A Phase 3 Double-Blind Randomized Controlled Trial to Compare the Immunogenicity and Safety of a Three-dose Regimen of Sci-B-Vac® to a Three-dose Regimen of Engerix-B® in Adults (PROTECT)
Phase: PHASE3
Conditions: Hepatitis B Vaccines
Sponsor: VBI Vaccines Inc.

STUDY PROTOCOL 
 
 
Official Title:  A Phase 3 Double-Blind Randomized Controlled Trial to Compare 
the Immunogenicity and Safety of a Three-dose Regimen of Sci-B-Vac® to a Three-
dose Regimen of Engerix-B® in Adults (PROTECT)  
 
 
Protocol Identifying Number:  Sci-B-Vac–001  
 
 
NCT Number:  NCT03393754 
 
 
Version:  2.0, Amendment 1  
 
 
Date of Version:  July 17, 2017  
 
 
Study Sponsor:  
VBI Vaccines Inc.  
310 Hunt Club Road East Ottawa, ON K1V 1C1 Canada  
Telephone: (613) 749-4200  
 
 
 
 
 

TITLE: 
A Phase 3 Double-Blind Randomized Controlled Trial to Compare the 
Immunogenicity and Safety of a Three-dose Regimen of Sci-B-Vac™ to a 
Three-dose Regimen of Engerix-B® in Adults (PROTECT) 
 
 
 
Protocol Identifying Number: 
 
Sci-B-Vac–001 
EudraCT Number: 2017-001819-36 
 
 
Version: 2.0 
Amendment 1 
 
Date of version: 
 
July 17, 2017 
 
 
Study sponsor: 
 
VBI Vaccines Inc. 
 
310 Hunt Club Road East 
Ottawa, ON K1V 1C1 
Canada 
Telephone: (613) 749-4200 
 
Confidentiality Statement 
The information in this document contains trade secrets and proprietary or commercial 
information that are privileged or confidential and may not be disclosed to any third party 
without the prior written authorization of VBI Vaccines Inc. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
ii | P a g e 
CONFIDENTIAL 
 
 
 
Sponsor Signature Page 
Sponsor Signatory: 
 
 
 
 
 
Chief Medical Officer 
VBI Vaccines Inc. 
310 Hunt Club Road East 
Ottawa, ON K1V 1C1 
Canada 
 
Telephone: (613) 749-4200 
21/07/2017 
 
Date (dd/mm/yyyy) 
 
 
Francisco Diaz-Mitoma 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
iii | P a g e 
CONFIDENTIAL 
 
 
 
