4.3. 
Scientific rationale for study design ............................................................. 33 
4.4. 
Justification for dose ................................................................................... 33 
4.5. 
End of Study definition ................................................................................ 34 
5. 
STUDY POPULATION ........................................................................................... 34 
5.1. 
Inclusion criteria .......................................................................................... 34 
5.2. 
Exclusion criteria ......................................................................................... 35 
5.2.1. 
Medical conditions ....................................................................... 35 
5.2.2. 
Prior/Concomitant therapy ........................................................... 35 
5.2.3. 
Prior/Concurrent clinical study experience ................................... 36 
5.2.4. 
Other exclusions .......................................................................... 36 
5.2.5. 
.................... 37 
5.3. 
Lifestyle considerations ............................................................................... 37 
5.4. 
Screening failures ....................................................................................... 37 
5.4.1. 
Rescreening ................................................................................ 37 
5.5. 
Criteria for temporarily delaying enrolment/study intervention 
administration. ............................................................................................ 37 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ................................ 38 
6.1. 
Study interventions administered ................................................................ 38 
6.1.1. 
Medical devices ........................................................................... 40 
6.2. 
Preparation, handling, storage, and accountability ...................................... 40 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 40 
6.3.1. 
Participant identification ............................................................... 40 
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6.3.2. 
Randomization to study intervention ............................................ 40 
6.3.3. 
Intervention allocation to the participant ....................................... 41 
6.3.4. 
............................. 41 
6.3.5. 
Allocation of participants to assay subsets ................................... 41 
6.4. 
Blinding and unblinding ............................................................................... 41 
6.5. 
Study intervention compliance .................................................................... 42 
6.6. 
Dose modification ....................................................................................... 42 
6.7. 
Continued access to study intervention after the end of the study ............... 42 
6.8. 
Treatment of overdose ................................................................................ 42 
6.9. 
Concomitant therapy ................................................................................... 42 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 43 
7.1. 
Discontinuation of study intervention ........................................................... 43 
7.1.1. 
Contraindications to subsequent study intervention(s) 
administration .............................................................................. 43 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 44 
7.3. 
Lost to follow-up.......................................................................................... 45 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 45 
8.1. 
Immunogenicity assessments ..................................................................... 46 
8.1.1. 
Biological samples ....................................................................... 46 
8.1.2. 
Laboratory assays ....................................................................... 47 
8.1.3. 
Immunological read-outs .............................................................. 48 
8.1.4. 
Clinical safety laboratory assessments ........................................ 49 
8.1.5. 
Immunological correlates of protection ......................................... 49 
8.2. 
Safety assessments .................................................................................... 50 
8.2.1. 
Pre-intervention administration procedures .................................. 50 
8.2.1.1. 
Collection of demographic data .................................. 50 
8.2.1.2. 
Medical/vaccination history ......................................... 50 
8.2.1.3. 
Physical examination .................................................. 50 
8.2.1.4. 
Pregnancy test ........................................................... 51 
8.2.1.5. 
Warnings and precautions to administration of 
study intervention ....................................................... 51 
8.2.2. 
Clinical safety laboratory tests ..................................................... 51 
8.2.3. 
Study holding rules and safety monitoring.................................... 51 
8.2.3.1. 
Staggered administration of study intervention ........... 51 
8.2.3.2. 
Outcome of safety evaluation ..................................... 52 
8.2.3.3. 
Study holding rules ..................................................... 53 
8.3. 
Other assessments ..................................................................................... 54 
............................... 54 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and other 
safety reporting ........................................................................................... 55 
8.4.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 55 
8.4.2. 
Method of detecting AEs and SAEs, pregnancies and 
other events ................................................................................. 56 
8.4.2.1. 
Clinically significant abnormal laboratory 
findings ....................................................................... 56 
8.4.3. 
Regulatory reporting requirements for SAEs, pregnancies 
and other events .......................................................................... 57 
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8.4.3.1. 
Contact information for reporting SAEs, pIMDs, 
pregnancies and study holding rules .......................... 58 
8.4.4. 
Treatment of AEs ......................................................................... 58 
8.4.5. 
Participant card ............................................................................ 58 
8.4.6. 
Medical device deficiencies ......................................................... 58 
8.4.6.1. 
Detection, follow-up and prompt reporting of 
medical device deficiency ........................................... 58 
8.4.6.2. 
Regulatory reporting of medical device 
deficiency when used as combination product ............ 59 
8.5. 
.................................................................................... 59 
8.6. 
.................................................................................... 59 
8.7. 
.................................................................................... 59 
8.8. 
.................................................................................... 59 
8.9. 
Immunogenicity assessments ..................................................................... 60 
8.10. 
Health outcomes ......................................................................................... 60 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 60 
9.1. 
Statistical hypotheses ................................................................................. 60 
9.2. 
Analysis sets ............................................................................................... 60 
9.2.1. 
Criteria for elimination from analysis ............................................ 60 
9.3. 
Statistical analyses ..................................................................................... 61 
9.3.1. 
Primary endpoints analyses ......................................................... 61 
9.3.2. 
Secondary endpoints analyses .................................................... 62 
9.4. 
Interim analyses .......................................................................................... 62 
9.4.1. 
Sequence of analyses.................................................................. 64 
9.4.1.1. 
Main analysis .............................................................. 64 
9.4.1.2. 
Final analysis .............................................................. 64 
9.5. 
Sample size determination .......................................................................... 65 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 68 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 68 
10.1.1. 
Regulatory and ethical considerations ......................................... 68 
10.1.2. 
Financial disclosure ..................................................................... 69 
10.1.3. 
Informed consent process ............................................................ 69 
10.1.4. 
Data protection ............................................................................ 69 
10.1.5. 
Committees’ structure .................................................................. 70 
10.1.6. 
Dissemination of clinical study data ............................................. 70 
10.1.7. 
Data quality assurance ................................................................ 71 
10.1.8. 
Source documents ....................................................................... 72 
10.1.9. 
Study and site start and closure ................................................... 73 
10.1.10. Publication policy ......................................................................... 74 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 74 
10.2.1. 
Protocol-required safety laboratory assessments ......................... 74 
10.2.2. 
Protocol-required immunogenicity assessments .......................... 76 
10.2.2.1. Total Ig Anti-Hepatitis B Surface antigen CLIA ........... 76 
.................................................... 76 
10.2.2.3. Intracellular cytokine staining for HBs-specific 
CD4+/CD8+ T-cells .................................................... 77 
...................... 77 
10.2.2.5. B-cell ELISPOT assay ................................................ 78 
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............ 78 
............ 78 
............ 79 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 79 
10.3.1. 
Definition of an AE ....................................................................... 79 
10.3.1.1. Events Meeting the AE Definition ............................... 79 
10.3.1.2. Events NOT Meeting the AE Definition ....................... 80 
10.3.2. 
Definition of an SAE ..................................................................... 81 
10.3.3. 
Solicited events............................................................................ 82 
10.3.4. 
Unsolicited AEs............................................................................ 82 
10.3.5. 
Adverse events of special interest (AESIs) .................................. 83 
10.3.5.1. Potential immune-mediated disorders......................... 83 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs ...................................... 84 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs ..................... 84 
10.3.7.1. Pregnancy .................................................................. 84 
10.3.8. 
Recording and follow-up of AEs, SAEs, pIMDs and 
pregnancies ................................................................................. 85 
10.3.8.1. Time period for collecting and recording AEs, 
SAEs, MAEs, pIMDs and pregnancies........................ 85 
10.3.8.2. Follow-up of AEs, SAEs, pIMDs, pregnancies ............ 86 
10.3.8.2.1. Follow-up during the study ...................... 86 
10.3.8.2.2. Follow-up after the participant is 
discharged from the study ...................... 86 
10.3.8.2.3. Follow-up of pregnancies ........................ 86 
10.3.8.3. Updating of SAE, pIMD and pregnancy 
information after removal of write access to the 
participant’s eCRF ...................................................... 87 
10.3.9. 
Assessment of intensity and toxicity ............................................. 87 
10.3.9.1. Assessment of intensity .............................................. 87 
10.3.9.2. Assessment of causality ............................................. 89 
10.3.9.3. Medically attended visits ............................................. 90 
10.3.9.4. Assessment of outcomes............................................ 90 
10.3.10. Reporting of SAEs, pIMDs, pregnancies ...................................... 90 
10.3.10.1. Events requiring expedited reporting to GSK .............. 90 
10.3.10.2. Back-up system in case the electronic 
reporting system does not work .................................. 91 
10.4. 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information .................................................................................................. 91 
10.4.1. 
Definitions .................................................................................... 91 
10.4.1.1. Woman of childbearing potential (WOCBP) ................ 91 
10.4.1.2. Women not considered as women of 
childbearing potential .................................................. 91 
10.4.2. 
Contraception guidance ............................................................... 92 
10.4.3. 
Collection of pregnancy information ............................................. 93 
10.4.3.1. Female participants who become pregnant ................ 93 
10.5. 
 .................................................................................. 93 
10.6. 
Appendix 6: Definition of medical device AE, adverse device effect 
(ADE), serious adverse device effect (SADE) and unanticipated 
SADE (USADE) .......................................................................................... 93 
10.6.1. 
Definition of medical device AE and ADE..................................... 94 
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10.6.2. 
Definition of medical device SAE, SADE and USADE .................. 94 
10.6.3. 
Recording and reporting of medical device AE, ADEs, 
SADEs and USADE ..................................................................... 95 
10.7. 
Appendix 7: Country-specific requirements ................................................. 95 
10.7.1. 
Requirements for Germany .......................................................... 95 
10.8. 
Appendix 8: Abbreviations and glossary of terms ........................................ 95 
10.8.1. 
List of abbreviations ..................................................................... 95 
10.8.2. 
Glossary of terms ......................................................................... 98 
10.9. 
Appendix 9: List of potential immune-mediated disorders ......................... 103 
10.10. Appendix 10: Protocol Amendment history ............................................... 108 
11. REFERENCES ..................................................................................................... 113 
 

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LIST OF TABLES  
PAGE 
Table 1 
Schedule of Activities ............................................................................. 20 
Table 2 
Intervals between study visits ................................................................. 25 
Table 3 
Study objectives and endpoints .............................................................. 28 
Table 4 
Study groups, intervention and blinding .................................................. 33 
Table 5 
Study interventions administered ........................................................... 38 
Table 6 
Biological samples ................................................................................. 47 
Table 7 
Laboratory assays at screening .............................................................. 47 
........................................................................... 47 
Table 10 
Study holding rules ................................................................................. 53 
Table 11 
Timeframes for collecting and reporting of safety information ................. 55 
Table 12 
Timeframes for submitting SAE, pIMD, pregnancy and other 
events reports to GSK ............................................................................ 57 
Table 13 
Contact information for reporting SAEs, pIMDs, pregnancies and 
study holding rules ................................................................................. 58 
Table 14 
Analysis sets .......................................................................................... 60 
...... 65 
...... 66 
...... 66 
...... 67 
...... 67 
Table 20 
Protocol-required safety laboratory assessments ................................... 74 
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Table 21 
Hematology and biochemistry read-outs ................................................ 74 
Table 22 
Toxicity Grading Scales for Hematology and Biochemistry 
Parameters Applicable for this Study ...................................................... 75 
Table 23 
Solicited administration site events......................................................... 82 
Table 24 
Solicited systemic events ....................................................................... 82 
Table 25 
Intensity scales for solicited events ........................................................ 87 
Table 26 
Highly effective contraceptive methods .................................................. 92 
Table 27 
List of pIMDs ........................................................................................ 103 
 

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LIST OF FIGURES  
PAGE 
Figure 1 
Study design overview ........................................................................... 30 
Figure 2 
Risk assessment curves for study holding rules after 5 
participants (sentinel participants)* ......................................................... 63 
Figure 3 
Risk assessment curves for study holding rules after 23 
participants (minimum sample size for a whole group) * ......................... 64 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol title: A Phase 1/2a, open-label, randomized, controlled, multi-country, dose-
escalation study to assess the safety and immunogenicity of AS37 in combination with 
the Hepatitis B surface antigen (HBsAg), according to a 0-1-month schedule, in healthy, 
HBs naïve, adults aged 18-45 years. 
Brief title: A study on the safety and immune response of AS37 together with Hepatitis 
B antigen in adults aged 18-45 years. 
Rationale: 
The novel adjuvant named Adjuvant System 37 (AS37) consists of the combination of 
aluminum hydroxide (Al(OH)3) 
, a 
synthetic toll-like receptor 7 (TLR7) agonist, and has the potential to have a tolerability 
profile comparable to alum-based vaccines. When combined with an antigen, it has been 
shown to generate, after a single injection, high concentrations of antigen-specific 
antibodies. 
Preclinical studies of AS37 demonstrated a superior capacity in eliciting an effective 
immune response when compared to alum-based vaccines in several preclinical models. 
 
 In a Phase 1 
clinical study using MenC-CRM antigen and Menjugate as control, AS37 formulations 
containing 
 doses of up to 50 µg demonstrated a tolerability profile 
comparable to alum-based vaccine [Gonzalez-Lopez, 2019]. There was no appreciable 
difference in functional Ab titers (hSBA), but a dosing effect was observed for MenC PS-
specific Ab titers (Enzyme-Linked ImmunoSorbent Assay) and plasmablasts. 
Clinically relevant data evaluating how AS37 compares to other adjuvants is lacking. 
Therefore, this study will be conducted to address this lack of data and differentiate AS37 
from other approved Adjuvant Systems (AS03 and AS04), and from an alum-containing 
control group. 
 
 
 
HBs-naïve adults aged 18-45 years will receive 2 injections, one month apart of a 
constant dose of HBs antigen (20 µg) formulated with AS37B (containing 50 µg of 
) or AS37A (containing 100 µg of 
). 
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Objectives and endpoints: 
Objectives 
Endpoints 
Primary 
To evaluate the reactogenicity and 
safety in all study groups. 
• 
Percentage of participants with solicited administration site and 
systemic AEs within 14 days (Day 1 till Day 14) after Dose 1 and 
Dose 2. 
• 
Duration of solicited AEs (administration site and systemic) after 
Dose 1 and Dose 2. 
• 
Percentage of participants with any unsolicited AEs within 31 days 
(Day 1 till Day 31) after Dose 1 and Dose 2. 
• 
Percentage of participants with SAEs, MAEs and AEs leading to 
study withdrawal throughout the entire study period. 
• 
Percentage of participants with pIMDs throughout the entire study 
period. 
• 
The absolute values and changes in hematology and biochemistry 
parameters post-Dose 1 (Day 8 and Day 31) and post-Dose 2 
(Day 38 and Day 61) from baseline (pre-vaccination, Day 1). 
• 
Percentage of participants with abnormal laboratory parameter 
values at pre-vaccination (Day 1), post-Dose 1 (Day 8 and Day 31) 
and post-Dose 2 (Day 38 and Day 61). 
Secondary 
To evaluate the humoral immune 
response in all study groups. 
• 
GMC of Anti-HBs Ab concentrations at Day 1, Day 31, Day 61 and 
Day 361. 
• 
Anti-HBs seroconversion and seroprotection rates at Day 31, 
Day 61 and Day 361. 
AE = adverse event; SAE = serious adverse event; MAE = medically attended event; pIMD = potential 
immune-mediated disorder; GMC = geometric mean concentration; HBs = Hepatitis B surface antigen; Ab = 
antibody. 
Refer to Table 3 for details of all objectives and endpoints. 
Overall design: This is a Phase 1/2a, dose-escalation, open-label, multi-country study 
with 5 parallel groups. For details of the study design, refer Section 4. 
Number of participants: A minimum of 23 (and maximum of 30) participants per group 
will be enrolled in this study.  
Data monitoring/other committee: Safety monitoring will be conducted by an internal 
Safety Review Team (SRT). The SRT will review interim and cumulative safety data and 
will escalate concerns to the Global Safety Board (GSB).  
1.2. 
Schema 
Refer to Figure 1 for a schematic presentation of the study design. 
 