Table of contents 
SPONSOR SIGNATURE PAGE .................................................................................................................................. II 
TABLE OF CONTENTS ............................................................................................................................................ III 
LIST OF FIGURES .................................................................................................................................................. VII 
LIST OF TABLES .................................................................................................................................................... VII 
LIST OF ABBREVIATIONS ..................................................................................................................................... VIII 
STATEMENT OF COMPLIANCE ................................................................................................................................ X 
PROTOCOL SUMMARY .......................................................................................................................................... XI 
SCHEMATIC OF STUDY DESIGN .......................................................................................................................... XXII 
PROTOCOL AMENDMENTS SCI-B-VAC-001 ........................................................................................................ XXIII 
1 
BACKGROUND AND RATIONALE .................................................................................................................... 1 
1.1 EPIDEMIOLOGY .................................................................................................................................................................................................. 1 
1.2 IMMUNOGENICITY OF LICENSED VACCINES ....................................................................................................................................................... 1 
1.3 SCI-B-VAC™ ................................................................................................................................................................ 2 
1.3.1 
Description ............................................................................................................................................... 2 
1.3.2 
Overview of clinical pharmacology .......................................................................................................... 2 
1.3.3 
Potential risks and benefits ...................................................................................................................... 3 
1.4 RATIONALE FOR CONDUCTING THE STUDY ........................................................................................................................................................ 3 
2 
OBJECTIVES ................................................................................................................................................... 3 
2.1 CO-PRIMARY OBJECTIVES .................................................................................................................................................................................. 3 
2.2 SECONDARY OBJECTIVES .................................................................................................................................................................................... 4 
2.3 EXPLORATORY OBJECTIVES ................................................................................................................................................................................ 4 
3 
STUDY DESIGN AND ENDPOINTS ................................................................................................................... 5 
3.1 STUDY DESIGN.................................................................................................................................................................................................... 5 
3.2 PRIMARY ENDPOINT .......................................................................................................................................................................................... 6 
3.3 SECONDARY ENDPOINTS .................................................................................................................................................................................... 6 
3.4 EXPLORATORY ENDPOINTS ................................................................................................................................................................................ 6 
4 
STUDY ENROLLMENT AND WITHDRAWAL ..................................................................................................... 7 
4.1 SUBJECTS POPULATION ...................................................................................................................................................................................... 7 
4.1.1 
Inclusion criteria ...................................................................................................................................... 7 
4.1.2 
Exclusion criteria ...................................................................................................................................... 8 
4.2 ENROLLMENT PROCEDURES ........................................................................................................................................................................... 10 
4.3 SUBJECT WITHDRAWAL................................................................................................................................................................................... 10 
4.3.1 
Subject withdrawal from the study ........................................................................................................ 11 
4.3.2 
Subject withdrawal from investigational product ................................................................................. 11 
4.4 TERMINATION OF STUDY OR SUSPENSION OF STUDY .................................................................................................................................... 12 
5 
STUDY AGENTS ............................................................................................................................................ 12 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
iv | P a g e 
CONFIDENTIAL 
 
 
5.1 SCI-B-VAC™ .............................................................................................................................................................. 12 
5.1.1 
Acquisition ............................................................................................................................................. 12 
5.1.2 
Formulation and labelling ...................................................................................................................... 12 
5.1.3 
Product storage ..................................................................................................................................... 13 
5.2 COMPARATOR: ENGERIX B ................................................................................................................................................... 13 
5.2.1 
Acquisition ............................................................................................................................................. 13 
5.2.2 
Formulation and labelling ...................................................................................................................... 13 
5.2.3 
Product storage ..................................................................................................................................... 13 
5.3 DOSAGE, PREPARATION ADMINISTRATION OF STUDY VACCINES................................................................................................................... 13 
5.4 ACCOUNTABILITY PROCEDURES FOR THE STUDY VACCINES ........................................................................................................................... 14 
5.5 DESTRUCTION OF UNUSED PRODUCTS ........................................................................................................................................................... 14 
5.6 RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................................................................................................ 14 
5.6.1 
Safety Follow-up and management of reactions to vaccines ................................................................ 14 
5.6.2 
Management of non-responders ........................................................................................................... 15 
6 
STUDY PROCEDURES ................................................................................................................................... 15 
6.1 DETAILED DESCRIPTION .................................................................................................................................................................................. 15 
6.1.1 
Informed consent ................................................................................................................................... 15 
6.1.2 
Check inclusion and exclusion criteria .................................................................................................... 15 
6.1.3 
Collect demographic data ...................................................................................................................... 15 
6.1.4 
Medical history ...................................................................................................................................... 15 
6.1.5 
Physical examination ............................................................................................................................. 15 
6.1.6 
Vital signs ............................................................................................................................................... 15 
6.1.7 
Treatment allocation ............................................................................................................................. 16 
6.1.8 
Study product administration ................................................................................................................ 16 
6.1.9 
Check and Record Concomitant Medication and Intercurrent Medical Conditions ............................... 16 
6.1.10 Recording of adverse events .................................................................................................................. 17 
6.2 LABORATORY EVALUATIONS ........................................................................................................................................................................... 18 
6.2.1 
Urine pregnancy test.............................................................................................................................. 18 
6.2.2 
Screening laboratory evaluations .......................................................................................................... 18 
6.2.3 
Immunogenicity ..................................................................................................................................... 19 
6.2.4 
Sub-Studies ............................................................................................................................................ 19 
6.2.5 
Biological samples handling, analysis and storage ................................................................................ 20 
6.3 STUDY SCHEDULE OF EVENTS ......................................................................................................................................................................... 21 
6.3.1 
Screening ............................................................................................................................................... 21 
6.3.2 
Vaccination visits ................................................................................................................................... 21 
6.3.3 
Safety follow-up ..................................................................................................................................... 22 
6.3.4 
Supplemental visit(s) .............................................................................................................................. 22 
6.3.5 
Immunogenicity visits ............................................................................................................................ 22 
6.3.6 
Sub-study additional visits ..................................................................................................................... 23 
6.3.7 
End of study visit .................................................................................................................................... 23 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
v | P a g e 
CONFIDENTIAL 
 
 
7 
ASSESSMENT OF SAFETY ............................................................................................................................. 24 
7.1 SPECIFICATION OF SAFETY PARAMETERS ........................................................................................................................................................ 24 
7.1.1 
Adverse Events ....................................................................................................................................... 24 
7.1.2 
Serious Adverse Events .......................................................................................................................... 24 
7.1.3 
Preexisting conditions ............................................................................................................................ 25 
7.1.4 
Procedures ............................................................................................................................................. 25 
7.1.5 
Laboratory test abnormalities and other abnormal assessments ......................................................... 25 
7.1.6 
Grading of AEs ....................................................................................................................................... 25 
7.1.7 
Assessment of the outcomes ................................................................................................................. 26 
7.1.8 
Causality ................................................................................................................................................ 26 
7.1.9 
Unexpectedness ..................................................................................................................................... 26 
7.1.10 Suspected adverse reaction ................................................................................................................... 27 
7.2 METHODS AND TIMING FOR ASSESSING, AND RECORDING SAFETY PARAMETERS ........................................................................................ 27 
7.2.1 
AEs ......................................................................................................................................................... 27 
7.2.2 
Vital signs and vaccine reactions ........................................................................................................... 27 
7.2.3 
Laboratory test abnormalities ............................................................................................................... 28 
7.2.4 
SAEs, Medically Significant Event and New Onset of Chronic Illness ..................................................... 28 
7.3 EXPEDITED REPORTING PROCEDURES TO STUDY SPONSOR AND PHARMACOVIGILANCE AGENT .................................................................. 28 
7.3.1 
Serious Adverse Events .......................................................................................................................... 28 
7.3.2 
Reporting of pregnancy ......................................................................................................................... 29 
7.4 REPORTING TO REGULATORY AUTHORITIES ................................................................................................................................................... 29 
7.5 INSTITUTIONAL REPORTING OF AES AND SAES ............................................................................................................................................. 30 
7.6 TYPE AND DURATION OF FOLLOW-UP OF SUBJECTS AFTER AES .................................................................................................................... 30 
7.7 UNBLINDING ................................................................................................................................................................................................... 30 
7.8 STOPPING RULES ............................................................................................................................................................................................ 31 
7.9 SAFETY OVERSIGHT ......................................................................................................................................................................................... 31 
8 
MONITORING .............................................................................................................................................. 32 
9 
STATISTICAL CONSIDERATIONS ................................................................................................................... 32 
9.1 SAMPLE SIZE .................................................................................................................................................................................................... 33 
9.2 RANDOMIZATION ............................................................................................................................................................................................ 33 
9.3 ANALYSIS SETS ................................................................................................................................................................................................ 34 
9.3.1 
All Enrolled Set ....................................................................................................................................... 34 
9.3.2 
Safety Set ............................................................................................................................................... 34 
9.3.3 
Intent-to-Treat (ITT) ............................................................................................................................... 34 
9.3.4 
Full Analysis Set (FAS) ............................................................................................................................ 34 
9.3.5 
Per Protocol Set (PPS) ............................................................................................................................ 34 
9.3.6 
Sub Study Analysis Set (SSA) .................................................................................................................. 34 
9.3.7 
Sub Groups ............................................................................................................................................. 35 
9.4 ANALYSIS OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................................................... 35 
9.5 CO-PRIMARY OBJECTIVES............................................................................................................................................................................... 35 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
vi | P a g e 
CONFIDENTIAL 
 