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1.3. 
Schedule of Activities (SoA)  
Table 1 
Schedule of Activities  
Type of contact (V / PC) Screening 
Visit 
V1 
V2 PC1 PC2 V3 PC3 PC4 PC5 V4 
V5 PC6 PC7 V6 PC8 PC9 PC10 V7 
V81 
V9 
Notes 
Timepoints 
Day -7 
Day 
1 
Day 
2 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
Day 
12 
Day 
15 
Day 
31 
Day 
32 
Day 
34 
Day 
36 
Day 
38 
Day
40 
Day
42 
Day 
45 
Day 
61 
Day 
181 
Day 
361 
Sampling timepoints 
D-7 
D1 
D2 
D4 
D6 
D8 D10 D12 D15 D31 D32 D34 D36 D38 D40 D42 D45 D61 D181 D361 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 10.1.3 for 
details 
Check 
inclusion/exclusion 
criteria 
● 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recheck clinical status 
before randomization 
and/or first dose of study 
intervention. See Sections 
5.1 and 5.2 for Inclusion 
and Exclusion criteria 
Collect demographic 
data 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.1.1 for 
more information 
Medical and vaccination 
history 
● 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.1.2 for 
more information 
Physical examination 
● 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
● 
 
See Section 8.2.1.3 for 
more information 
Randomization 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 6.3 for more 
information 
Study interventions 
Check contraindications, 
warnings and precautions 
to study intervention 
administration 
 
○ 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
See Sections 7.1.1 and 
8.2.1.5 for more 
information 
Check criteria for 
temporary delay for 
enrolment and study 
intervention 
administration 
○ 
○ 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
○ 
 
See Section 5.5 for more 
information 

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Type of contact (V / PC) Screening 
Visit 
V1 
V2 PC1 PC2 V3 PC3 PC4 PC5 V4 
V5 PC6 PC7 V6 PC8 PC9 PC10 V7 
V81 
V9 
Notes 
Timepoints 
Day -7 
Day 
1 
Day 
2 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
Day 
12 
Day 
15 
Day 
31 
Day 
32 
Day 
34 
Day 
36 
Day 
38 
Day
40 
Day
42 
Day 
45 
Day 
61 
Day 
181 
Day 
361 
Sampling timepoints 
D-7 
D1 
D2 
D4 
D6 
D8 D10 D12 D15 D31 D32 D34 D36 D38 D40 D42 D45 D61 D181 D361 
Urine pregnancy test 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
● 
 
See Section 8.2.1.4 for 
more information 
Study group allocation 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Sections 6.3.2 and 
6.3.3 for more information 
Intervention number 
allocation for subsequent 
doses 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
○1 
 
 
Body temperature before 
study intervention 
administration 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
●1 
 
The preferred location for 
measuring temperature will 
be the oral cavity. Fever is 
defined as temperature 
≥38.0°C regardless of the 
location of measurement 
Study intervention 
administration 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
●1 
 
See Section 6.1 for more 
information 
Recording of 
administered study 
intervention number 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
●1 
 
 
Laboratory Assessment 
Blood sampling for 
anti-HBs Ab, anti-HBc Ab 
and-HBs Antigen 
screening tests (~5 mL) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.1.1 for more 
information 
Blood sampling for 
antibody determination 
 
(~20 mL)2 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
● See Section 8.1.1 for more 
information 
Blood sampling 
 
 
(~5 mL) 
 
● 
● 
 
 
● 
 
 
 
● 
● 
 
 
● 
 
 
 
 
 
 
See Section 8.1.1 for more 
information 
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Type of contact (V / PC) Screening 
Visit 
V1 
V2 PC1 PC2 V3 PC3 PC4 PC5 V4 
V5 PC6 PC7 V6 PC8 PC9 PC10 V7 
V81 
V9 
Notes 
Timepoints 
Day -7 
Day 
1 
Day 
2 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
Day 
12 
Day 
15 
Day 
31 
Day 
32 
Day 
34 
Day 
36 
Day 
38 
Day
40 
Day
42 
Day 
45 
Day 
61 
Day 
181 
Day 
361 
Sampling timepoints 
D-7 
D1 
D2 
D4 
D6 
D8 D10 D12 D15 D31 D32 D34 D36 D38 D40 D42 D45 D61 D181 D361 
Blood sampling 
 
 
) (~5 mL) 
 
● 
● 
 
 
● 
 
 
 
● 
● 
 
 
● 
 
 
 
 
 
 
See Section 8.1.1 for more 
information 
Blood sampling for CMI 
response (~50 mL) 
 
● 
 
 
 
● 
 
 
 
● 
 
 
 
● 
 
 
 
● 
 
● See Section 8.1.1 for more 
information 
Blood sampling for 
hematology/biochemical 
analysis at screening and 
for safety monitoring 
(~7mL) 
● 
● 
 
 
 
● 
 
 
 
● 
 
 
 
● 
 
 
 
● 
 
 
See Section 8.1.1 for more 
information 
Safety assessments 
Record any concomitant 
medications/vaccinations 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● See Section 6.9 for more 
information 
Record any intercurrent 
medical conditions  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● See Section 9.2.1 for more 
information 
Download eDiary 
application or distribution 
of eDiary devices and 
training of participants on 
how to use eDiaries 
 
○ 
 
 
 
 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
Recording of solicited 
events (Days 1–14) 
post-Dose 1 and Dose 2 
of study intervention 
administration by 
participants 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
 
See Section 10.3.8 for 
more information 
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Type of contact (V / PC) Screening 
Visit 
V1 
V2 PC1 PC2 V3 PC3 PC4 PC5 V4 
V5 PC6 PC7 V6 PC8 PC9 PC10 V7 
V81 
V9 
Notes 
Timepoints 
Day -7 
Day 
1 
Day 
2 
Day 
4 
Day 
6 
Day 
8 
Day 
10 
Day 
12 
Day 
15 
Day 
31 
Day 
32 
Day 
34 
Day 
36 
Day 
38 
Day
40 
Day
42 
Day 
45 
Day 
61 
Day 
181 
Day 
361 
Sampling timepoints 
D-7 
D1 
D2 
D4 
D6 
D8 D10 D12 D15 D31 D32 D34 D36 D38 D40 D42 D45 D61 D181 D361 
Review of eDiary data by 
the investigator or 
delegate 
 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
 
Return of eDiary devices 
or removal of eDiary 
application from partici-
pant personal device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
 
Recording of unsolicited 
events (Days 1-31) 
post-Dose 1 and 
post-Dose 2 of study 
intervention 
administration 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
See Section 10.3.8 for 
more information 
Recording of SAEs, 
MAEs, pIMDs and 
pregnancies  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● See Section 10.3.8 for 
more information 
Recording of SAEs 
related to study 
participation, or to a 
concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● See Section 10.3.8 for 
more information 
Recording of AEs/SAEs 
leading to withdrawal 
from the study 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● See Section 10.3.8 for 
more information 
Study Conclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● See Section 4.5 for more 
information 
V = visit; PC = phone contact; D = day; HBs = Hepatitis B surface antigen; HBc = Hepatitis B core antigen; CMI = cell-mediated immunity; eDiary = electronic diary; SAE = serious 
adverse event; MAE = medically attended event; pIMD = potential immune-mediated disorder; AE = adverse event; eCRF = electronic case record form; 
 
. 
Note: The double-line border following Day 61 indicates the main analyses that will be performed on all data (i.e., data that are as clean as possible) obtained up to Day 61. 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
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1Only for participants in the HBs-alum group. 
2Note: Participants with anti-HBs Ab concentration < 100 mIU/mL at Day 361 will be offered a dose of Engerix-B after the study. 
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Table 2 
Intervals between study visits  
Interval 
Optimal length of interval1 
Allowed interval2 
Screening Visit → Visit 1 
7 days 
2-28 days 
Visit 1 → Visit 2* 
1 day 
1 day 
Visit 2 → PC1 
2 days 
2 days 
PC1 → PC2 
2 days 
2 days 
Visit 1 → Visit 3 
7 days 
7-8 days 
Visit 3 → PC3 
2 days 
2 days 
PC3 → PC4 
2 days 
2 days 
PC4 → PC5 
3 days 
3 days 
Visit 1 → Visit 4 
30 days (1 month) 
21-42 days 
Visit 4 → Visit 5* 
1 day 
1 day 
Visit 5 → PC6 
2 days 
2 days 
PC6 → PC7 
2 days 
2 days 
Visit 4 → Visit 6 
7 days 
7-8days 
Visit 4 → Visit 7 
30 days (1 month) 
21-42 days 
Visit 4 → Visit 83 
150 days (5 months) 
136-164 days 
Visit 6 → PC8 
2 days 
2 days 
PC8 → PC9 
2 days 
2 days 
PC9 → PC10 
3 days 
3 days 
Visit 7 → Visit 94 
300 days (10 months) 
286-314 days 
Visit 8 → Visit 93 
180 days (6 months) 
166-194 days 
PC = phone contact 
1Whenever possible the investigator should arrange study visits within this interval. 
2Participants will not be eligible for inclusion in the Per-Protocol Set for analysis of immunogenicity if they make the 
study visit outside this interval. 
3For participants in the HBs-alum group. 
4For participants in all groups except the HBs-alum group. 
 
2. 
INTRODUCTION  
2.1. 
Study rationale  
The novel adjuvant named AS37 consists of the combination of Al(OH)3 and 
 
 a synthetic TLR7 agonist, and has the potential to 
have a tolerability profile comparable to alum-based vaccines. When combined with an 
antigen, it has been shown to generate after a single injection, high concentrations of 
antigen-specific antibodies. 
Preclinical studies of AS37 demonstrated a superior capacity in eliciting an effective 
immune response when compared to alum-based vaccines in several preclinical models. 
In some specific studies (using cytomegalovirus or Clostridium difficile antigens), AS37 
generated high levels of Ab concentrations after one dose. In a Phase 1 clinical study 
using MenC-CRM antigen and Menjugate as control, AS37 formulations containing 
 doses of up to 50 µg demonstrated a tolerability profile comparable to 
alum-based vaccine [Gonzalez-Lopez, 2019]. There was no appreciable difference in 
functional Ab titers (hSBA), but a dosing effect was observed for MenC PS-specific Ab 
titers (ELISA) and plasmablasts. 
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Clinically relevant data evaluating how AS37 compares to other adjuvants is lacking. 
Therefore, this study will be conducted to address this lack of data and differentiate AS37 
from other approved Adjuvant Systems (AS03 and AS04), and from an alum-containing 
control group. 
 
 
 
HBs-naïve adults aged 18-45 years will receive 2 injections, one month apart of a 
constant dose of HBs antigen (20 µg) formulated with AS37B (containing 50 µg of 
) or AS37A (containing 100 µg of 
). 
2.2. 
Background  
Please refer to the current IB for information regarding preclinical studies of HBs-AS37 
investigational vaccine and clinical studies, and the risks and benefits, of HBs-AS03, 
Engerix-B and Fendrix. 
2.3. 
Benefit/Risk assessment  
2.3.1. 
Risk assessment  
Detailed information about the known and expected benefits and risks and expected 
adverse events of the study interventions can be found in the IB. 
Hypersensitivity reactions may occur following exposure to allergens from a variety of 
sources including food, aeroallergens, venom, drugs, and immunizations. Vaccines are a 
mixture of compounds and allergic sensitization can occur to any component. While 
cutaneous reactions, such as rash or urticaria, are common, anaphylactic reactions are 
very rare. Administration of the study vaccination is to be preceded by a review of the 
participants’ medical history (especially regarding previous vaccination and possible 
occurrence of undesirable events) and a clinical examination. All participants will remain 
under observation at the clinical center for at least 60 minutes after vaccination, with 
appropriate medical treatment readily available. 
Based on the theoretical concern that vaccination with vaccines containing potent 
immunostimulants (e.g., adjuvant systems) may interfere with immunological self-
tolerance, pIMDs are considered AESIs undergoing special safety monitoring for GSK 
vaccines containing Adjuvant Systems. pIMDs are a subset of adverse events that include 
autoimmune diseases and other inflammatory and/or neurological disorders of interest 
which may or may not have an autoimmune etiology. Risk mitigation strategy includes 
close monitoring of pIMDs as per study protocol and analysis of safety data generated 
through clinical trials and other sources. The potential risk of adverse events of possible 
immune-mediated etiology is mentioned in the ICF. In addition, the ICF advises 
participants to contact the study doctor or the study staff immediately, should they get 
any symptoms that they feel may be serious. 
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The AS37 adjuvant has been tested in a Phase 1 clinical study with MenC antigen and the 
AS37 formulations containing 
 doses from 12.5 to 50 µg had clinically 
acceptable safety profile, with no clear trend in the incidence of AEs in relation to the 
dose-escalation. There were no reports of AEs leading to withdrawal or AEs of special 
interest including new onset chronic diseases. Only one unrelated SAE (joint injury) was 
reported. However, for the group receiving AS37A (100 µg of 
, an 
increase in number of solicited general AEs as compared with the other AS37 groups and 
the control was observed. Additionally, in the AS37A group, there were 3 reports 
(18.8%) of severe solicited systemic AEs (headache, nausea and fever) [Gonzalez-Lopez, 
2019]. Therefore, there is a potential risk that AS37A may be more reactogenic than 
AS37B (50 µg of 
. The risk mitigation measures include staggered 
vaccination with dose-escalation in AS37 groups, and appropriate safety monitoring with 
holding rules (see Section 8.2.3). 
Intramuscular vaccination commonly precipitates a transient and self-limiting local 
inflammatory reaction. This may typically include pain at injection site, erythema, and 
swelling. 
In addition to potential risks related to the vaccine, there may be risks related to the blood 
sampling planned in the study: 
• 
Pain and bruising may occur at the site where blood is drawn; as a mitigation 
strategy, a topical analgesic may be applied to the site where blood will be taken. 
• 
Syncope (fainting) can occur following or even before any blood draw as a 
psychogenic response to the needle insertion. 
• 
A nerve may be injured in the process of collecting blood. 
• 
An infection may occur at the injection site. 
To mitigate these risks, blood samples will be obtained by a trained professional and 
medical assistance will be available. The potential risk of feeling faint, or experiencing 
mild local pain, bruising, irritation, redness, nerve injury or infection at the site where 
blood was taken, is mentioned in the ICF. The amount of blood to be taken for sampling 
will not be harmful to the participant’s health. 
For details of study procedures, dose, and study design justification, refer to Section 1.3 
and Section 4.3. 
2.3.2. 
Benefit assessment  
The participants may directly benefit from study intervention administration by being 
protected against Hepatitis B virus. For participants with insufficient anti-HBs titers at 
the end of the study, a dose of Engerix-B will be offered. 
An indirect benefit is that the information obtained in this study will help in determining 
whether the AS37 adjuvant can be used in the development of future vaccines. 
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Another benefit for all study participants may include gaining information about their 
general health status through the medical evaluations/assessments associated with this 
study (i.e., physical examination). 
2.3.3. 
Overall benefit/risk conclusion  
All study vaccines are based on HBsAg, which is a component of registered Hepatitis B 
vaccines, Engerix-B and Fendrix, used in this study. Engerix-B has established safety and 
efficacy profile and it is expected that Fendrix will provide a good immune response with 
acceptable reactogenicity compared to Engerix-B. The combination of HBsAg and AS37 
has not been tested in human to date so information on safety and efficacy of this 
formulation is currently not available. However, AS37 with MenC antigen has already 
been tested in humans with no safety concern identified, though a higher systemic 
reactogenicity with AS37A was observed (see Section 2.3.1). 
The combination of HBsAg and AS03 has been tested in humans in one Phase 2 clinical 
study (NCT00805389) and the tolerability was acceptable, with no serious AEs related to 
vaccination reported [Burny, 2017]. 
Measures to minimize risk to study participants are described in this protocol and include, 
among others, staggered vaccination with dose-escalation in AS37 groups, and 
appropriate safety monitoring with holding rules. Based on the theoretical concern that 
vaccination with vaccines containing potent immunostimulants (e.g., adjuvant systems) 
may interfere with immunological self-tolerance, pIMDs will be monitored as AESIs. 
Considering the measures taken to minimize the risk to participants in this study, the 
potential risks are justified by the potential benefits linked to the development of this 
adjuvant and study participation. 
3. 
OBJECTIVES AND ENDPOINTS  
Table 3 
Study objectives and endpoints  
Objectives 
Endpoints 
Primary 
To evaluate the reactogenicity and 
safety in all study groups. 
• 
Percentage of participants with solicited administration site and 
systemic AEs within 14 days (Day 1 till Day 14) after Dose 1 and 
Dose 2. 
• 
Duration of solicited AEs (administration site and systemic) after 
Dose 1 and Dose 2. 
• 
Percentage of participants with any unsolicited AEs within 31 days 
(Day 1 till Day 31) after Dose 1 and Dose 2. 
• 
Percentage of participants with SAEs, MAEs and AEs leading to 
study withdrawal throughout the entire study period. 
• 
Percentage of participants with pIMDs throughout the entire study 
period. 
• 
The absolute values and changes in hematology and biochemistry 
parameters post-Dose 1 (Day 8 and Day 31) and post-Dose 2 
(Day 38 and Day 61) from baseline (pre-vaccination, Day 1). 

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Objectives 
Endpoints 
• 
Percentage of participants with abnormal laboratory parameter 
values at pre-vaccination (Day 1), post-Dose 1 (Day 8 and Day 31) 
and post-Dose 2 (Day 38 and Day 61). 
Secondary 
To evaluate the humoral immune 
response in all study groups. 
• 
GMC of Anti-HBs Ab concentrations at Day 1, Day 31, Day 61 and 
Day 361. 
• 
Anti-HBs seroconversion and seroprotection rates at Day 31, 
Day 61 and Day 361. 
Tertiary 
To evaluate the cell-mediated immune 
response induced in all study groups. 
• 
Frequency of HBsAg-specific CD4+/CD8+ T-cells per 106 
CD4+/CD8+ T-cells producing at least 2 activation markers 
including at least 1 cytokine among IFN-γ, IL-2, TNF-α, IL-13, IL-17, 
4-1BB and/or CD40L at Day 1, Day 8, Day 31, Day 38, Day 61 and 
Day 361. 
• 
Frequency of plasmablasts, T Follicular Helper cells (TFH) and 
memory B-cells (flow cytometry) at Day 1, Day 8, Day 31, Day 38 
and Day 61, in a subset of participants. 
• 
Frequency of HBsAg-specific memory B-cells (ELISPOT) at Day 1, 
Day 31, Day 61 and Day 361. 
AE = adverse event; SAE = serious adverse event; MAE = medically attended event; pIMD = potential 
immune-mediated disorder; GMC = geometric mean concentration; HBs = Hepatitis B surface antigen; Ab = 
antibody; 
 
 
 
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4. 
STUDY DESIGN  
4.1. 
Overall design  
Figure 1 
Study design overview  
 
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V = visit; PC = phone contact; D = Day; N = number of participants; SRT = safety review team; TP = timepoint;
 
¥Only for participants in the HBs-alum group 
Phone contact at Day 4, Day 6, Day 10, Day 12, Day 15, Day 34, Day 36, Day 40, Day 42, and Day 45 
*First safety review after the first 5 participants in the HBs-AS37_50 group have completed 7 days safety follow-up post-Dose 1, before administering the second dose to these 
participants, and before enrolment of the remaining participants in this group in the next cohorts, and the first 5 participants in the HBs-AS37_100 group in the second cohort. The 
enrolment in the second cohort will start after the second dose is administered to all 20 participants in the first cohort. 
**Second safety review after the first 5 participants in the HBs-AS37_50 group have completed 7 days safety follow-up post-Dose 2, before administering the second dose to the 
remaining participants in this group in the next cohorts. 
***Third safety review after the first 5 participants of the HBs-AS37_100 group have completed 7 days safety follow-up post-Dose 1, before administering the second dose to these 
participants, and before enrolment of the remaining participants in this group in the third cohort. The enrolment in the third cohort will start after the third SRT review. 
****Fourth safety review after the first 5 participants in the HBs-AS37_100 group have completed 7 days safety follow-up post-Dose 2, before administering the second dose to the 
remaining participants in this group in the third cohort. 
#Timepoints for safety data cut-off. 
 
Note: Cohort 3 will enroll a minimum of 70 (and maximum of 105) participants distributed between the groups as follows: a minimum of 23 (and maximum of 30) participants in 
HBs- Alum, HBs-AS03, HBs-AS04, HBs-AS37_50, HBs AS37_100 
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• 
Type of study: Self-contained. 
• 
Experimental design: Phase 1/2a, dose-escalation, open-label, multi-country study 
with 5 parallel groups. 
• 
Duration of the study: ~ 361 days for all participants. 
• 
Primary completion date: Day 361. 
• 
Control: Active comparators: Engerix-B, Fendrix and HBs-AS03. 
• 
Blinding: Open-label. Refer to Section 6.4 for details. 
• 
Data collection: Standardized eCRF. Solicited events will be collected using a 
Participant Diary (eDiary). 
• 
Safety monitoring: Refer to Section 8.2.3 for the review of safety data by an 
internal SRT and details of holding rules and safety monitoring. 
4.2. 
Study groups  
Refer to Figure 1 and Table 4 for an overview of the study groups. 
4.2.1. 
Overview of the recruitment plan  
There will be 3 different cohorts recruited into this study, which will be enrolled in a 
staggered way. Cohort 1 will enroll 20 participants distributed between the groups as 
follows: 5 in HBs-Alum, 5 in HBs-AS03, 5 in HBs-AS04, and 5 in HBs-AS37_50. 
Cohort 2 will enroll 25 participants distributed between the groups as follows: 5 in 
HBs-Alum, 5 in HBs-AS03, 5 in HBs-AS04, 5 in HBs-AS37_50, and 5 in 
HBs-AS37_100. Cohort 3 will enroll a minimum of 70 (and maximum of 105) 
participants distributed among the groups to reach a total sample size across the three 
cohorts as follows: a minimum of 23 (and maximum of 30) participants in HBs-Alum, 
HBs-AS03, HBs-AS04, HBs-AS37_50, and HBs-AS37_100. Sample sizes per group are 
presented in terms of minimums and maximums to allow early stop of enrollment due to 
reasons of feasibility linked to recruitment of the study population. The choice of the 
minimum sample size for each group is guided by statistical considerations on the 
precision of the safety evaluation and on the power for the immunogenicity comparison. 
For more details, refer to Section 9.4 and Section 9.5. 
There will be a screening phase whereby participants will be screened for eligibility 
before recruitment. The study is planned to be conducted at sites in multiple countries. 
Recruitment plan will be defined by each participating site. 
The recruitment plan may be adapted based on the actual number of participants enrolled 
in each country. In case a site would fall behind in participant recruitment, a 
redistribution of the enrolment target per site in the participating countries may be made. 
This would allow the other participating sites to enroll additional participants to ensure 
full and timely enrolment of the overall targeted number of participants specified in this 
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The procedures for participants identification/recruitment must be approved by the 
IEC/IRB together with the material intended for participants identification/recruitment 
and participants use. Refer to the SPM for additional details. 
Table 4 
Study groups, intervention and blinding  
Study groups 
Number of 
participants 
Age 
(Min-Max) 
Study interventions 
Timing of intervention 
Visit 1 
Visit 4 
Visit 8 
HBs-alum 
23-30 
18-45 years 
Engerix-B 
X 
X 
X 
HBs-AS03 
23-30 
HBsAg/AS03A 
X 
X 
 
HBs-AS04 
23-30 
Fendrix 
X 
X 
 
HBs-AS37_50 
23-30 
HBsAg/AS37B* 
X 
X 
 
HBs-AS37_100 
23-30 
HBsAg/AS37A** 
X 
X 
 
*AS37B refers to 
 aluminum hydroxide + 50 µg 
 
**AS37A refers to 
 aluminum hydroxide + 100 µg 
 
4.3. 
Scientific rationale for study design  
Previous preclinical and clinical data suggest that AS37 could have the potential to 
generate a rapid and high-quality immune response, while demonstrating an acceptable 
safety profile. However, the MenC/AS37 clinical study did not provide a clear answer to 
several questions 
 
 that would allow to position this adjuvant in the adjuvant portfolio. 
The choice of MenC antigens did not allow to benefit from many historical data which 
were mainly generated with HBsAg. In general, most GSK vaccines are composed of 
adjuvanted recombinant protein, whereas the MenC study involved a carbohydrate-
protein conjugated antigen. Also, using MenC led to the fact that many responses 
emerging from that study were in primed participants meaning innate immune responses 
are difficult to interpret. In order to describe a comprehensive set of immune responses 
(both adaptive and innate), and to document the safety profile of AS37 in combination 
with a protein-based vaccine in a naïve population, the current study is proposed. A 
control group receiving licensed Hepatis B vaccine (Engerix-B) and 2 other adjuvanted 
(AS03 and AS04) Hepatitis B vaccines are included to compare with AS37, and 
potentially position AS37 in the adjuvant portfolio. Although AS37A generated 
somewhat higher systemic reactogenicity in the MenC study, it is still considered 
necessary to test this formulation in the current study with appropriate safety oversight 
and holding rules, because the vaccine constructs are different (conjugate versus protein) 
and the population in the current study is naïve. 
4.4. 
Justification for dose  
The AS37 adjuvant has been used in a previous clinical study (MenC/AS37) where the 
AS37 formulations containing 
 doses from 12.5 to 50 µg had clinically 
acceptable safety profile with no clear trend in the incidence of AEs in relation to the 
dose-escalation. However, for the group receiving AS37A, an increase in the frequency 
and severity of systemic solicited AEs was observed, as compared with the other AS37 
groups and the control (see Section 2.3.1). Therefore, there is a potential risk that AS37A 
may be more reactogenic than AS37B. 
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To mitigate this risk, this study will be conducted in a staggered manner whereby 
initiation of the HBs-AS37_100 group will be conditional to whether any holding rule is 
met in the HBs-AS37_50 group. Once the first 5 participants of the HBs-AS37_100 
group complete the 7 days safety follow-up after the first dose, the data will be evaluated 
before enrolment of the remaining participants (see Section 8.2.3.1 for more information 
on the staggered approach and planned safety reviews). 
In terms of immunogenicity, including AS37A in the current study is based on the dose 
effect observed in enzyme linked immunosorbent assay data from the AS37/MenC study. 
Given the difference in population and vaccine construct versus the MenC study, adding 
a AS37A group would optimize the probability to differentiate AS37 from other 
adjuvants included in the study. 
4.5. 
End of Study definition  
A participant is considered to have completed the study if he/she returns for the last visit 
or is available for the last scheduled procedure as described in the protocol. 
End of Study (EoS): Date of the LSLV. 
5. 
STUDY POPULATION  
Adherence to the inclusion and exclusion criteria specified in the protocol is essential. 
Deviations from these criteria are not allowed because they can jeopardize the scientific 
integrity, regulatory acceptability of the study or safety of the participant. 
5.1. 
Inclusion criteria  
All participants must satisfy ALL the following criteria at study entry: 
• 
Participants who the investigator believe can and will comply with the requirements 
of the protocol (e.g., completion of the eDiaries, return for follow-up visits). INC#1 
• 
Written informed consent obtained from the participant prior to performance of any 
study-specific procedure. INC#2 
• 
Healthy participants as established by medical history, clinical examination and 
clinical laboratory assessment before entering the study. INC#3 
• 
A male or female between, and including, 18 and 45 years at the time of the first 
study intervention administration. INC#4 
• 
Female participants of non-childbearing potential may be enrolled in the study. 
Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause. INC#5 
• 
Female participants of childbearing potential may be enrolled in the study if the 
participant: INC#6 
− 
Has practiced adequate contraception for 1 month prior to study intervention 
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− 
Has a negative pregnancy test on the day of study intervention administration, 
and, 
− 
Has agreed to continue adequate contraception during the entire treatment period 
and for at least 3 months after completion of the study intervention 
administration series. 
Blood sample for simultaneous FSH and estradiol levels may be collected at the 
discretion of the investigator to confirm non-reproductive potential according to local 
laboratory reference range. 
5.2. 
Exclusion criteria  
The following criteria should be checked at the time of study entry. The potential 
participant MAY NOT be included in the study if ANY exclusion criterion applies: 
5.2.1. 
Medical conditions  
• 
Previous vaccination against Hepatitis B. EXC#1 
• 
Positive for anti-HBs antibodies or anti-HBc antibodies or HBsAg. EXC#2 
• 
Any previous administration of monophosphoryl lipid (MPL) and/or AS37. EXC#3 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
EXC#4 
• 
Any confirmed or suspected autoimmune disease. EXC#5 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the study interventions. EXC#6 
• 
Recurrent history or uncontrolled neurological disorders or seizures. EXC#7 
• 
Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the participant due to participation in the study. EXC#8 
• 
Any clinically significant* hematological (hemoglobin level, white blood cell, 
lymphocyte, neutrophil, eosinophil, platelet and red blood cell count) and/or 
biochemical (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
creatinine) laboratory abnormality. EXC#9 
*The investigator should use his/her clinical judgment to decide which abnormalities 
are clinically significant. 
• 
Any past or current malignancies and lymphoproliferative disorders. EXC#10 
5.2.2. 
Prior/Concomitant therapy  
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study interventions during the period beginning 30 days before the first dose of study 
intervention or their planned use during the study period. EXC#11 

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• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before each dose and ending 30 days after 
each dose of study intervention administration with the exception of influenza 
vaccine (pandemic or seasonal). EXC#12 
• 
A vaccine not foreseen by the study protocol administered during the period starting 
at Visit 1 or 30 days before each dose and ending 30 days after the last dose of study 
intervention administration*, with the exception of influenza vaccine (pandemic or 
seasonal). EXC#13 
*In case emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is organized by public health authorities outside the routine immunization 
program, the time period described above can be reduced if necessary for that 
vaccine, provided it is licensed/authorized and used according to its Product 
Information. 
• 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g., infliximab). EXC#14 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 
3 months before the first study intervention dose(s). For corticosteroids, this will 
mean prednisone equivalent ≥20 mg/day. Inhaled and topical steroids are allowed. 
EXC#15 
• 
Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 3 months before the administration of the first dose of 
study intervention or planned administration during the study period. EXC#16 
5.2.3. 
Prior/Concurrent clinical study experience  
Concurrently participating in another clinical study, at any time during the study period, 
in which the participant has been or will be exposed to an investigational intervention. 
EXC#17 
5.2.4. 
Other exclusions  
• 
Pregnant or lactating female. EXC#18 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions. EXC#19 
• 
History of chronic alcohol consumption and/or drug abuse. EXC#20 
• 
Any study personnel or their immediate dependents, family, or household members. 
EXC#21 

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5.3. 
Lifestyle considerations  
Not applicable for this study. 
5.4. 
Screening failures  
A screen failure is an individual who consents to participate in this study but is not 
randomized to a study intervention. 
Limited data for screening failures (at least informed consent date, demographic data, 
eligibility criteria check, reason for screening failure and any SAEs that occurred at the 
visit) will be collected and reported in the eCRF. 
5.4.1. 
Rescreening  
Participants who met the eligibility criteria in the previous cohorts but could not be 
randomized as either the cohort threshold was attained, or the screening window had 
elapsed, can be re-screened. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Individuals who failed initial screening but passed rescreening 
may be admitted into the study based upon clinical judgment and after consultation with 
the CSL. 
Participants with hematological/biochemical values out of normal range which are 
expected to be temporary may be rescreened/dosed later within the allowed time interval. 
Participants that are rescreened will be recorded with the same participant number. 
Reason for rescreening will also be recorded. 
5.5. 
Criteria for temporarily delaying enrolment/study 
intervention administration.  
Enrollment/study intervention administration may be postponed within the permitted time 
interval until transient conditions cited below are resolved: 
• 
Acute disease and/or fever at the time of enrolment and/or study intervention 
administration. Refer to the SoA (Table 1) for definition of fever and preferred 
location for measuring temperature in this study. 
• 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be enrolled and/or dosed at the discretion of the 
investigator. 
• 
Use of antipyretics and/or analgesics and/or antibiotics within 3 days prior to study 
intervention administration. 
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6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY  
Refer to the Glossary of terms for the definition of study intervention. 
6.1. 
Study interventions administered  
Table 5 
Study interventions administered  
 
Study 
intervention 
1 
Study intervention 2 
Study 
intervention 3 
Study intervention 4 
Study intervention 5 
Study inter-
vention 
name: 
Engerix-B 
HBsAg/AS03A 
Fendrix 
HBsAg/AS37B* 
(*
 Al(OH)3 + 50 µg 
) 
HBsAg/AS37A** 
(** 
 Al(OH)3 + 100 µg 
 
Study 
intervention 
formulation 
Dose Form 
(presentation) 
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Study 
intervention 
1 
Study intervention 2 
Study 
intervention 3 
Study intervention 4 
Study intervention 5 
Type 
Combination 
product 
Biologic 
Combination 
product 
Biologic  
Biologic 
Use  
Comparator  
Comparator  
Comparator  
IMP 
IMP 
Authorized 
AxMP/ 
Unauthorized 
AxMP  
Not applicable  
Route of 
administration 
Intramuscular 
Administration site: 
Location 
Deltoid 
Directionality  
Not applicable 
Laterality*** 
Non-dominant 
Number of 
doses to be 
administered 
3 
2 
Volume to be 
administered**
** 
1.0 mL 
0.5 mL 
Packaging, 
labeling and 
TM 
Refer to the SPM for more details 
Manufacturer 
GSK 
AxMP = auxiliary medicinal product; MPL = monophosphoryl lipid; SPM = study procedures manual. 
***The non-dominant arm is the preferred arm for injection. In case it is not possible to administer the study intervention in the non-dominant arm, an injection in the dominant arm may 
be performed. 
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Study participants must be observed closely for at least 60 minutes after the 
administration of the study interventions. Appropriate medical treatment must be readily 
available during the observation period in case of anaphylaxis or syncope. 
6.1.1. 
Medical devices 
• 
The GSK manufactured medical devices (or devices manufactured for GSK by a 
third party) provided for use in this study are pre-filled syringes for Engerix-B and 
Fendrix. 
• 
No other medical devices (not manufactured by or for GSK) are provided for use in 
this study. 
• 
Instructions for medical device use are provided in SPM. 
• 
All device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical 
investigation (see Sections 8.4.6 and 10.6) and appropriately managed by GSK. 
6.2. 
Preparation, handling, storage, and accountability  
The study interventions must be stored in a secured place within the temperature range 
specified on the study intervention’s label. The storage temperature should be 
continuously monitored and recorded with a calibrated (if not validated) temperature 
monitoring device(s). 
Only authorized study personnel should be allowed access to the study interventions. 
Storage conditions will be assessed by a sponsor study contact during pre-study activities. 
Refer to the SPM for more details on storage and handling of the study interventions. 
6.3. 
Measures to minimize bias: randomization and blinding  
6.3.1. 
Participant identification  
Participant identification numbers will be assigned sequentially to the individuals who 
have consented to participate in the study. Each study center will be allocated a range of 
participant identification numbers. 
6.3.2. 
Randomization to study intervention  
The randomization of supplies within blocks will be performed at GSK, using MATerial 
EXcellence (MATEX), a program developed for use in Statistical Analysis System 
(SAS®) (Cary, NC, USA) by GSK. Entire blocks will be shipped to the study 
centers/warehouse(s). 

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6.3.3. 
Intervention allocation to the participant  
The randomization algorithm will use a minimization procedure accounting for center 
and sex, as well as cohort to improve balance between groups for the SRT reviews. 
Once a participant identification number is allocated, the randomization system will 
determine study group and will provide the study intervention number to be used for the 
first dose. The study intervention number(s) to be used for subsequent dosing will be 
provided by the same automated Internet-based system (SBIR). 
The actual treatment number used for first vaccination of the participant must be recorded 
by the investigator in the eCRF (Randomization/Treatment Allocation section). 
When an automated, Internet-based system, SBIR is not available, please refer to the 
SBIR user guide or SPM for specific instructions. 
Refer to the SPM for additional information about the study intervention number 
allocation. 
6.4. 
Blinding and unblinding  
This is an open-label study. 
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The laboratory in charge of sample testing will be blinded to the study intervention 
assignment. Codes will be used to link the participant and study to each sample. There 
will be no link between the study intervention groups and the identity of the participant. 
6.5. 
Study intervention compliance  
When the study intervention is administered at the site, participants will receive it directly 
from the investigator or designee, under medical supervision. The date of administration 
of each study intervention dose in the clinic will be recorded in the source documents. 
6.6. 
Dose modification  
Section is not applicable. 
6.7. 
Continued access to study intervention after the end of the 
study  
The investigator is encouraged to share the immunological assay results of non-
responders with the study participants. 
An extra dose of Engerix-B to be provided by GSK will be offered at the end of the study 
to non-responders (anti-HBs Ab concentration <100 mIU/mL) by the investigator 
irrespective of the study intervention received in the study. 
6.8. 
Treatment of overdose  
Section is not applicable. 
6.9. 
Concomitant therapy  
At each study visit/contact the investigator or his/her delegate should question the 
participant about all medications/products taken, and vaccinations received by the 
participant. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF: 
• 
All concomitant medication associated with an adverse event, including 
vaccines/products, except vitamins and dietary supplements, administered during a 
31-day follow-up after each dose of study intervention (i.e., day of vaccination and 
30 subsequent days). 
• 
All concomitant medication leading to discontinuation of the study intervention or 
elimination from the analysis, including products/vaccines. Please refer to Sections 
5.2.2 and 9.2.1 for further details. 

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• 
All concomitant medication which may explain/cause/be used to treat an SAE/pIMD 
including vaccines/products, as defined in Sections 8.4.1 and 10.3.2. These must also 
be recorded in the Expedited Adverse Event Report. 
The LML should be contacted if there are any questions regarding concomitant or prior 
therapy. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1. 
Discontinuation of study intervention  
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of study intervention. A participant who discontinued study intervention 
may continue other study procedures (e.g., safety or immunogenicity), planned in the 
study protocol at the discretion of the investigator. 
The primary reason for premature discontinuation of the study intervention will be 
documented on the eCRF as follows: 
• 
AE requiring expedited reporting to GSK. Refer to Section 10.3.10.1 for details. 
• 
Unsolicited non-serious AE. 
• 
Solicited AE. 
• 
Not willing to be vaccinated. 
• 
Other (specify). 
7.1.1. 
Contraindications to subsequent study intervention(s) 
administration  
The eligibility for subsequent study intervention administration must be confirmed before 
administering any additional dose. 
Participants who meet any of the criteria listed below or criteria listed in Sections 5.2.1 
and 5.2.2 should not receive additional doses of study intervention. Such participants 
should be encouraged to continue other study procedures, at the investigator’s discretion 
(Section 10.3.8.2). All relevant criteria for discontinuation of study intervention 
administration must be recorded in the eCRF. 
• 
Participants who experience any SAE judged to be possibly or probably related to 
study intervention or non-study concomitant vaccine/product, including 
hypersensitivity reactions. 
• 
Participants who develop any new condition which, in the opinion of the 
investigator, may pose additional risk to the participant if he/she continues to 
participate in the study. 
• 
Anaphylaxis following the administration of study interventions. 