 
9.5.1 
Co-Primary Hypotheses .......................................................................................................................... 35 
9.5.2 
Statistical Methods for Co-Primary Analyses ......................................................................................... 36 
9.6 SECONDARY IMMUNOGENICITY OBJECTIVES ................................................................................................................................................. 36 
9.6.1 
Secondary Immunogenicity Hypotheses ................................................................................................ 36 
9.6.2 
Statistical Methods for Secondary Immunogenicity Analyses ............................................................... 37 
9.7 EXPLORATORY IMMUNOGENICITY ENDPOINTS .............................................................................................................................................. 37 
9.8 ANALYSIS OF SAFETY OBJECTIVES .................................................................................................................................................................. 38 
9.8.1 
Analysis of Extent of Exposure ............................................................................................................... 38 
9.8.2 
Analysis of Solicited Local, Systemic and Other Adverse Events ............................................................ 38 
9.8.3 
Analysis of Spontaneously Reported Adverse Events ............................................................................. 38 
9.8.4 
Analysis of Vital Signs and Laboratory Parameters ............................................................................... 39 
9.9 INTERIM ANALYSIS .......................................................................................................................................................................................... 39 
10 
DATA HANDLING AND RECORD KEEPING..................................................................................................... 39 
10.1 
DATA MANAGEMENT RESPONSIBILITIES ............................................................................................................................................... 39 
10.2 
DATA CAPTURE METHODS .................................................................................................................................................................... 39 
10.3 
TYPES OF DATA ...................................................................................................................................................................................... 40 
10.4 
STUDY RECORDS RETENTION ................................................................................................................................................................. 40 
10.5 
PROTOCOL DEVIATIONS ........................................................................................................................................................................ 40 
11 
QUALITY CONTROL AND QUALITY MANAGEMENT ...................................................................................... 41 
12 
STUDY REGISTRATION AND RESULTS INFORMATION .................................................................................. 41 
13 
ETHICAL / REGULATORY CONSIDERATIONS ................................................................................................. 41 
13.1 
RELEVANT ETHICAL BODY ...................................................................................................................................................................... 41 
13.2 
ETHICS REVIEW AND INFORMED CONSENT .......................................................................................................................................... 42 
14 
REFERENCES ................................................................................................................................................ 43 
15 
APPENDICES ................................................................................................................................................ 45 
15.1 
APPENDIX 1: CHSA* FRAILTY SCALE17 ................................................................................................................ 46 
15.2 
APPENDIX 2: SCHEDULE OF EVENTS ..................................................................................................................................................... 47 
15.3 
APPENDIX 3: FDA GUIDELINES FOR GRADING VACCINE REACTIONS ................................................................................................... 49 
15.4 
APPENDIX 4: FDA GUIDELINES FOR GRADING CLINICAL LABORATORY ABNORMALITIES .................................................................... 52 
15.5 
APPENDIX 5: NYHA FUNCTIONAL CLASSIFICATION ............................................................................................................................. 57 
List of figures 
Figure 1: Schematic of Study Design .......................................................................................................... xxii 
Figure 2: Sci-B-Vac™ (left) compared to a 2nd generation HBV vaccine (right) ............................................. 2 
List of tables 
Table 1: Unsolicited AEs severity scale ....................................................................................................... 25 
Table 2: CHSA Frailty Scale .......................................................................................................................... 46 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
vii | P a g 
CONFIDENTIAL 
 