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• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, expose the participant to unacceptable risk from 
subsequent vaccination. In such cases, the investigator should use his/her clinical 
judgment prior to administering the next dose of the study intervention(s). Refer to 
Section 10.3.5.1 for the definition of pIMDs. 
7.2. 
Participant discontinuation/withdrawal from the study  
A participant is considered to have withdrawn from the study if no new study procedure 
has been performed or no new information has been collected for him/her since the date 
of withdrawal/last contact. 
From an analysis perspective, a study ‘withdrawal’ refers to any participant who did not 
return for the concluding visit planned in the protocol. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 
The primary reason for study withdrawal will be documented in the eCRF, based on the 
list below: 
• 
AEs requiring expedited reporting to GSK. Refer to Section 10.3.10.1 for details. 
• 
Unsolicited non-serious AEs. 
• 
Solicited AE. 
• 
Withdrawal by participant, not due to an AE. * 
• 
Migrated/moved from the study area. 
• 
Lost to follow-up. 
• 
Sponsor study termination. 
• 
Other (specify). 
*If a participant is withdrawn from the study because he/she has withdrawn consent 
and the reason for withdrawal was provided, the investigator must document this 
reason in the eCRF. 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.8.2). 

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7.3. 
Lost to follow-up  
A participant will be considered ‘lost to follow-up’ if he/she fails to return for scheduled 
visits and cannot be contacted by the study site. 
Please refer to the SPM for a description of actions to be taken before considering the 
participant lost to follow-up. 
8. 
STUDY ASSESSMENTS AND PROCEDURES  
Protocol waivers or exemptions are only permitted when necessary for the management 
of immediate safety concerns for the participant. 
Immediate safety concerns should be discussed with the sponsor as soon as they occur or 
when the study team becomes aware of them. The purpose of this communication is to 
determine if the participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
All screening evaluations must be completed, and the results reviewed before confirming 
that potential participants meet all eligibility criteria. 
The investigator will maintain a log of all participants screened. All relevant information, 
such as confirmation of eligibility and reasons for screening failure will be mentioned in 
this screening log. 
Procedures conducted as part of routine clinical management (e.g., hematologic profiles), 
and obtained before the participant signed the ICF, may be used for screening and/or for 
establishing a clinical baseline (provided the procedure met protocol specified criteria 
and was performed within the time frame defined in the SoA (Section 1.3)). 
The SPM provides the investigator and site personnel with detailed administrative and 
technical information that does not impact participant safety. 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be followed. For the duration of such special circumstances, the 
following measures may be implemented for enrolled participants: 
• 
Safety follow-up may be made by a telephone call, other means of virtual contact or 
home visit (from the site staff or from the home care service system), if appropriate. 
• 
If the eDiary device was provided to the participant, it may be returned to the study 
center by conventional mail after the end of the relevant data collection period (refer 
to the SPM for details). If the eDiary app was provided to the participant for use on 
their personal device, the app can be disabled remotely. 
• 
Biological samples may be collected at a different location* other than the study site 
or at participant’s home. Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use. 

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*Note: It is the investigator’s responsibility to identify an alternate location. The 
investigator should ensure that this alternate location meets ICH GCP requirements, 
such as adequate facilities to perform study procedures, appropriate training of the 
staff, and documented delegation of responsibilities in this location. This alternate 
location may need to be covered by proper insurance for the conduct of study on 
participants by investigator and study center staff other than the designated study 
center and must be compliant according to local laws and/or regulations. 
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval pre-defined in the protocol (see Table 2), then the interval may be extended 
up to a maximum length of 60 days after Visit 1 to Visit 4 and after Visit 4 to Visit 7. 
The impact on the Per-Protocol Set for immunogenicity will be determined on a 
case-by-case basis. 
8.1. 
Immunogenicity assessments  
Biological samples will be used for research planned in the protocol and for purposes 
related to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. 
If allowed by informed consent, the samples collected in this study may also be used for 
further research to better understand the study disease(s) under evaluation and/or further 
characterize the immune response to the study vaccine(s) and/or to further understand 
other diseases and/or inform the development of new products. In addition, the samples 
may be used to develop new research methods, assays, and tests. To this end, all 
participants in countries where this is allowed will also be asked to give consent to 
further research at the time they give consent to join the study. Biological samples may 
also be shared with a contracted partner for further research. The further research will be 
subject to prior IEC/IRB approval, if required by local legislation. 
Information on further research and its rationale can be obtained from GSK. 
Sample testing will be done in accordance with the recorded consent of the individual 
participant. 
By default, collected samples will be stored for a maximum of 20 years. This storage 
period begins when the last participant performs the last study visit. This timeline can be 
adapted based on local laws, regulations or guidelines requiring different timeframes or 
procedures. In all cases, the storage period should be aligned with participant’s consent. 
These additional requirements must be formally communicated to, discussed and agreed 
with GSK. 
8.1.1. 
Biological samples  
An overall volume of ~490.5 mL per participant will be collected during the entire study 
period, over a one-year period. Refer to Table 6 and SoA (Section 1.3) for details of 
volumes collected for different assessments. 

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Table 6 
Biological samples  
Sample type 
Quantity 
Unit 
Timepoint 
 
Blood sampling for anti-HBs 
Ab, anti-HBc Ab and-HBs 
Antigen screening tests 
~8.5 
mL 
SCREEN (Day -7) 
All screened 
Blood sampling for antibody 
determination 
 
 
~20 
Day 1, Day 31, Day 61 and 
Day 361 
All participants  
Blood sampling 
 
 
~5 
Blood sampling 
 
 
~5 
Blood sampling for CMI 
response 
~50 
Day 1, Day 8, Day 31, Day 38, 
Day 61 and Day 361 
All participants 
Blood sampling for 
hematology/biochemical 
analysis at screening and for 
safety monitoring 
~7 
SCREEN (Day -7) 
All screened 
Day 1, Day 8, Day 31, Day 38, 
and Day 61 
All participants 
8.1.2. 
Laboratory assays  
Table 7 
Laboratory assays at screening  
Timepoint 
Study timing 
Blood analyzed for: 
Laboratory 
Day -7 
Screening Visit (SCREEN) 
Anti-HBs antibodies, anti-HBc 
antibodies, HBsAg 
GSK* 
*GSK designated central laboratory 
Table 8 
Laboratory assays  
Assay type 
System 
Component 
Challenge 
Method 
Laboratory* 
Humoral Immunity 
(antibody 
quantification and 
characterization) 
Serum 
HBs-specific Ab 
quantification 
Chemiluminescence 
immunoassay (CLIA) 
GSK** 
CMI 
PBMC 
Anti-HBs-specific 
CD4+/CD8+ T-cells 
HBs peptide 
pool 
Intracellular 
cytokine staining / 
Flow cytometry 
GSK** 
PBMC 
 and Memory 
B-cells 
HBs antigen 
Flow cytometry  
GSK** 
PBMC 
Memory B-cells 
HBs antigen or 
peptide pool 
B-cell ELISPOT 
GSK** 
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The addresses of clinical laboratories used for sample analysis are provided in a separate 
document accompanying this study protocol. 
GSK clinical laboratories have established a Quality System supported by procedures. 
The activities of GSK clinical laboratories are audited regularly for quality assessment by 
an internal (sponsor-dependent) but laboratory-independent Quality Department. 
8.1.3. 
Immunological read-outs  
Refer to Table 9 for the number of participants planned to be evaluated per time point and 
laboratory assessment. 
 
 
Table 9 
Laboratory testings and timepoints 
Blood sampling timepoint 
Subset name 
No. 
participants 
Component 
Type of contact and 
timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-Dose 
All 
~150 
Anti-HBsAg-specific antibodies 
(quantification 
) 
HBs-specific CD4+/CD8+ T-cells 
HBs-specific memory B-cells 
and Memory B-cells 
and Memory B-cells 
Visit 4 (Day 31) 
Pre-Dose 2 
All 
~150 
Anti-HBsAg-specific antibodies 
(quantification 
 
HBs-specific CD4+/CD8+ T-cells 
HBs-specific memory B-cells 
and Memory B-cells 
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Blood sampling timepoint 
Subset name 
No. 
participants 
Component 
Type of contact and 
timepoint 
Sampling 
timepoint 
Visit 6 (Day 38) 
Post-Dose 2 
All 
~150 
and Memory B-cells 
Visit 7 (Day 61) 
Post-Dose 2 
All 
~150 
Anti-HBsAg-specific antibodies 
(quantification 
) 
HBs-specific CD4+/CD8+ T-cells 
HBs-specific memory B-cells 
and Memory B-cells 
 
Visit 9 (Day 361) 
Post-Dose 2 
or post-Dose 3 
for participants 
receiving 
HBs/Alum 
All 
~150 
Anti-HBsAg-specific antibodies 
(quantification 
) 
HBs-specific CD4+/CD8+ T-cells 
HBs-specific memory B-cells 
HBsAg = hepatitis B surface antigen; HBs = hepatitis B surface; CD = cluster of differentiation. 
Details of assay subsets is described in Section 6.3.5.  
8.1.4. 
Clinical safety laboratory assessments  
Refer to Section 10.2.1 for the list of clinical laboratory safety assessments required by 
the protocol. These assessments must be conducted according to the clinical laboratory 
manual and the SoA. 
8.1.5. 
Immunological correlates of protection  
For the Hepatitis B surface antigen, the conventional correlate of protection (CoP) is 
anti-HBs antibody concentrations above 10 mIU/mL [Kane, 2000]. 
The investigator is encouraged to share the immunological assay results of 
non-responders with the study participants. 
After the end of the study, GSK will provide investigators with data that may potentially 
be relevant to the care of their respective participants. This may include the results of 
research immunological assays (as detailed in Section 8.1) that the investigator may 
consider to be indicative of responders and non-responders in the study. 
An extra dose of Engerix-B will be offered by the investigator at the end of the study to 
non-responders irrespective of the study intervention received in the study (as described 
in Section 6.7). 
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8.2. 
Safety assessments  
The investigator and his/her designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. The investigator and designees 
are responsible for following up AEs that are serious, considered related to the study 
intervention or the study, or that caused the participant’s withdrawal from the study 
interventions. Refer to the SoA (Section 1.3) for the timepoints for safety assessments. 
8.2.1. 
Pre-intervention administration procedures  
8.2.1.1. 
Collection of demographic data  
Record demographic data such as date of birth, sex and race in the participant’s eCRF. 
8.2.1.2. 
Medical/vaccination history  
Obtain the participant’s medical/vaccination history* by interviewing the participant or 
review of the participant’s medical records. Record any pre-existing conditions, signs 
and/or symptoms present prior to the first dose of study intervention in the eCRF. 
*Any vaccines administered within 30 days before Visit 1 (Day -29 to Day 1). 
8.2.1.3. 
Physical examination  
At screening, perform a targeted physical examination based on the clinical history of the 
patient and collect temperature, vital signs at rest (heart rate and respiratory rate, blood 
pressure), height, weight and BMI. 
During Visit 1, Visit 4 and Visit 8, perform a physical examination and collect 
temperature, vital signs at rest (heart rate and respiratory rate, blood pressure). Collected 
information should be recorded in the eCRF. 
Vital signs are to be taken before blood collection for laboratory tests and will consist of 
one pulse and one blood pressure measurement. 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
If the investigator determines that the participant’s health on the day of study intervention 
administration temporarily precludes dosing, the visit will be rescheduled. Refer to 
Section 5.5 for the list of criteria for temporary delay of study intervention 
administration. 
Physical examination at each visit after the study intervention administration visits, will 
be performed only if the participant indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the investigator or delegate. 

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Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
8.2.1.4. 
Pregnancy test  
Female participants of childbearing potential must perform a urine pregnancy test before 
the administration of any dose of study intervention. Pregnancy testing must be done 
even if the participant is menstruating at the time of the study visit. The study 
intervention may only be administered if the pregnancy test is negative. 
Refer to Section 10.4.3.1 for the information on study continuation for participants who 
become pregnant during the study. 
8.2.1.5. 
Warnings and precautions to administration of study intervention  
Warnings and precautions to administration of Engerix-B and Fendrix, as listed in their 
respective Prescribing Information (PI), must be checked at each visit with planned 
administration of study intervention. 
8.2.2. 
Clinical safety laboratory tests  
Refer to Section 10.2.1. 
8.2.3. 
Study holding rules and safety monitoring  
This study will be overseen by an internal SRT. Four safety reviews by the SRT are 
planned during the study conduct. In addition, ad hoc SRT reviews can be triggered in 
case any safety concern is observed. 
If any safety concern is identified by the investigator (i.e., meeting of holding rules (see 
Section 7.2), or any other safety concern), he/she will inform GSK Global Safety 
immediately (within 24 hours), and vaccination may be put on hold at all sites as a 
consequence. Following an internal review, GSK will then decide to suspend, modify or 
continue the conduct of the study. This decision will be documented and provided in 
writing to the investigators. 
8.2.3.1. 
Staggered administration of study intervention  
The study will be conducted following a staggered design, and the initiation of the 
HBs-AS37_100 group will be conditional to whether any holding rule is met in the 
HBs-AS37_50 group. 
If ≥ 2 participants from the HBs-AS37 groups are to be vaccinated at the same study site 
on the same day, these participants should be vaccinated sequentially with at least 
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During the first SRT review, all available safety data will be reviewed once the first 
5 participants in the HBs-AS37_50 group have completed 7 days safety follow-up 
post-Dose 1 (and data are available for analysis), before administering the second dose to 
these participants, and before enrolment of the remaining participants in this group in the 
next cohorts, and the first 5 participants in the HBs-AS37_100 group in the second 
cohort. The enrolment in the second cohort will start after the second dose is 
administered to all 20 participants in the first cohort. 
During the second SRT review, all available safety data will be reviewed once the first 
5 participants in the HBs-AS37_50 group have completed 7 days safety follow-up 
post-Dose 2, before administering the second dose to the remaining participants in this 
group in the next cohorts. 
During the third SRT review, all available safety data will be reviewed once the first 
5 participants of the HBs-AS37_100 group have completed 7 days safety follow-up 
post-Dose 1, before administering the second dose to these participants, and before 
enrolment of the remaining participants in this group in the third cohort. The enrolment in 
the third cohort will start after the third SRT review. 
During the fourth SRT review, all available safety data will be reviewed once the first 
5 participants in the HBs-AS37_100 group have completed 7 days safety follow-up 
post-Dose 2, before administering the second dose to the remaining participants in this 
group, in the third cohort. 
Seven days safety follow-up data will also include hematological and biochemical 
laboratory parameters tested at Day 8 post-study intervention administration. 
The investigator can only start vaccinating the participants in the AS37 groups with the 
second dose or in a subsequent cohort upon notification from the sponsor and receipt of 
written documentation of a favorable outcome of the scheduled SRT reviews. 
8.2.3.2. 
Outcome of safety evaluation  
• 
If no safety signal is observed, the favorable outcome of the safety evaluations will 
be documented and provided in a written way, authorizing the investigator to start 
the administration of the subsequent dose of study intervention to participants, as 
well as enrolment and study intervention administration to the remaining participants 
in the next step of the study. 
• 
If any of the holding rules 2a-d (Table 10) is met, vaccination will be put on hold, 
but other procedures relating to safety, immunology and monitoring will continue. 
• 
If any of the holding rules 1a-d (Table 10) is met, or if a signal is identified during 
ongoing safety monitoring, the study may be put on hold if needed for safety 
reasons. 
• 
Following an internal review, GSK will then decide to suspend, modify or continue 
the conduct of the study. This decision will be documented and provided in writing 
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• 
The study CSL will be accountable for notifying all investigators of the decision 
whether to suspend, modify or continue the conduct of the study on all groups or on 
selected groups. 
8.2.3.3. 
Study holding rules  
Study holding rules are defined in Table 10. Holding rules 1a-d will be assessed by the 
investigator on a continuous basis and meeting any of these holding rules will trigger a 
hold of vaccination irrespective of number of participants enrolled and/or timing of the 
event relative to vaccination. Holding rules 2a-d will be assessed by the SRT during the 
scheduled meetings for evaluation of safety data. 
The initiation of the HBs-AS37_100 group will be conditional to whether any holding 
rule is met in the HBs-AS37_50 group and can only occur upon review of the available 
safety data during the SRT meetings scheduled as per the staggered approach (see 
Section 8.2.3.2). 
If a safety signal is observed during the SRT review, or if any of the holding rules is met, 
the SRT can recommend to: (1) continue the study, (2) modify the study, or (3) stop the 
study. The SRT can recommend stopping vaccination in all groups, or only in a specific 
study group, while proceeding with vaccination in the other groups. The SRT 
recommendation should be communicated to the GSB Chair, who will make the final 
decision on the path forward. GSB Chair must immediately be notified if a holding rule is 
met. 
Table 10 
Study holding rules  
Holding 
rule 
Event 
Number/percentage of 
participants per group 
1a 
Death or any life-threatening SAE regardless of causality 
≥1 
1b 
Any SAE considered at least possibly related to the study intervention as per 
Investigator or Sponsor assessment  
≥1 
1c 
Any withdrawal from the study (by investigator or participant request) 
following a Grade 3 AE 
≥1 
1d 
Any administration site or systemic solicited AE leading to hospitalization or 
necrosis at the injection site, each with an event onset within the 7-day 
(Day 1-7) post-study intervention period 
≥1 
2a 
Any Grade 3 solicited administration site AE (lasting 48h or more as 
Grade 3) in an investigational group, with an event onset within the 7-day 
(Day 1-7) post-study intervention period 
20% 
2b 
Any Grade 3 solicited systemic AE (lasting 48h or more as Grade 3) in an 
investigational group, with an event onset within the 7-day (Day 1-7) 
post-intervention period 
20% 
2c 
Any Grade 3 unsolicited AE in an investigational group, that can be 
reasonably attributed to the study intervention, with an event onset within the 
7-day (Day 1-7) post-study intervention period or 
Any Grade 3 or above abnormality in pre-specified hematological or 
biochemical laboratory parameters* in an investigational group at Day 8 
post-study intervention 
20% 
2d 
Any Grade 3 non-serious AE considered as, at least, possibly related to the 
study intervention as per Investigator or Sponsor assessment, independent 
of within or not within the same system-organ-class 
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AE = adverse event; SAE = serious adverse event; FDA = Food and Drugs Administration  
*Refer to Table 22 for the FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adults and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
If the investigator becomes aware of a holding rule 1a-d being met, he/she must suspend 
administration of the study intervention and inform GSK immediately Refer to Table 13 
for contact information. 
The following communication sequence must be followed: 
• 
The concerned site staff must put study intervention administration on hold. 
• 
The concerned site staff must immediately inform their local GSK contact defined in 
Section 8.4.3.1. 
• 
LML will inform the other sites of his/her country, LMLs of other countries and the 
CSL. 
• 
All informed site staff will confirm to their local contact that action has been taken 
providing appropriate documentation to GSK. 
• 
GSK will further evaluate the case with the SRT and GSB and will take the decision 
to restart, modify, or stop the study. All site staff will be informed about that final 
decision by their local GSK contact. 
GSK will inform the investigator if holding rules 2a-d are met (see Section 8.2.3.2). 
8.3. 
Other assessments  
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8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
other safety reporting  
8.4.1. 
Time period and frequency for collecting AE, SAE and other 
safety information  
Table 11 
Timeframes for collecting and reporting of safety information  
Event 
Pre- 
Dose*  
Dose 
1 
 
 
 Dose2 
 
 
 
Dose 
3 
 
 
 
Study 
Conclusion 
D1 
D14 D31 
D31 D44 D61 
D181 D194 D211 
Administration site and 
systemic solicited 
events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to the 
study intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or 
concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D = day; M = month; AE = adverse event; SAE = serious adverse event; pIMD = potential immune-mediated disorder; 
MAE = medically attended event 
*i.e., consent obtained 
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The investigator or designee will record and immediately report all SAEs in enrolled 
participants to the sponsor or designee via the Expedited AE Reporting Form. Reporting 
should, under no circumstances, occur later than 24 hours after the investigator becomes 
aware of an SAE, as indicated in Section 10.3.10. The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available. See Section 
10.3.10.1 for more information on the events requiring expedited reporting to GSK. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting periods defined in Table 11. Investigators are not obligated to actively seek AEs 
or SAEs from former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
he/she considers the event to be reasonably related to the study intervention, the 
investigator will promptly notify the study contact for reporting SAEs mentioned in Table 
13. 
8.4.2. 
Method of detecting AEs and SAEs, pregnancies and other 
events  
Detection and recording of AE/SAE/pIMD/pregnancies are detailed in Section 10.3.8. 
Assessment of AE/SAE intensity, causality and outcome are described in Section 10.3.9. 
Open-ended and non-leading verbal questioning of participants is the preferred method of 
acquiring information related to an AE/SAE/pIMD/pregnancy. 
8.4.2.1. 
Clinically significant abnormal laboratory findings  
The investigator must review the laboratory report, document that he/she did so, and 
record any clinically relevant changes occurring during the study in the AE section of the 
eCRF. Clinically significant abnormal laboratory findings are those which are not 
associated with an underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
• 
All clinically significant abnormal laboratory test values reported during the study or 
within 31 days after the last dose of study intervention should be repeated until the 
values return to normal/baseline, or until they are no longer considered significantly 
abnormal by the investigator or LML. Refer to Section 10.3.6 for more information 
on clinically abnormal laboratory assessments that qualify as an AE or SAE. 
• 
If such values do not return to normal/baseline after an interval judged reasonable by 
the investigator, the etiology of the abnormal value should be identified, and the 
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8.4.3. 
Regulatory reporting requirements for SAEs, pregnancies and 
other events  
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/pIMD/pregnancy, it must be reported to GSK using the required 
documentation and within the timeframes mentioned in Table 12. This is essential for 
meeting GSK legal obligations and ethical responsibilities for participant safety and the 
safety of a study intervention under clinical investigation. 
For SAEs/pIMDs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in Section 10.3.9.2. 
Local regulatory requirements and sponsor policy for preparation of an investigator 
safety report of Suspected Unexpected Serious Adverse Reactions (SUSAR) must be 
followed. These reports will be forwarded to investigators as necessary. 
The sponsor has the legal responsibility to notify local authorities/regulatory agencies 
about the safety of an investigational study intervention. The sponsor will comply with 
country-specific regulatory requirements related to safety reporting to the regulatory 
authority, IRB/IEC and investigators. 
Refer to Section 10.3.10 for further details regarding the reporting of 
SAEs/pIMDs/pregnancies. 
Table 12 
Timeframes for submitting SAE, pIMD, pregnancy and other events 
reports to GSK  
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  
24 hours* 
electronic pregnancy report 
24 hours* 
electronic pregnancy report  
pIMDs 
24 hours** ‡‡  
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
*Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD. 
‡‡The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD. 

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8.4.3.1. 
Contact information for reporting SAEs, pIMDs, pregnancies and study 
holding rules  
Table 13 
Contact information for reporting SAEs, pIMDs, pregnancies and 
study holding rules  
Study contact for questions regarding SAEs, 
pIMDs, pregnancies  
Study contact for reporting of study 
holding rules 
Refer to the local study contact information 
document 
As soon as the investigator is aware that a 
holding rule is met, he/she must 
immediately inform the LML 
Back-up study contact for reporting SAEs, 
pIMDs, pregnancies. 
Available 24/24 hours and 7/7 days: 
Back-up study contact for escalation of 
holding rules. 
CSL 
GSK Global Safety 
 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: ogm28723@gsk.com 
 
8.4.4. 
Treatment of AEs  
Any medication administered for the treatment of an SAE/pIMDs should be recorded in 
the Expedited Adverse Event Report of the participant’s eCRF page/screen (refer to 
Section 10.3.10.1). 
8.4.5. 
Participant card  
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in his/her/their possession for the duration of the study. 
In an emergency, this card serves to inform the responsible attending physician that the 
participant is in a clinical study and that relevant information may be obtained by 
contacting the investigator or his/her back-up. 
8.4.6. 
Medical device deficiencies  
The study intervention Engerix-B and Fendrix is a combination product constituted of a 
device and biologic product (e.g., pre-filled syringes). Refer to the Glossary of terms for 
the definition of combination product and medical device deficiency. 
8.4.6.1. 
Detection, follow-up and prompt reporting of medical device deficiency  
The investigator is responsible for the detection, documentation and prompt reporting of 
any medical device deficiency occurring during the study to GSK. This applies to any 
medical device provided for the conduct of the study. 
Device deficiencies will be reported to GSK within 24 hours after the investigator 
determines that the event meets the protocol definition of a device deficiency. Refer to 
Section 10.6 for definitions and details on recording and reporting of these events. 

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The investigator will ensure that follow-up includes any additional investigations to 
elucidate the nature and/or related of the device deficiency to the incident. Follow-up 
applies to all participants, including those who discontinue study intervention or the 
study. 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator and reported to GSK within 24 hours. 
8.4.6.2. 
Regulatory reporting of medical device deficiency when used as 
combination product  
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study to GSK. GSK has a legal responsibility to notify 
appropriate regulatory authorities and other entities about safety information linked to 
medical devices being used in clinical studies. Refer to Section 10.6 for details of 
reporting. 
The investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC. 
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8.9. 
Immunogenicity assessments  
Immunogenicity is described in Section 8.1. 
8.10. 
Health outcomes  
Not applicable for this study. 
9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical hypotheses  
No confirmatory statistical hypotheses are to be tested. All analyses are descriptive. The 
use of these descriptive analyses will be limited to hypotheses generation or to supportive 
analyses of other confirmatory analyses or hypotheses generation. 
9.2. 
Analysis sets  
Table 14 
Analysis sets  
Analysis Set 
Description 
Screened 
All participants who were screened for eligibility. 
Enrolled 
All participants who entered the study (who were randomized or received study 
intervention or underwent a post-screening procedure). 
NOTE: Screening failures (who never passed screening even if rescreened) and 
participants screened but never enrolled into the study (i.e., met eligibility but not 
needed) are excluded from the Enrolled Set as they did not enter the study. 
Exposed 
All participants who received at least 1 dose of the study intervention. Analysis per 
group using the Enrolled Set is based on the administered intervention. 
Per-Protocol 
All eligible participants who received all doses as per protocol, had immunogenicity 
results post-dose, complied with dosing/blood draw intervals, without intercurrent 
conditions that may interfere with immunogenicity and without prohibited concomitant 
medication/vaccination. 
9.2.1. 
Criteria for elimination from analysis  
If the participant meets one of the criteria mentioned below or ones listed in Section 
7.1.1, he/she may be eliminated from Per-Protocol analysis. 
Participants may be eliminated from the Per-Protocol Set for immunogenicity if, during 
the study, they incur an intercurrent medical condition that could alter their immune 
response (i.e., varicella, HIV, lymphoma) or are confirmed to have an alteration of their 
initial immune status. For further details on criteria for elimination from Per-Protocol set, 
refer to the Statistical Analysis Plan. 
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9.3. 
Statistical analyses  
The SAP will be finalized prior to the First Subject First Visit and it will include a more 
technical and detailed description of the statistical analyses. This section is a summary of 
the planned statistical analyses. 
The analyses will be descriptive with the aim to characterize the safety/reactogenicity and 
immunogenicity of the vaccine groups. 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final clinical study report (CSR). 
9.3.1. 
Primary endpoints analyses  
The analysis of the primary objective will be performed on the Exposed Set (ES). 
Endpoint 
description 
Analysis 
set 
Statistical analysis methods 
Reactogenicity and 
Safety 
Exposed 
Descriptive statistics: 
• 
Percentage of participants with solicited administration site and systemic 
AEs within 14 days (Day 1 till Day 14) and severity grading will be 
tabulated with exact 95% CI for each group after Dose 1 and Dose 2 of 
the study intervention and overall. 
• 
Descriptive statistics of duration of solicited AEs (administration site and 
systemic) will be tabulated for each group after Dose 1 and Dose 2 of 
the study intervention and overall. 
• 
Percentage of participants with any unsolicited AEs within 31 days (Day 1 
till Day 31) and severity grading will be tabulated with exact 95% CI for 
each group after Dose 1 and Dose 2 of the study intervention and overall. 
• 
Percentage of participants with SAEs, related SAEs, MAEs and AEs 
leading to study withdrawal throughout the entire study period will be 
tabulated with exact 95% CI for each group. 
• 
Percentage of participants with pIMDs throughout the entire study period 
will be tabulated with exact 95% CI for each group. 
• 
Descriptive statistics of the absolute values and changes in hematology 
and biochemical parameters from baseline at each protocol specified 
timepoints will be tabulated for each group. 
• 
Percentage of participants with abnormal laboratory parameter values 
will be tabulated with exact 95% CI for each group pre-vaccination, after 
Dose 1 and after Dose 2 of the study intervention and overall. 
AE = adverse event; CI = confidence interval; SAE = serious adverse event; MAE = medically attended event; 
pIMD = potential immune-mediated disorder. 

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9.3.2. 
Secondary endpoints analyses  
The analysis of the secondary objective will be performed on the Per-Protocol Set (PPS). 
If 5% or more of the vaccinated participants are eliminated from the PPS at one 
timepoint, an additional sensitivity analysis will be performed on the ES. 
Endpoint 
description 
Analysis 
set 
Statistical analysis methods 
Immunogenicity 
Per-
Protocol 
Descriptive statistics: 
• 
Anti-HBs antibody GMCs and their 95% CI will be tabulated and represented 
graphically for each group at each timepoint. 
• 
GMCs ratios, their 95% CI and related p-value for difference will be tabulated 
for post-Dose 1 and Dose 2 for all pairwise comparisons between groups. 
 
 
• 
Antibody concentrations will be displayed using reverse cumulative curves for 
each protocol defined timepoint. 
• 
Percentage of participants above seroconversion and seroprotection threshold 
will be tabulated with exact 95% CI for each group at each protocol specified 
timepoint. 
• 
Seroconversion and seroprotection rates will be compared, and the 95% CI 
and related p-value for the difference will be tabulated for post-Dose 1 and 
Dose 2 for all pairwise comparisons between groups. 
 
 
GMC = geometric mean concentration; CI = confidence interval; ANCOVA = Analysis of Covariance 
9.4. 
Interim analyses  
There will be no interim analyses, a main analysis is planned on data collected 
post-Dose 2 (Day 61 – Visit 7) and a final analysis including data up to study end 
(Day 361 - Visit 9). However, there will be interim safety monitoring. 
Interim safety monitoring will be performed based on all the available safety data after 5 
participants from each of the AS37 groups have completed the 7 days safety follow-up 
period post-Dose 1 and post-Dose 2, applying the safety holding rules as described in 
Table 10. Holding rules 1a-d from Table 10 will be assessed by the investigator on a 
continuous basis, holding rules 2a-d from Table 10 will be assessed by the SRT during 
the scheduled meeting for evaluation of safety data. These interim safety evaluations will 
be used to decide on the enrolment of the remaining participants and administration of the 
second dose in the AS37 groups, as well as the enrolment of the first 5 participants in 
HBs-AS37_100 group (when evaluating the first 5 participants post-Dose 1 from the 
HBs-AS37_50 group). 
Figure 2 shows the probability of meeting the holding rules described in Table 10, for a 
group of sentinel participants (5 participants). 
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Figure 2 
Risk assessment curves for study holding rules after 5 participants 
(sentinel participants)*  
 
*The binomial distribution was used to obtain the probabilities displayed in this figure 
Figure 3 shows the probability of meeting the holding rules described in Table 10, for 
each whole group (23 participants).  

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Figure 3 
Risk assessment curves for study holding rules after 23 participants 
(minimum sample size for a whole group) *  
 
*A binomial distribution was used to obtain the probabilities displayed in this figure 
9.4.1. 
Sequence of analyses  
9.4.1.1. 
Main analysis  
The main analysis will be performed on safety and reactogenicity data (primary 
endpoints) and immunogenicity data (secondary endpoints) when all data post-Dose 2 
(Day 61 – Visit 7) are cleaned and available. 
 
. 
9.4.1.2. 
Final analysis  
The final analysis on primary and secondary endpoints (safety, reactogenicity and 
immunogenicity data) and 
 
 
 
  
An integrated CSR containing all the primary, secondary and when available tertiary data 
will be written and made available to the investigators. Tertiary endpoints data that become 
available at a later stage will be documented in annex(es) to the CSR and will be made 
available to the investigators at that time. 
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9.5. 
Sample size determination  
A minimum of 23 (and maximum of 30) participants per group will be enrolled in this 
study. The target sample size has been reduced from 30 to 23 participants per group for 
reasons of feasibility, as discussed in Section 4.2.1. 
 
 
 
 
 
 
 
The sample size is not based on formal hypothesis testing and is typical for this kind of 
study where a treatment is tested for the first-time in human. 
 
 
 
 
 
The primary objectives of the study are to assess the reactogenicity and safety of each 
vaccine dose throughout the study. 
 
 
 
 
 
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations  
10.1.1. 
Regulatory and ethical considerations  
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the 
study is initiated. 
• 
Any protocol amendments will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following, as applicable: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
− 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 

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10.1.2. 
Financial disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
10.1.3. 
Informed consent process  
The investigator or his/her representative must fully explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. 
Participants must be informed that their participation is voluntary. 
Freely given and written/witnessed informed consent must be obtained from each 
participant as appropriate, prior to participation in the study. 
Participants will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
Sample testing will be done in accordance with the recorded consent of the individual 
participant. The medical record must include a statement that written or witnessed 
informed consent was obtained before the participant was enrolled in the study and the 
date the consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
Participants must be re-consented if a new version of the ICF(s) or an ICF addendum is 
released during their participation in the study. 
A copy of the ICF(s) must be provided to the participants. 
Participants who are rescreened are required to sign a new ICF, only if there are changes 
to the original ICF. 
10.1.4. 
Data protection  
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets transferred to the sponsor will contain only the identifier. Name and any other 
information which would identify the participant will not be transferred. 
GSK will ensure protection of the personal data of the investigator and site staff which is 
collected within the framework of and for the purpose of the study, in accordance with 
the Data Privacy Notice that will be sent to the site staff. 

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The participant must be informed that their personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant, that their data will be used as described in the 
informed consent. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  
GSK has a global, internal policy that requires all GSK staff and complementary workers 
to report data incidents or breaches immediately, using dedicated tools. Clear procedures 
are defined for assessing and investigating data breaches to identify and to take 
appropriate remediation steps, to contain and to mitigate any risks for individuals 
resulting from a breach, in compliance with applicable laws. 
10.1.5. 
Committees’ structure  
The protocol will be reviewed and approved by an IEC/IRB before study initiation (see 
Section 10.1.1 for further details). 
Safety monitoring will be conducted by an internal SRT. The SRT will review interim 
and cumulative safety data and will escalate concerns to the GSB (see Section 8.2.3). 
10.1.6. 
Dissemination of clinical study data  
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary/study 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines. 
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical study registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK 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 participants, as appropriate. 

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Where required by regulation, the names of the sponsor signatory and investigator 
signatory will be made public. 
GSK will provide the investigator with the randomization codes and participant-level line 
listings for their site only after completion of the full statistical analysis. 
GSK intends to make anonymized patient-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by study 
participants are used to maximum effect in the creation of knowledge and understanding. 
Data will be shared with researchers in a non-identifying way, and appropriate measures 
will be taken to protect PI; these measures will comply with data protection and privacy 
laws that apply. 
10.1.7. 
Data quality assurance  
The investigator should maintain a record of the location(s) of their respective essential 
documents, including source documents (see Glossary of terms for the exact definition of 
essential and source documents). The document storage system used during the study and 
for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval. 
Essential study documents may be added or removed where justified (in advance of study 
initiation) based on their importance and relevance to the study. When a copy is used to 
replace an original document (e.g., source documents, eCRF), the copy should fulfill the 
requirements for certified copies (see Glossary of terms for the exact definition of 
certified copies). 
All participant data related to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
The investigator must maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s study participants (see 
Glossary of terms for the exact definition of source documents) that supports information 
entered in the eCRF. 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies for such review and inspection. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data (see Glossary of terms for the exact definition of 
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Study monitors will perform ongoing source data verification to confirm that data entered 
in the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data must be traceable, not obscure 
the original entry, and be fully explained if necessary (e.g., via an audit trail). The safety 
and rights of participants must be protected, and the study conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
Quality tolerance limits (QTLs) will be pre-defined in the Quality Management Plan to 
identify systematic issues that can impact participant safety and/or the reliability of study 
results. These pre-defined parameters will be monitored during the study. Important 
deviations from the QTLs and remedial actions taken will be summarized in the CSR. 
Study records and source documents pertaining to the conduct of this study, including 
signed ICFs, must be retained by the investigator for 25 years from issuance of the final 
CSR/equivalent summary or in accordance with Applicable Law, whichever is longer. No 
records may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
When source data are sent for external assessment or adjudication (e.g., endpoint 
adjudication committee; expert reader), source data are stored by the external body for 
25 years.  
10.1.8. 
Source documents  
Source documents provide evidence to establish the existence of the participant and 
substantiate the integrity of collected data. The investigator should maintain a record of 
the location(s) of their source documents. 
Data transcribed into the eCRF from source documents must be consistent with those 
source documents; any discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.  
Definitions of what constitutes source data and documents can be found in the Glossary 
of terms. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
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Source data are shared with third parties contracted by GSK for external assessment or 
adjudication (e.g., endpoint adjudication committee; expert reader). The non-exhaustive 
list of source data shared may include, discharge summaries, imaging reports, scans, 
videos, pathology reports, biological specimens, ECG reports, etc. Participant names or 
any information which would make the participant identifiable or is not essential for the 
external assessment or adjudication will be redacted by the investigator sites prior to 
transfer. Details of the participant information redaction strategy are provided in the 
relevant third party manuals and/or study plans. These source data will be used by the 
third party solely for the purpose indicated within this protocol. 
10.1.9. 
Study and site start and closure  
First act of recruitment 
The start of study is defined as First Subject First Visit (FSFV) at a country-level. 
Study/site termination 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion, provided there is sufficient notice given to 
account for all participants safe exit from study. 
Regular closure of study sites will occur upon study completion. A study site is 
considered closed when all required data/documents and study supplies have been 
collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and enough notice in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
• 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
At the end of the study, the investigator will: 
• 
Review data collected to ensure accuracy and completeness. 
• 
Complete the Study Conclusion screen in the eCRF. 