 
Table 3: Schedule of Events (main study and sub-studies) ......................................................................... 47 
Table 4: FDA Grading of Injection site reactions ......................................................................................... 49 
Table 5: FDA Grading of vital signs abnormalities ...................................................................................... 50 
Table 6: FDA Grading of systemic reactions ............................................................................................... 51 
Table 7: FDA Grading of blood chemistry abnormalities ............................................................................ 52 
Table 8: FDA Grading of hematology tests abnormalities .......................................................................... 54 
Table 9: FDA Grading of urinalysis abnormalities ....................................................................................... 56 
Table 10: NYNA Classification of physical activity ....................................................................................... 57 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
viii | P a g e 
CONFIDENTIAL 
 
 
 
List of abbreviations 
 
aa: amino acid 
AE: adverse event 
Al(OH)3: aluminum hydroxide 
AlPO4: aluminum phosphate 
ALT: alanine transaminase 
Anti-HBc: hepatitis B core antibody 
Anti-HBs: hepatitis B surface antibody 
AP: alkaline phosphatase 
AST: aspartate transaminase 
BMI: body mass index 
BUN: Blood Urea Nitrogen 
CBC: complete blood count 
CG: Cockcroft-Gault 
CHO: Chinese hamster ovary cell 
CI: confidence interval 
CMP: clinical monitoring plan 
CPK: creatine phosphokinase 
CRO: contract research organization 
CVID: common variable immune deficiency 
DBP: diastolic blood pressure 
dL: deciliter 
DNA: deoxyribonucleic acid. 
EEA: European economic area 
EPO: erythropoietin 
E.U.: European union 
FAS: full analysis set 
FDA: food and drug administration 
FIMEA: Finish Medicine Agency 
g: gram 
GCP: good clinical practice 
GGT: gamma-glutamyl transferase 
GMC: geometric mean concentration 
GMCSF: Granulocyte macrophage colony-stimulating factor 
HBA1C: Hemoglobin A1C 
HBsAg: hepatitis B surface antigen 
HBV: hepatitis B virus 
HCT: hematocrit 
HCV: hepatitis C virus 
HIV: human immunodeficiency virus 
ICH: international conference on harmonization 
IEC: independent ethics committee 
IM: intramuscular 
IRB: institutional review board 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
ix | P a g e 
CONFIDENTIAL 
 
 
 
ITT: intent-to-treat 
IWRS: interactive web response system 
LLN: lower limit of normal range 
MCAR: missing completely at random 
MCH: mean cell hemoglobin 
MCHC: mean cell hemoglobin concentration 
MCV: mean corpuscular volume 
MedDRA: medical dictionary for regulatory activities 
mEq: milliequivalent 
mg: milligram 
mIU: milli-international unit 
mm: millimeter 
mL: milliliter 
μg: microgram 
NOCI: new onset of chronic illness 
PPS: per protocol set 
SAE: serious adverse event 
SBP: systolic blood pressure 
DMC: data monitoring committee 
SOP: standard operating procedure 
SPR: seroprotection rate 
SUSAR: suspected unexpected serious adverse reactions 
SVR: sustained virologic response 
ULN: upper limit of normal range 
U.S.: United states 
VBI: VBI Vaccines Inc 
WBC: whilte blood cell count 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
x | P a g e 
CONFIDENTIAL 
 
 
 
Statement of Compliance 
By signing below, the Principal Investigator agrees to adhere to the protocol. Any change in the study 
must be reviewed by a formal protocol amendment procedure and the Principal Investigator will submit 
all changes, amendments and revisions to the appropriate Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Any change to the protocol that affects subject selection, safety, or 
changes in the conduct of the trial will require written approval from the IRB/IEC before implementing 
the change. 
The Principal Investigator also agrees to conduct the study in accordance with 
x 
All applicable Laws and Regulations 
x 
The International Conference on Harmonization guidelines on Good Clinical Practice (ICH GCP), 
copies of which have been provided to the principal investigator. 
The Principal Investigator also thereby agrees that the IRB/IEC will approve all subject informed consent 
form templates before the study is initiated. The investigator will obtain informed consent and document 
this process for all subjects enrolled in this study. 
 