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10.1.10. 
Publication policy  
GSK seeks to publish medically or scientifically significant results in searchable peer-
reviewed scientific literature within 18 months from LSLV. We follow International 
Committee of Medical Journal Editors standards for authorship and use Good 
Publications practices to guide our publications. 
10.2. 
Appendix 2: Clinical laboratory tests  
10.2.1. 
Protocol-required safety laboratory assessments  
The addresses of the clinical laboratories in charge of the testing can be found in the “List 
of Clinical Laboratories and Key Vendors”. 
Table 20 
Protocol-required safety laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Platelet count, 
Red blood cell count, 
Hemoglobin level, 
White blood cell count, 
Neutrophils, 
Lymphocytes, 
Monocytes, 
Eosinophils 
Clinical chemistry 
Sodium, 
Potassium, 
Chloride, 
Bicarbonate, 
Blood urea nitrogen, 
Creatinine, 
Liver function tests (ALT, AST) 
C-reactive protein 
Other screening tests 
• 
Urine human chorionic gonadotropin (hCG) pregnancy test 
(as needed for women of childbearing potential)] 
• 
Serology: Hepatitis B surface antigen [HBsAg], anti-HBs 
antibodies, anti-HBc antibodies 
• 
All study-required laboratory assessments will be performed 
by a central laboratory. 
The tests detailed in Table 20 will be performed by the central laboratory. 
Table 21 
Hematology and biochemistry read-outs  
Blood sampling timepoint 
Subset 
name 
No. 
participants 
Component 
Type of contact and timepoint 
Sampling timepoint 
Visit 1 (Day 1) 
Pre-Dose 1 
All 
~150 
Platelet count, 
RBC count, 
Hemoglobin level, 
WBC count, 
Neutrophils, 
Lymphocytes, 
Visit 3 (Day 8) 
Post-Dose 1 
All 
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Blood sampling timepoint 
Subset 
name 
No. 
participants 
Component 
Type of contact and timepoint 
Sampling timepoint 
Visit 4 (Day 31) 
Pre-Dose 2 
All 
~150 
Monocytes, 
Eosinophils, 
Sodium, 
Potassium, 
Chloride, 
Bicarbonate, 
Blood urea nitrogen, 
Creatinine, 
Liver function tests (ALT, AST), 
C-reactive protein 
Visit 6 (Day 38) 
Post-Dose 2 
All 
~150 
Visit 7 (Day 61) 
Post-Dose 2 
All 
~150 
WBC = white blood cells; RBC = red blood cells; ALT = alanine aminotransferase; AST = aspartate aminotransferase 
Grading of laboratory parameters (Table 21) will be based on the Food and Drug 
Administration [FDA, 2007] Guidance for Industry “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” as 
presented in Table 22. 
Table 22 
Toxicity Grading Scales for Hematology and Biochemistry 
Parameters Applicable for this Study  
Component 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
life-threatening 
(Grade 4) 
Hematology (whole blood) 
Hemoglobin (g/dL) – female 
11.0 - 12.0 
9.5 - 10.9 
8.0 - 9.4 
< 8.0 
Hemoglobin (g/dL) – male 
12.5 - 13.5 
10.5 - 12.4 
8.5 - 10.4 
< 8.5 
Hemoglobin (g/dL) - female change 
from baseline value 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (g/dL) - male change 
from baseline value 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC increase (cell/mm3) 
10 800 - 15 000 
15 001 - 20 000 20 001 - 25 000 
> 25 000 
WBC decrease (cell/mm3) 
2500 - 3500 
1500 - 2499 
1000 - 1499 
< 1 000 
Lymphocytes Decrease (cell/mm3) 
750 – 1000 
500 – 749 
250 - 499 
< 250 
Neutrophils Decrease (cell/mm3) 
1500 – 2000 
1000 – 1499 
500 - 999 
< 500 
Eosinophils (cell/mm3) 
650 – 1500 
1501 – 5000 
> 5000 
Hyper-eosinophilic 
Platelets decrease (cell/mm3) 
125 000 - 140 000 100 000 - 124 000 25 000 - 99 000 
< 25 000 
Biochemistry (serum) 
AST and ALT (increase by factor) 
1.1 - 2.5 x ULN 
2.6 - 5.0 x ULN 5.1 - 10 x ULN 
> 10.0 x ULN 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkaliemia mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Creatinine (mg/dL) 
1.5 - 1.7 
1.8 - 2.0 
2.1 - 2.5 
> 2.5 or requires dialysis 
Blood urea nitrogen (mg/dL) 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
WBC = white blood cells; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of 
the normal range 
FDA toxicity grading for red blood cell count, bicarbonate, chloride and C-reactive 
protein is not available. Laboratory ranges of normality should be consulted for these 
parameters. See Section 10.3.6 for further information on clinical laboratory parameters 
qualifying as AEs or SAEs, and Section 10.3.9.1 for the assessment of intensity. 

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10.2.2. 
Protocol-required immunogenicity assessments  
10.2.2.1. 
Total Ig Anti-Hepatitis B Surface antigen CLIA  
The ADVIA Centaur Anti-HBS2 assay is a sandwich immunoassay using direct, 
chemiluminometric technology. HBsAg (ad and ay) are covalently coupled to magnetic 
latex particles in the Solid Phase. In the Lite Reagent, the HBsAg (ad and ay) is labeled 
with acridinum ester. Non-magnetic latex particles are added from the ancillary well. The 
sample is incubated simultaneously with Lite Reagent, Solid Phase and Ancillary 
Reagent. Antibody-antigen complexes will form if anti-HBs is present in the sample. A 
direct relationship exists between the amount of anti-HBs activity present in the patient 
sample and the amount of relative light units (RLUs) detected by the system. 
Note: ad and ay are 2 different subtypes of S antigen. 
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10.2.2.3. 
Intracellular cytokine staining for HBs-specific CD4+/CD8+ T-cells  
The assay quantifies the Hepatitis B Surface Protein-specific CD4+/CD8+ T-cells elicited 
after vaccination or natural infection, with data on polyfunctionality of T-cells. 
ICS has been used to assess CMI responses as previously described [Moris, 2011]. 
Briefly, thawed PBMCs are stimulated in vitro with Hepatitis B Surface Protein peptides 
(1 peptide pool, 15mer overlapping by 11) or with culture medium only in the presence of 
anti-CD28 and anti-CD49d antibodies. After 2 h of incubation at 37 ◦C, Brefeldin A is 
added to inhibit cytokine secretion during an additional overnight incubation. Cells are 
subsequently harvested, stained with live/dead dye and then fixed. Fixed cells are then 
permeabilized and stained with fluorescently labeled antibodies specific for the following 
immune markers: 
• 
CD3, CD4, CD8: phenotyping T-cells. 
• 
CD40L (CD154), 4-1BB: expressed on activated CD4 and CD8 T-cells, respectively 
[Chattopadhyay, 2005; Frentsch, 2005; Samten, 2000; Stubbe, 2006]. 
• 
IL-2: key for the development, survival, and function of T-cells [Boyman, 2012]. 
• 
TNF-α: anti-viral/intracellular factor, pro-inflammatory cytokine, cytotoxicity 
[Sedger, 2014]. 
• 
IFN-γ: anti-viral factor, associated with the Th1 profile (and CD8) T-cells 
[Schoenborn, 2007]. 
• 
IL-13: associated with the Th2 profile [Bao, 2015]. 
• 
IL-17: associated with the Th17 profile [Korn, 2009]. 
Acquisition of data is performed via a flow cytometer, and data analysis is performed on 
FlowJo software. 
Other cell populations (e.g., plasmablast, memory B cells or TFH cells), or other 
activation markers or cytokines produced by different cell types may also be evaluated by 
flow cytometry. Further details on these assessments will be available in the Annex 
Clinical Study Report. 
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10.2.2.5. 
B-cell ELISPOT assay  
B-cell ELISPOT will be used to quantify vaccine antigen-specific memory B-cells which 
are responsible for long term (humoral) memory and will be the cells recalled during an 
infection subsequent to vaccination. This assay is designed to evaluate the frequency (per 
million memory B-cells) of HBs-specific memory B-cells from peripheral blood samples. 
PBMCs are stimulated with Cytosine phosphate Guanine (CpG) for 5 days to induce in 
vitro cell differentiation. Differentiated cells (plasmablasts) are then incubated with IgG 
antibody directed against immunoglobulins (to quantify total memory B-cells) or with the 
recombinant HBs protein (to quantify vaccine specific memory B-cells) coated on 
nitrocellulose plates. Antibodies bound to their target are revealed by the addition of a 
secondary antibody, an antibody/substrate complex allowing colorimetric detection. 
Finally, the plate(s) are read and analyzed on an ELISPOT reader. This B-cells ELISPOT 
is an optimized assay. 
The clinical testing will be performed at GSK laboratory (Rixensart, Belgium). 
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10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting  
10.3.1. 
Definition of an AE  
An AE is any untoward medical occurrence (an unfavorable/unintended sign - including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical 
study participant that is temporally associated with the study intervention. The AE may or 
may not be considered related to the study intervention. 
10.3.1.1. 
Events Meeting the AE Definition  
• 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
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• 
New conditions detected or diagnosed after administration of the study 
intervention even though they may have been present before study start. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug, disease or other 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
study intervention or a concurrent medication. 
• 
Signs or symptoms temporally associated with administration of the study 
intervention. 
• 
Signs, symptoms that require medical attention (e.g., hospital stays, physician 
visits and emergency room visits). 
• 
Significant failure of an expected pharmacologic or biological action. 
• 
Pre- or post- intervention events that occur as a result of protocol-mandated 
procedures (i.e., invasive procedures, modification of participant’s previous 
therapeutic regimen). 
• 
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. 
• 
AEs to be recorded as solicited AEs are described in Section 10.3.3. All other AEs 
will be recorded as UNSOLICITED AEs. 
10.3.1.2. 
Events NOT Meeting the AE Definition  
• 
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 participant before 
the first dose of study intervention These events will be recorded in the medical 
history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 

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10.3.2. 
Definition of an SAE  
An 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 participant 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 hospitalization or prolongation of existing hospitalization. 
Note: In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in disability/incapacity. 
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, diarrhea, 
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 participant. 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g. Other situations. 
Medical or scientific judgment must be exercised in deciding whether reporting is 
appropriate in other situations. Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition should 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; and 
convulsions that do not result in hospitalization. 

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10.3.3. 
Solicited events  
Solicited events are predefined administration site events and systemic events for which 
the participant is specifically questioned, and which are noted by the participant in their 
eDiary. 
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 23 
Solicited administration site events  
Pain at administration site 
Redness at administration site 
Swelling at administration site 
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 24 
Solicited systemic events  
Fever 
Fatigue 
Myalgia 
Arthralgia 
Headache 
Chills 
Malaise 
Loss of appetite 
Nausea 
Vomiting 
Diarrhea 
Note: participants will be instructed to measure and record the oral temperature in the 
evening. If additional temperature measurements are taken at other times of the day, 
participants will be instructed to record the highest temperature in the eDiary. Other 
options for temperature records include the axilla, ear canal and forehead; but oral 
temperature remains the preferred option. 
10.3.4. 
Unsolicited AEs  
An unsolicited AE is an AE that was either not included in the list of solicited events or 
could be included in the list of solicited events but with an onset outside the specified 
period of follow-up for solicited events. Unsolicited events must have been 
spontaneously communicated by a participant who has signed the informed consent. 
Unsolicited AEs include both serious and non-serious AEs. 

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Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or an emergency room visit, or visit to/by a health care 
provider). The participants will be instructed to contact the site as soon as possible to 
report medically attended event(s), as well as any events that, though not medically 
attended, are of participant’s concern. Detailed information about reported unsolicited 
AEs will be collected by qualified site personnel and documented in the participant’s 
records. 
Unsolicited AEs that are not medically attended or perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 
10.3.5. 
Adverse events of special interest (AESIs)  
pIMDs are the only AESIs collected during this study. 
10.3.5.1. 
Potential immune-mediated disorders  
Potential immune-mediated disorders (pIMDs) include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest which may or may not have an 
autoimmune etiology. AEs that need to be recorded and reported as pIMDs include those 
listed in Table 27 (refer to Section 10.3.8.1 for reporting details). 
The investigator must exercise his/her medical/scientific judgment to determine whether 
other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or 
organ-specific pathogenic autoantibodies) and should also be recorded as a pIMD. 
In addition, the investigator should categorize each pIMD either as a new onset condition 
(if it started following vaccination) or as an exacerbation of a preexisting chronic 
condition (if it exacerbated following vaccination) in the eCRF. 
When there is enough evidence to make any of the diagnoses mentioned in Table 27, the 
AE must be reported as a pIMD. Symptoms, signs or conditions which might (or might 
not) represent the above diagnoses, should be recorded and reported as AEs but not as 
pIMDs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) will be available to investigators at study 
start. 
Once a pIMD is diagnosed (serious or non-serious) in a study participant, the investigator 
(or designate) must complete, date and sign an electronic Expedited Adverse Events 
Report. 
The list of pIMDs is provided in Section 10.9 (Appendix 9). 

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10.3.6. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs  
In the absence of a diagnosis, abnormal laboratory findings assessments (hematology or 
clinical chemistry) or other abnormal results the investigator considers clinically 
significant will be recorded as an AE or SAE, if they meet the definition of an AE or 
SAE (refer to Sections 10.3.1 and 10.3.2). 
The investigator must exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding, or other abnormal assessment is clinically 
significant. 
10.3.7. 
Events or outcomes not qualifying as AEs or SAEs  
10.3.7.1. 
Pregnancy  
Female participants who become pregnant after the first study intervention dose must not 
receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any abnormal pregnancy 
outcome or complication or elective termination of a pregnancy for medical reasons will 
be recorded and reported as an SAE. Please refer to Section 10.3.2 for definition of 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 
Section 10.3.8 and Section 10.3.10: 
• 
Spontaneous pregnancy loss, including: 
− 
Spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation). 
− 
Ectopic and molar pregnancy. 
− 
Stillbirth (intrauterine death of fetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-International 
Classification of Diseases 10 noted in the EMA Guideline on pregnancy 
exposure [EMA, 2006]. It is recognized that national regulations might be 
different. 
• 
Any early neonatal death (that is death of a live born infant occurring within the first 
7 days of life). 
• 
Any congenital anomaly or birth defect (as per [CDC] guidelines) identified in the 
offspring of a study participant (either during pregnancy, at birth or later) regardless 
of whether the fetus 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. 

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Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccine will be reported to GSK 
Global Safety as described in Section 10.3.10. 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. 
10.3.8. 
Recording and follow-up of AEs, SAEs, pIMDs and pregnancies  
The participants will be instructed to contact the investigator immediately should they 
experience any signs or symptoms they perceive as serious. 
When an AE/SAE occurs, it is the investigator’s responsibility to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) related 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE on the eCRF. The investigator may not send photocopies of the participant’s 
medical records to GSK instead of appropriately completing the eCRF. 
There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers will be blinded on copies of the medical 
records prior to submission to GSK. 
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 instead of individual signs/symptoms. 
Electronic Diary (eDiary) will be used in this study to capture solicited administration 
site or systemic events. The participant should be trained on how and when to complete 
the eDiary. 
Participants should be trained on using the eDiary. This training must be documented in 
the participant’s source record. 
Verify completed eDiary (via the web portal) during discussions with the participant at 
subsequent contacts (visit or phone call) after Dose 1 and Dose 2 of the study 
intervention administration. 
Any unreturned eDiary will be sought from the participant through telephone call(s) or 
any other convenient procedure. 
Refer to the SPM for more information regarding the use of eDiary. 
10.3.8.1. 
Time period for collecting and recording AEs, SAEs, MAEs, pIMDs and 
pregnancies  
All solicited events that occur up to 14 days following administration of Dose 1 and Dose 
2 of study intervention (Day 1 to Day 14 and Day 31 to Day 44, respectively) must be 
recorded into the eDiary, irrespective of intensity. All other AEs occurring within 31 days 
following Dose 1 and Dose 2 of study intervention administration should be recorded 
onto the appropriate section of the eCRF, irrespective of their intensity or whether or not 
they are considered related to the study intervention. 

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The time period for collecting and recording of SAEs, MAEs, pIMDs, and pregnancies 
will begin at the first receipt of study interventions and will continue throughout the 
whole study period. 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study intervention until the participant is discharged from 
the study. SAEs related to study participation or to a concurrent GSK medication/vaccine 
will be collected from the time consent is obtained until the participant is discharged from 
the study. 
10.3.8.2. 
Follow-up of AEs, SAEs, pIMDs, pregnancies  
After the initial AE/SAE/pIMD/pregnancy or any other event of interest, the investigator 
is required to proactively follow each participant at subsequent visits/contacts. All SAEs 
and pIMDs (Section 10.3.5.1), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up. 
10.3.8.2.1. Follow-up during the study  
AEs/pIMDs documented at a previous visit/contact and defined as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study or the participant is lost to follow-up. 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
10.3.8.2.2. Follow-up after the participant is discharged from the study  
The investigator will provide any new or updated relevant information to GSK on a 
previously reported SAE/pIMD using a paper/electronic Expedited Adverse Events 
Report and/or pregnancy report as applicable. The investigator is obliged to perform or 
arrange for the conduct of supplemental clinical examinations/tests and/or evaluations to 
elucidate the nature and/or causality of the SAE/pIMD as fully as possible. 
10.3.8.2.3. Follow-up of pregnancies  
Pregnant participants 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 using the electronic pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period does not 
need to be longer than 6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, if the investigator becomes aware of any SAE occurring as a result of a 
post-study pregnancy AND it is considered by the investigator to be reasonably related to 
the study intervention, he/she must report this information to GSK as described in Section 
10.3.10. 

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10.3.8.3. 
Updating of SAE, pIMD and pregnancy information after removal of 
write access to the participant’s eCRF  
When additional SAE, pIMD or pregnancy information is received after write access to 
the participant’s eCRF is removed, 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 Section 
8.4.3.1 or to GSK Global Safety department within the defined reporting timeframes 
specified in Table 12. 
10.3.9. 
Assessment of intensity and toxicity  
10.3.9.1. 
Assessment of intensity  
The intensity of the following solicited AEs will be assessed as described: 
Table 25 
Intensity scales for solicited events  
Event 
Intensity grade 
Parameter 
Pain at 
administration site 
0 
None 
1 
Mild: Pain that does not interfere with activity 
 
2 
Moderate: Pain that interferes with activity 
 
3 
Severe: Pain that prevents daily activity 
Redness at 
administration site 
0 
< 25 mm 
1 
25 - 50 mm 
2 
51 - 100 mm 
3 
> 100 mm 
Swelling at 
administration site 
0 
< 25 mm 
1 
25 - 50 mm 
2 
51 - 100 mm 
3 
> 100 mm 
Temperature* 
0 
< 38.0 °C 
1 
38.0 – 38.4 °C 
2 
38.5 – 38.9 °C 
3 
≥ 39.0 °C 
Headache 
0 
None 
 
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 
Myalgia 
0 
None 
 
1 
Mild: Myalgia present but does not interfere with activity 
 
2 
Moderate: Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
Arthralgia 
0 
None 
 
1 
Mild: Arthralgia present but does not interfere with activity 
 
2 
Moderate: Arthralgia that interferes with normal activity 
 
3 
Severe: Arthralgia that prevents normal activity 
Chills 
0 
None 

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Event 
Intensity grade 
Parameter 
1 
Mild: Chills present but do not interfere with activity 
2 
Moderate: Chills that interfere with normal activity 
3 
Severe: Chills that prevent normal activity 
Malaise 
0 
None 
1 
Mild: Malaise present but do not interference with activity 
2 
Moderate: Malaise that interferes with normal activity 
3 
Severe: Malaise that prevents normal activity 
Loss of appetite 
0 
None 
1 
Mild: Loss of appetite without decreased oral intake 
2 
Moderate: Loss of appetite with decreased oral intake but without weight loss 
3 
Severe: Loss of appetite with decreased oral intake and weight loss 
Nausea 
0 
None 
1 
Mild: Nausea present but not interfering with oral intake 
2 
Moderate: Nausea leading to decreased oral intake 
3 
Severe: Nausea leading to minimal to no oral intake 
Vomiting 
0 
None 
1 
Mild: 1 - 2 episodes/24 hours 
2 
Moderate: 2 episodes/24 hours 
3 
Severe: Requires outpatient IV hydration 
Diarrhea 
0 
None 
1 
2 - 3 loose stools/24 hours 
2 
4 - 5 loose stools/24 hours 
3 
6 or more watery stools/24 hours or requires outpatient IV hydration 
IV = intravenous 
*Refer to the SoA (Section 1.3) for the definition of fever and the preferred location for temperature measurement 
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 judgment. 
The intensity should be assigned to 1 of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the participant, 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 an 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 10.3.2. 

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10.3.9.2. 
Assessment of causality  
The investigator must assess the relationship between study intervention and the 
occurrence of each unsolicited AE/SAE using clinical judgment. Where several different 
interventions were administered, the investigator should specify, when possible, if the 
unsolicited AE/SAE could be causally related to a specific intervention. When a causal 
relationship to a specific study intervention cannot be determined, the investigator should 
indicate the unsolicited AE/SAE to be related to all interventions. 
Alternative possible causes, such as the natural history of underlying disease, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study intervention will be considered and investigated. The investigator will also consult 
the IB and/or PI for marketed products to assist in making his/her assessment. 
Causality should be assessed by the investigator using the following question: Is there a 
reasonable possibility that the unsolicited AE may have been caused by the study 
intervention? 
YES: 
There is a reasonable possibility that the study intervention contributed to the 
AE. 
NO: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study intervention. There are other, more likely causes 
and administration of the study intervention is not suspected to have 
contributed to the AE. 
If an event meets the criteria to be determined ‘serious’ (see Section 10.3.2), additional 
examinations/tests will be performed by the investigator 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 study intervention, if applicable. 
• 
An error in study intervention administration. 
• 
Other cause (specify). 
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important to 
record an assessment of causality for every event before submitting the Expedited 
Adverse Events Report to GSK. 

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The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. The investigator may change his/her opinion of causality after 
receiving additional information and update the SAE information accordingly. 
10.3.9.3. 
Medically attended visits  
For each solicited and unsolicited AE the participant experiences, the participant will be 
asked if he/she received medical attention (defined as hospitalization, 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/paper Expedited Adverse 
Events Report, and/or, if applicable eDiary. 
10.3.9.4. 
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). 
10.3.10. 
Reporting of SAEs, pIMDs, pregnancies  
10.3.10.1. Events requiring expedited reporting to GSK  
Once an investigator becomes aware that an SAE has occurred in an enrolled participant, 
the investigator (or designee) must complete information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS, even if the investigator does not have 
complete information on the SAE. It must be completed as thoroughly as possible, with 
all available details of the event. 
The SAE report must be updated WITHIN 24 HOURS of the receipt of updated 
information on the SAE. The investigator will always provide an assessment of causality 
at the time of the initial report. 
Refer to Table 12 for the details on timeframes for reporting of SAEs/pIMD/pregnancies. 
The investigator will be required to confirm the review of SAE causality by ticking the 
‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of 
submission of the SAE. 
Refer to Section 10.3.10.2 for information on back-up systems in case the electronic 
reporting system does not work. 

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10.3.10.2. Back-up system in case the electronic reporting system does not work  
If the electronic reporting system does not work, the investigator (or designee) must fax 
or email a completed, dated and signed paper Expedited Adverse Events Report to the 
study contact for reporting SAEs (refer to Sponsor Information) or to GSK Global Safety 
department within 24 hours of becoming aware of the SAE. 
Investigator (or designee) must complete the electronic Expedited Adverse Events Report 
within 24 hours after the electronic reporting system is working again. The information 
reported through the electronic SAE reporting system will be considered valid for 
regulatory reporting purposes. 
10.4. 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information  
10.4.1. 
Definitions  
10.4.1.1. 
Woman of childbearing potential (WOCBP)  
Women in the following categories are considered WOCBP (fertile): 
• 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
• 
From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below). 
10.4.1.2. 
Women not considered as women of childbearing potential  
Women in the following categories are considered WONCBP: 
• 
Premenarchal Tanner stage 1 (prepubertal) 
Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development 
and pubic hair growth. 
Additional evaluation should be considered if a participant’s fertility status is unclear 
(e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention. 
• 
Premenopausal female with ONE of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 

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• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use a 
non-hormonal, highly effective contraception method if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrolment. 
10.4.2. 
Contraception guidance  
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective contraceptive method consistently and correctly according to the 
methods listed in GSK’s list of highly effective contraceptive methods (Table 26). 
Table 26 
Highly effective contraceptive methods  
Highly Effective Contraceptive Methods That Are User Dependent* 
Failure rate of <1% per year when used consistently and correctly 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation. 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Injectable 
• 
Oral 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation. 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Male partner sterilization prior to the female participant’s entry into the study, and this male 
is the sole partner for that participant, 
The information on the male sterility can come from the site personnel’s review of the 
participant’s medical records; medical examination and/or semen analysis, or medical history 
interview provided by her or her partner. 

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Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
*Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
10.4.3. 
Collection of pregnancy information  
10.4.3.1. 
Female participants who become pregnant  
Refer to Sections 8.4.1, 8.4.2, 10.3.8.1, 10.3.8.2, and 10.3.8.3 for further information on 
detection, recording, reporting and follow-up of pregnancies. 
Any female participant who becomes pregnant during the study will discontinue study 
intervention or be withdrawn from the study. 
10.6. 
Appendix 6: Definition of medical device AE, adverse device 
effect (ADE), serious adverse device effect (SADE) and 
unanticipated SADE (USADE)  
• 
Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices. 
• 
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list 
of sponsor medical devices. 
CCI

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10.6.1. 
Definition of medical device AE and ADE  
• 
Medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether considered related to a medical device or not. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medical device. This definition includes events related to the medical device 
or comparator and events related to the procedures involved. 
• 
An ADE is an AE related to the use of a medical device. This definition includes any 
AE resulting from: 
− 
Insufficient or inadequate instructions for use (i.e., user error), or 
− 
Any malfunction of a medical device, or 
− 
Intentional misuse of the medical device. 
10.6.2. 
Definition of medical device SAE, SADE and USADE  
A medical device SAE is any SAE that: 
a. 
Led to death 
b. Led to serious deterioration in the health of the participant, that either resulted in: 
− 
A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of ‘serious' refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
− 
A permanent impairment of a body structure or a body function. 
− 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
− 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
− 
Chronic disease (MDR 2017/745) 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
SADE definition 
• 
A SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of a serious adverse event. 
• 
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less 
fortunate. 

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Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the IB. 
10.6.3. 
Recording and reporting of medical device AE, ADEs, SADEs and 
USADE  
• 
Any device deficiency must be reported to GSK within 24 hours after the 
investigator determines that the event meets the definition of a device deficiency. 
• 
Email/Facsimile transmission of the paper ‘Medical device or combination product 
with device deficiency/incident report form’ is the preferred method to transmit this 
information to the sponsor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of ‘Medical device or combination product with 
device deficiency/incident report form’ sent by overnight mail or courier service. 
• 
Contacts for reporting can be found in Section 8.4.3.1. 
• 
GSK will review all device deficiencies, determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs/IECs as required by national regulations. 
10.7. 
Appendix 7: Country-specific requirements  
10.7.1. 
Requirements for Germany 
EXPLANATORY STATEMENT CONCERNING SEX DISTRIBUTION (ARTICLE 7, 
PARAGRAPH 2 (12) OF THE GERMAN GCP ORDER) 
There is no intention to conduct specific analyses investigating the relationship between 
the sex of the participants and the efficacy, immunogenicity or safety of the GSK’s 
HBsAg adjuvanted with the different adjuvants systems. The ratio of male to female 
participants recruited into the EARLY-CLINRES-017 study is expected to be in line with 
the demographics of the population of healthy, HBs-naïve adults aged 18-45 years in the 
Member State. 
10.8. 
Appendix 8: Abbreviations and glossary of terms  
10.8.1. 
List of abbreviations  
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ADE: 
Adverse Device Effect 
AE: 
Adverse Event 
AESI: 
Adverse Event of Special Interest 
AI: 
Artificial Intelligence 
ALT: 
Alanine Aminotransferase 
AST: 
Aspartate Aminotransferase 
CDC: 
Centers for Disease Control 
CLIA: 
Chemiluminescence Immunoassay 
CLS: 
Clinical Laboratory Sciences 
CMI: 
Cell-Mediated Immunity 
CoP: 
Correlate of Protection 
CPMG: 
Carr-Purcell-Meiboom-Gill 
CSL: 
Clinical Science Lead 
CSR: 
Clinical Study Report 
eCRF: 
electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
EMA: 
European Medicines Agency 
EoS: 
End of Study 
FDA: 
Food and Drug Administration, United States of America 
FSH: 
follicle-stimulating hormone 
FTIH: 
First-Time in Human 
GCP: 
Good Clinical Practice 
CCI
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GMC: 
Geometric Mean Concentration 
GSB 
Global Safety Board 
GSK: 
GlaxoSmithKline 
HBsAg: 
Hepatitis B surface Antigen 
IAF: 
Informed Assent Form 
IB: 
Investigator’s Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council for Harmonisation 
ICMJE: 
International Committee of Medical Journal Editors  
IDMC: 
Independent Data Monitoring Committee 
IEC: 
Independent Ethics Committee 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
LAR: 
Legally Acceptable Representative 
LML: 
Local Medical lead 
LSLV: 
Last Subject Last Visit 
MAE: 
Medically Attended Adverse Event 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MPL: 
Monophosphoryl Lipid 
PBMC: 
Peripheral Blood Mononuclear Cell 
PC: 
PI: 
Phone Contact 
Personal Information 
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pIMD: 
Potential Immune-Mediated Disorder 
QTL: 
Quality Tolerance Limit 
RBC: 
Red Blood Cell 
RLU: 
Relative Light Unit 
SADE: 
Serious Adverse Device Effect 
SAE: 
Serious Adverse Event 
SBIR: 
Source data Base for Internet Randomization  
SD: 
Standard Deviation 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SoA: 
Schedule of Activity 
SPM: 
Study Procedures Manual 
SRT: 
Safety Review Team 
SUSAR: 
Suspected Unexpected Serious Adverse Reactions 
TFH 
T Follicular Helper  
USADE: 
Unanticipated Serious Adverse Device Effect 
WHO: 
World Health Organization 
WOCBP: 
WONCBP: 
Woman of Childbearing Potential 
Woman of Non-childbearing Potential 
10.8.2. 
Glossary of terms  
Adverse drug 
reaction: 
An adverse event (AE) where a causal relationship between 
a medicinal product and the AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
In the context of a clinical trial, an ADR can be serious or 
nonserious. Serious ADRs may be subject to expedited 
reporting if they are considered unexpected (see SUSAR 
definition). 
For marketed products, ADRs are subject to expedited 
reporting within the country where they are authorized. 
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Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the use 
of a medicinal product, whether or not considered related to 
the medicinal product. 
An AE can therefore be any unfavorable 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. 
Blinding: 
A procedure in which one or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the study, 
and only when the data are cleaned to an acceptable level of 
quality will appropriate personnel be unblinded or when 
required in case of a SAE. 
In an open-label study, no blind is used. Both the 
investigator and the participant know the identity of the 
intervention assigned. 
Certified copy: 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e., by a dated 
signature or by generation through a validated process) to 
have the same information, including data that describe the 
context, content, and structure, as the original. 
Combination product: Combination product comprises any combination of: 
• 
Drug 
• 
Device 
• 
Biological product 
Each drug, device and biological product included in a 
combination product is a constituent part.  
Comparator: 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an investigational 
product being tested in a clinical trial. This is any product 
that is being used to assess the safety, efficacy, or other 
measurable value against the test product (IMP). 
Co-administered 
(concomitant) 
products: 
A product given to clinical trial participants as required in 
the protocol as part of their standard care for a condition 
which is not the indication for which the IMP is being tested 
and therefore is not part of the objective of the study. 

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eDiary: 
Electronically recorded patient data and automated data 
entries on, for example, a handheld mobile device, tablet, or 
computer. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrollment: 
The process of registering a participant into a clinical study 
by assigning participant identification number after signing 
the ICF. 
Essential documents: 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the 
data produced. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, included 
in the Per-Protocol analysis. 
Immunological 
correlate of protection: 
A correlate of risk that has been validated to predict a certain 
level of protection from the targeted endpoint. 
Intervention: 
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 participant. 
Intervention number: 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational 
medicinal product: 
A pharmaceutical form of an active substance or placebo 
being tested or used as reference in a clinical trial, including 
products already with a marketing authorization but used as 
assembled (formulated or packaged) in a way different from 
the authorized form, or when used for an unauthorized 
indication, or when used to gain further information of the 
authorized form. 
Investigator: 
A person responsible for the conduct of the clinical study at 
a study site. If a study is conducted by a team of individuals 
at a study site, the investigator is the responsible leader of 
the team and may be called the principal investigator. 
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified individual 
or party to perform those study-related duties and functions. 
Last subject last visit: 
The date on which the last participant in a clinical study was 
examined or received an intervention/treatment to collect 
final data for the primary outcome measures, secondary 
outcome measures, and AEs (that is, the last participant’s 
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Medical device 
deficiency: 
A device deficiency is an inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, 
safety, or performance. Device deficiencies include 
malfunctions, use errors and information supplied by the 
manufacturer. 
Participant: 
Term used throughout the protocol to denote an individual 
who has been contacted to participate or who participates in 
the clinical study as a recipient of the study intervention 
(vaccine(s)/product(s)/control). 
Synonym: subject. 
Participant number: 
A unique identification number assigned to each participant 
who consents to participate in the study. 
Placebo 
An inactive substance or treatment that looks the same as, 
and is given in the same way, as an active drug or 
intervention/treatment being studied. 
Primary completion 
date: 
The date that the final participant was examined or received 
an intervention for the purpose of final collection of data for 
all primary outcomes, whether the clinical study was 
concluded according to the pre-specified protocol or was 
terminated. 
Protocol amendment: 
The ICH defines a protocol amendment as: ‘A written 
description of a change(s) to or formal clarification of a 
protocol.’ GSK further details this to include a change to an 
approved protocol that affects the safety of participants, 
scope of the investigation, study design, or scientific integrity 
of the study. 
Protocol 
administrative change: 
A protocol administrative change addresses changes to only 
logistical or administrative aspects of the study. 
Randomization: 
Process of random attribution of intervention to participants 
to reduce selection bias. 
Remote visit: 
This term refers to the visit conducted in the place other than 
the study site. 
Self-contained study: 
Study with objectives not linked to the data of another study. 
Solicited event: 
Events to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the participant or an observer during a 
specified follow-up period following study intervention 
administration. 