 
 
 
 
Principal Investigator 
Signature 
Date 
(dd/mmm/yyyy) 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xi | P a g e 
CONFIDENTIAL 
 
 
 
PROTOCOL SUMMARY 
 
Long Title 
A Phase 3 Double-Blind Randomized Controlled Trial to 
Compare the Immunogenicity and Safety of a Three-dose 
Regimen of Sci-B-Vac™ to a Three-dose Regimen of Engerix-B® 
in Adults 
Clinical Trial Phase 
3 
Study sponsor 
VBI Vaccines Inc. 
Number of sites 
~ 30 sites (Canada, Europe, United States) 
Background & Rationale 
Hepatitis B virus (HBV) is a human double-stranded enveloped 
DNA virus that causes an acute infection which, in some cases, 
may develop into a chronic disease. 
Approximately 260 million people are chronically infected by 
the hepatitis B virus (HBV) worldwide1. In 2013, it is estimated 
that 686,000 people of all ages died of complications of 
hepatitis B, such as liver cirrhosis and liver cancer2. The 
progressive implementation of universal immunization 
programs in infants, children, and adolescents in a total of 184 
countries1 has resulted in vaccine coverage of 82% of children 
and a drop in the incidence of hepatitis B in these countries. 
However, adults remain at risk of becoming infected with HBV. 
For instance, according to the European Centre for Disease 
Prevention and Control, the most affected age group for both 
acute and chronic infections is the group of 25–34-year-olds, 
accounting for 33.8% of the 22,442 cases reported in 2014 by 
the 30 EU/EEA Member States3. 
Monovalent HBV vaccines licensed in the European Union 
(E.U.), the United States (U.S.) and Canada, such as Engerix-B®, 
are second-generation vaccines using recombinant DNA 
technology to express the HBV DNA sequence coding for the 
small hepatitis B surface antigen (HBsAg) in yeasts. The 1 mL 
dose of Engerix-B® containing 20 μg of HBsAg is the form 
approved for the immunization of healthy adults. In adults, the 
most commonly recommended immunization schedule 
consists of three injections of vaccine, two injections 4 weeks 
apart, followed by a third injection 24 weeks after the initial 
injection. A serum concentration of hepatitis B surface 
antibody (anti-,ƐͿ шϭϬŵ/hͬŵ>͕ ϰ ǁĞĞŬƐ ĂĨƚĞƌ ƚŚĞ ƚŚŝƌĚ
vaccination, is considered protective4, and is associated with 
long term immunity to hepatitis B5. The seroprotection rate 
(SPR),  defined  as  the  percentage  of  individuals  achieving a 
serum concentration of hepatitis B surface antibody (anti-HBs) 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xii | P a g e 
CONFIDENTIAL 
 
 
 
 
 