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Source data: 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction 
and evaluation of the study. Source data are contained in 
source documents (original records or certified copies). 
Source documents: 
Original legible documents, data, and records (e.g. hospital 
records, clinical and office charts, laboratory notes, 
memoranda, participants' diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-
rays, participant files, and records kept at the pharmacy, 
laboratories and at medico-technical departments involved in 
the clinical study). 
Study intervention: 
Term used throughout the clinical study to cover all types of 
investigational and non-investigational products including 
medical devices and vaccines intended to be administered to 
the study participants during the study conduct. Procedures 
conducted to manage participants or to collect data are 
excluded from the usage of this term. 
Study monitor: 
An individual assigned by the sponsor and responsible for 
assuring proper conduct of clinical studies at 1 or more 
investigational sites. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction; in a 
clinical trial, a serious adverse reaction that is considered 
unexpected i.e., the nature or severity of which is not 
consistent with the reference safety information (e.g., 
Investigator’s Brochure for an unapproved investigational 
medicinal product). All adverse drug reactions (ADRs) that 
are both serious and unexpected are subject to expedited 
reporting. 
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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10.9. 
Appendix 9: List of potential immune-mediated disorders  
Table 27 
List of pIMDs  
Blood disorders and coagulopathies 
Cardio-pulmonary inflammatory disorders 
Endocrine disorders 
− 
Antiphospholipid syndrome 
− 
Autoimmune aplastic anemia 
− 
Autoimmune hemolytic anemia, including: 
− 
Warm antibody hemolytic anemia 
− 
Cold antibody hemolytic anemia 
− 
Autoimmune lymphoproliferative syndrome (ALPS) 
− 
Autoimmune neutropenia  
− 
Autoimmune pancytopenia 
− 
Autoimmune thrombocytopenia 
− 
Frequently used related terms include: 
“autoimmune thrombocytopenic purpura”, 
“idiopathic thrombocytopenic purpura (ITP)”, 
“idiopathic immune thrombocytopenia”, 
“primary immune thrombocytopenia”. 
− 
Evans syndrome 
− 
Pernicious anemia 
− 
Thrombosis with thrombocytopenia syndrome (TTS) 
− 
Thrombotic thrombocytopenic purpura 
− 
Also known as “Moschcowitz-syndrome” or 
“microangiopathic hemolytic anemia” 
− 
Idiopathic Myocarditis/Pericarditis, including: 
− 
Autoimmune / Immune-mediated myocarditis 
− 
Autoimmune / Immune-mediated pericarditis 
− 
Giant cell myocarditis 
− 
Idiopathic pulmonary fibrosis, including: 
− 
Idiopathic interstitial pneumonia (Interstitial lung disease, 
Pulmonary fibrosis, Immune-mediated pneumonitis) 
− 
Pleuroparenchymal fibroelastosis (PPFE) 
− 
Pulmonary alveolar proteinosis (PAP) 
− 
Frequently used related terms include: “pulmonary alveolar 
lipoproteinosis”, “phospholipidosis” 
− 
Addison’s disease 
− 
Autoimmune / Immune-mediated thyroiditis, 
including: 
− 
Hashimoto thyroiditis (autoimmune 
hypothyroidism, lymphocytic thyroiditis) 
− 
Atrophic thyroiditis  
− 
Silent thyroiditis  
− 
Thyrotoxicosis 
− 
Autoimmune diseases of the testis and ovary, 
including: 
− 
Autoimmune oophoritis 
− 
Autoimmune ovarian failure 
− 
Autoimmune orchitis 
− 
Autoimmune hyperlipidemia 
− 
Autoimmune hypophysitis 
− 
Diabetes mellitus type I 
− 
Graves’ or Basedow’s disease, including: 
− 
Marine Lenhart syndrome 
− 
Graves' ophthalmopathy, also known as 
thyroid eye disease (TED) or endocrine 
ophthalmopathy 
− 
Insulin autoimmune syndrome 
− 
Polyglandular autoimmune syndrome, including: 
− 
Polyglandular autoimmune syndrome type I, 
II and III 

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Eye disorders 
Gastrointestinal disorders 
Hepatobiliary disorders 
− 
Ocular Autoimmune / Immune-mediated disorders, 
including: 
− 
Acute macular neuroretinopathy (also known 
as acute macular outer retinopathy) 
− 
Autoimmune/Immune-mediated retinopathy  
− 
Autoimmune/Immune-mediated uveitis, 
including idiopathic uveitis and sympathetic 
ophthalmia  
− 
Cogan's syndrome: an oculo-audiovestibular 
disease 
− 
Ocular pemphigoid 
− 
Ulcerative keratitis 
− 
Vogt-Koyanagi-Harada disease 
− 
Autoimmune / Immune-mediated pancreatitis 
− 
Celiac disease 
− 
Inflammatory Bowel disease, including: 
− 
Crohn’s disease  
− 
Microscopic colitis  
− 
Terminal ileitis 
− 
Ulcerative colitis  
− 
Ulcerative proctitis 
− 
Autoimmune cholangitis 
− 
Autoimmune hepatitis 
− 
Primary biliary cirrhosis 
− 
Primary sclerosing cholangitis 
Musculoskeletal and connective tissue 
disorders 
Neuroinflammatory/neuromuscular disorders 
Renal disorders 
− 
Gout, including: 
− 
Gouty arthritis 
− 
Idiopathic inflammatory myopathies, including: 
− 
Dermatomyositis 
− 
Inclusion body myositis 
− 
Immune-mediated necrotizing myopathy 
− 
Polymyositis 
− 
Mixed connective tissue disorder 
− 
Polymyalgia rheumatica (PMR) 
− 
Psoriatic arthritis (PsA) 
− 
Relapsing polychondritis 
− 
Rheumatoid arthritis, including: 
− 
Rheumatoid arthritis associated conditions 
− 
Juvenile idiopathic arthritis 
− 
Acute disseminated encephalomyelitis (ADEM) and other 
inflammatory-demyelinating variants, including:  
− 
Acute necrotising myelitis 
− 
Bickerstaff's brainstem encephalitis  
− 
Disseminated necrotizing leukoencephalopathy (also 
known as Weston-Hurst syndrome, acute hemorrhagic 
leuko-encephalitis, or acute necrotizing hemorrhagic 
encephalomyelitis)  
− 
Myelin oligodendrocyte glycoprotein antibody-associated 
disease 
− 
Neuromyelitis optica (also known as Devic’s disease) 
− 
Noninfective encephalitis/ encephalomyelitis / myelitis 
− 
Postimmunization encephalomyelitis 
− 
Autoimmune/Immune-mediated glomerulonephritis, 
including: 
− 
IgA nephropathy 
− 
IgM nephropathy 
− 
C1q nephropathy 
− 
Fibrillary glomerulonephritis 
− 
Glomerulonephritis rapidly progressive 
− 
Membranoproliferative glomerulonephritis 
− 
Membranous glomerulonephritis 
− 
Mesangioproliferative glomerulonephritis 
− 
Tubulointerstitial nephritis and uveitis 
syndrome 

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− 
Palindromic rheumatism 
− 
Still's disease 
− 
Felty’s syndrome 
− 
Sjogren’s syndrome 
− 
Spondyloarthritis, including: 
− 
Ankylosing spondylitis 
− 
Juvenile spondyloarthritis 
− 
Keratoderma blenorrhagica 
− 
Psoriatic spondylitis  
− 
Reactive Arthritis 
− 
Undifferentiated spondyloarthritis 
− 
Systemic Lupus Erythematosus, including: 
− 
Lupus associated conditions (e.g., Cutaneous 
lupus erythematosus, Lupus nephritis, etc.) 
− 
Complications such as shrinking lung 
syndrome (SLS) 
− 
Systemic Scleroderma (Systemic Sclerosis), 
including: 
− 
Raynaud’s syndrome 
− 
Systemic sclerosis with diffuse scleroderma 
− 
Systemic sclerosis with limited scleroderma 
(also known as CREST syndrome) 
− 
Guillain-Barré syndrome (GBS)*, including: 
− 
Variants such as Miller Fisher syndrome and the acute 
motor and sensory axonal neuropathy (AMSAN) 
− 
Idiopathic cranial nerve palsies/paresis and inflammations 
(neuritis), including: 
− 
Cranial nerve neuritis (e.g., Optic neuritis) 
− 
Idiopathic nerve palsies/paresis (e.g., Bell’s palsy) 
− 
Melkersson-Rosenthal syndrome 
− 
Multiple cranial nerve palsies/paresis 
− 
Multiple Sclerosis (MS), including: 
− 
Clinically isolated syndrome (CIS)  
− 
Malignant MS (the Marburg type of MS)  
− 
Primary-progressive MS (PPMS) 
− 
Radiologically isolated syndrome (RIS) 
− 
Relapsing-remitting MS (RRMS) 
− 
Secondary-progressive MS (SPMS) 
− 
Uhthoff's phenomenon 
− 
Myasthenia gravis, including: 
− 
Ocular myasthenia 
− 
Lambert-Eaton myasthenic syndrome 
− 
Narcolepsy (with or without presence of unambiguous cataplexy) 
− 
Peripheral inflammatory demyelinating neuropathies and 
plexopathies, including 
− 
Acute Brachial Radiculitis (also known as Parsonage-
Turner Syndrome or neuralgic amyotrophy) 
− 
Antibody-mediated demyelinating neuropathy 
− 
Chronic idiopathic axonal polyneuropathy (CIAP) 
− 
Chronic Inflammatory Demyelinating 
Polyradiculoneuropathy (CIDP), including atypical CIDP 
variants (e.g., multifocal acquired demyelinating sensory 

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and motor neuropathy also known as Lewis-Sumner 
syndrome) 
− 
Multifocal motor neuropathy (MMN) 
− 
Transverse myelitis (TM), including: 
− 
Acute partial transverse myelitis (APTM) 
− 
Acute complete transverse myelitis (ACTM) 
Skin and subcutaneous tissue disorders 
Vasculitis 
Other (including multisystemic) 
− 
Alopecia areata 
− 
Autoimmune / Immune-mediated blistering 
dermatoses, including: 
− 
Bullous Dermatitis 
− 
Bullous Pemphigoid  
− 
Dermatitis herpetiformis  
− 
Epidermolysis bullosa acquisita (EBA)  
− 
Linear IgA-mediated bullous dermatosis 
(LABD), also known as Linear IgA disease 
− 
Pemphigus 
− 
Erythema multiforme 
− 
Erythema nodosum 
− 
Lichen planus, including: 
− 
Liquen planopilaris 
− 
Localised Scleroderma (Morphoea) 
− 
Eosinophilic fasciitis (also called Shulman 
syndrome) 
− 
Psoriasis 
− 
Pyoderma gangrenosum 
− 
Large vessels vasculitis*, including: 
− 
Arteritic anterior ischemic optic neuropathy (AAION or 
arteritic AION) 
− 
Giant cell arteritis (also called temporal arteritis)  
− 
Takayasu's arteritis 
− 
Medium sized and/or small vessels vasculitis*, including: 
− 
Anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified)  
− 
Behcet's syndrome  
− 
Buerger’s disease (thromboangiitis obliterans) 
− 
Churg–Strauss syndrome (allergic granulomatous angiitis)  
− 
Erythema induratum (also known as nodular vasculitis) 
− 
Henoch-Schonlein purpura (also known as IgA vasculitis) 
− 
Microscopic polyangiitis 
− 
Necrotizing vasculitis 
− 
Polyarteritis nodosa 
− 
Single organ cutaneous vasculitis, including 
leukocytoclastic vasculitis, hypersensitivity vasculitis and 
acute hemorrhagic edema of infancy (AHEI) 
− 
Granulomatosis with polyangiitis  
− 
Anti-synthetase syndrome 
− 
Capillary leak syndrome 
− 
Frequently used related terms include: 
“systemic capillary leak syndrome (SCLS)” or 
“Clarkson's Syndrome” 
− 
Goodpasture syndrome 
− 
Frequently used related terms include: 
“pulmonary renal syndrome” and 
“anti-Glomerular Basement Membrane 
disease (anti-GBM disease)” 
− 
Immune-mediated enhancement of disease, 
including: 
− 
Vaccine associated enhanced disease (VAED 
and VAERD). Frequently used related terms 
include “vaccine-mediated enhanced disease 
(VMED)”, “enhanced respiratory disease 
(ERD)”, “vaccine-induced enhancement of 
infection”, “disease enhancement”, “immune 
enhancement”, and “antibody-dependent 
enhancement (ADE) 
− 
Immunoglobulin G4 related disease 
− 
Langerhans' cell histiocytosis 

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− 
Reactive granulomatous dermatitis, including: 
− 
Interstitial granulomatous dermatitis 
− 
Palisaded neutrophilic granulomatous 
dermatitis 
− 
Stevens-Johnson Syndrome (SJS), including: 
− 
Toxic Epidermal Necrolysis (TEN)  
− 
SJS-TEN overlap 
− 
Sweet’s syndrome, including: 
− 
Acute febrile neutrophilic dermatosis 
− 
Vitiligo 
− 
Multisystem inflammatory syndromes, including: 
− 
Kawasaki’s disease 
− 
Multisystem inflammatory syndrome in adults 
(MIS-A) 
− 
Multisystem inflammatory syndrome in 
children (MIS-C) 
− 
Overlap syndrome 
− 
Raynaud’s phenomenon 
− 
Sarcoidosis, including: 
− 
Loefgren syndrome 
− 
Susac's syndrome 
 

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10.10. 
Appendix 10: Protocol Amendment history  
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 4 
17 Sep 2024 
Amendment 3 
17 November 2023 
Amendment 2 
01 March 2023 
Amendment 1 
10 August 2022 
Original Protocol 
25 April 2022 
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the TOC. 
Amendment 3 (17 November 2023) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because the change in the recruitment plan consists of a decrease in the 
target sample size with a consequent change in the precision of the statistical analysis.  
Overall rationale for the Protocol Amendment 3: 
Vaccination against Hepatitis B has been introduced with varying degrees depending on 
the countries where the study participants reside. Anti-HBs seroprevalence (essentially 
due to previous vaccination) in the adult population screened in the trial is therefore high 
and has led to a high screening failure rate (45%) and inadequate enrollment in the 
clinical study.  
The target sample size for the study has therefore been revisited and guided by statistical 
considerations on the precision of the safety evaluation and on the power for the 
immunogenicity comparison. The enrollment in the study will therefore be stopped 
earlier than initially expected to target a minimum of 23 and a maximum of 30 
participants in each study group (HBs- Alum, HBs-AS03, HBs-AS04, HBs-AS37_50, 
and HBs AS37_100). 

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Summary of changes table of previous amendment (Amendment 3): 
Section # and title 
Description of change 
Brief rationale 
Headers, title page, Protocol 
Amendment Summary of 
Changes (new) 
Headers and title page were 
updated with new document 
number and amendment 
information; Protocol 
Amendment Summary of 
Changes section was updated 
to include the rationale for this 
amendment; minor corrections 
and formatting adjustments 
were made to add clarification 
and/or remove discrepancies. 
Editorial changes have been 
implemented as needed. 
Table 14 Analysis sets 
To align with the Statistical 
Analysis Plan 
Section 9.3.2 Secondary 
endpoints analysis 
The statistical analysis 
proposed for seroconversion 
and seroprotection rates was 
updated  
No correction for baseline 
characteristics is considered 
needed for the analysis on 
seroconversion and 
seroprotection rates 
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Section # and title 
Description of change 
Brief rationale 
Section 9.4.1.1 Main analysis 
Description of endpoints 
included in the main analysis. 
To addressing operational 
changes 
Amendment 2 (1 March 2023) 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it significantly impacts the scientific value and procedures 
undertaken by participants in the study. 
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Overall rationale for the Protocol Amendment 2: 
 
 
 
Summary of changes table of previous amendment (Amendment 2):  
Section # and title 
Description of change 
Brief rationale 
1.3 Table 1 Schedule 
of activities 
3. Table 3 Study 
objectives and 
endpoints 
4. Figure 1 Study 
design overview 
5.2 Exclusion criteria 
5.4.1 Rescreening 
8.3 Other 
assessments 
9.2 Table 14 Analysis 
sets 
9.4.1.1 Main analysis 
Amendment 1 (10 August 2022) 
This amendment is considered substantial based on the criteria defined in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the safety monitoring of participants. 
Overall rationale for the Protocol Amendment 1: Following the review of the protocol 
by Medicines and Healthcare products Regulatory Agency (MHRA), the protocol is 
being amended to 
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• 
Update the study holding rules: Study holding rule (1b) related to serious adverse 
event (SAE) has been reworded and an additional holding (2d) rule related to non-
serious adverse event (AE) has been added. 
• 
Delete reference to emergency unblinding: Since the study is open-label, any 
reference to unblinding in the protocol has been deleted. 
• 
Minor correction and clarification: A minor error has been corrected in Table 2 
(Intervals between study visits) and a clarification on including the cohort in the 
minimization procedure has been added in the Section 6.3.3 (Intervention allocation 
to the participant). Figure 2 and Figure 3 have been updated to include additional 
holding rule added as per MHRA recommendation. 
Summary of changes table of previous amendments (Amendment 1): 
Section # and 
title 
Description of change 
Brief rationale 
8.2.3.3 Study 
holding rule 
The study holding rules in 
Table 10 are being updated. 
Study holding rules updated as per 
MHRA recommendation 
9.4. Interim 
analyses 
Figure 2 and Figure 3 have been 
updated  
To include in Figure 2 and Figure 3 
an additional holding rule added as 
per MHRA recommendation, along 
with other holding rules already 
displayed in these figures 
6.3.5.1 Emergency 
unblinding 
This section is being deleted 
The study is open-label and this 
section is not applicable. 
1.3 Schedule of 
activities 
A minor error in Visit interval in 
Table 2 has been corrected 
A minor error has been corrected. 
6.3.3 Invention 
allocation to the 
participant 
A clarification to include cohort in 
the minimization procedure has 
been added. 
Clarification added for minimization 
procedure. 

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11. 
REFERENCES  
CDC Metropolitan Atlanta Congenital Defects Program (MACDP), url: 
https://www.cdc.gov/ncbddd/birthdefects/macdp.html 
EMA Guideline on pregnancy exposure, 2006. 
FDA. Guidance For Industry: Toxicity Grading Scale For Healthy Adult And Adolescent 
Volunteers Enrolled In Preventive Vaccine Clinical Trials. 2007, url: 
https://www.fda.gov/media/73679/download 
Gonzalez-Lopez A, Oostendorp J, Koernicke T, et al. Adjuvant effect of TLR7 agonist 
adsorbed on aluminum hydroxide (AS37): A Phase I randomized, dose escalation study 
of an AS37-adjuvanted meningococcal C conjugated vaccine. Clin Immunol. 
2019;209:108275. 
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Signature Page for  215301 TMF-19647481 v1.0
Signature Page for TMF-19647481 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 17-Sep-2024 14:13:45 GMT+0000
PPD