шϭϬŵ/hͬŵ>͕ ŝƐ ĂĐĐĞƉƚĞĚ ĂƐ ĂŶ ŝŵŵƵŶŽůŽŐŝĐĂů ƐƵƌƌŽŐĂƚĞ ŽĨ
clinical protection against HBV infection. 
While the SPRs elicited by currently licensed hepatitis B 
ǀĂĐĐŝŶĞƐŝŶĐŚŝůĚƌĞŶĂŶĚĂĚŽůĞƐĐĞŶƚƐĂƌĞŚŝŐŚ;шϵϴйͿ6, up to 
10% of all adults fail to achieve anti-,Ɛ ůĞǀĞůƐ шϭϬŵ/hͬŵ>
after a three-dose schedule6, and are considered non- 
responders to hepatitis B vaccination. The proportion of adult 
non-responders is even higher in individuals age 30 years and 
above, where there is a well-documented age-dependent 
decline in response rate to currently licensed HBV vaccines7, 8. 
In recent phase 3 trials where Engerix-B® was the comparator, 
the SPR 4 weeks after completion of the three-dose regimen 
were 74%, 72% and 68%, in adults 40-49, 50-59 and 60-69 
years old, respectively8-10. Beyond age, other factors are known 
to be associated with reduced immunogenicity of HBV 
vaccines, including obesity11, male gender12, smoking12, 
diabetes12, and concomitant disease12. Moreover, compliance 
with the primary three-dose schedule is low, with up to 40% of 
vaccinees missing the third injection, resulting in inadequate 
clinical protection against HBV infection13. A more potent 
hepatitis B vaccine that is safe, more immunogenic, protects 
faster and with fewer injections and eliminates the need for re- 
vaccination 
therefore 
has 
important 
public 
health 
implications. 
Sci-B-Vac™ is a third-generation hepatitis B vaccine produced 
in mammalian Chinese hamster ovary (CHO) cells, genetically 
modified to produce the three HBV envelope proteins. Unlike 
the second-generation hepatitis B vaccines, which only contain 
the small S antigen, Sci-B-Vac™ includes the small S, pre-S1 and 
pre-S2 hepatitis B surface antigens. The putative biological 
function and incremental significance of the immune response 
to each of the envelope proteins (i.e., S, pre-S2 and pre-S1) has 
been described previously14 with the pre-S antigens expressing 
highly immunogenic T and B cell epitopes. The latter is an 
important property of Sci-B-Vac™15,16 that is believed to 
account for its heightened immunogenicity, resulting in high 
SPRs in older individuals following vaccination. 
Product distribution data globally estimates that over 500,000 
infants, children and adults have been vaccinated with Sci-B- 
Vac™. However, since its original development in 1989, Sci-B- 
Vac™ has undergone a number of changes in formulation, 
manufacturer and proprietary name. 
The sponsor, VBI Vaccines Inc., is proposing two phase III 
clinical trials to generate additional safety and immunogenicity 
data for the current adult Sci-B-Vac™ formulation [1 mL, 10 μg 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xiii | P a g e 
CONFIDENTIAL 
 
 
 
 
 
HBsAg, aluminum hydroxide (Al(OH)3) adjuvant, without 
thimerosal] in the adult population prior to seeking licensure 
in Canada, the U.S. and the E.U. The current study is being 
undertaken to compare the immunogenicity and safety of a 
three-dose regimen of Sci-B-Vac™ to a three-dose regimen of 
Engerix-B® in adults. 
Investigational products: 
INVESTIGATIONAL PRODUCT 
Sci-B-VacTM contains the three viral surface antigen forms: pre- 
S1, pre-S2, and S. 
Each single-ĚŽƐĞ ǀŝĂů ;ϭ͘Ϭ ŵ>Ϳ ĐŽŶƚĂŝŶƐ ϭϬ ʅŐ ŽĨ ŚĞƉĂƚŝƚŝƐ 
surface antigen adsorbed onto 0.5 mg of aluminum as 
aluminum hydroxide, sodium chloride, potassium chloride, 
disodium hydrogen phosphate dodecahydrate, potassium 
dihydrogen phosphate anhydrous and water for injection. 
ACTIVE COMPARATOR: 
Engerix-B® (1.0 mL single dose vials) 
Each vial contains 20 μg of hepatitis B surface antigen S 
adsorbed onto 0.5 mg of aluminum as aluminum hydroxide. 
Study Design 
(see also Figure 1) 
This study is a double-blind randomized controlled trial 
designed to establish the non-inferiority of Sci-B-Vac™ 
compared to Engerix-B® in adults ш 18 years old. Study subjects 
will be randomized 1:1 via a web-based system to receive 
either a total of 3 injections of Sci-B-Vac™ or 3 injections of 
Engerix-B® intra-muscularly (IM) (one injection on Study Day 0, 
one injection at 4 weeks (on Study Day 28) and one injection 
at 24 weeks (on Study Day 168)). 
Randomization will be stratified by study center, and age (18- 
44 years, 45-ϲϰǇĞĂƌƐĂŶĚшϲϱǇĞĂƌƐͿ͘dŚĞƌĞǁŝůůďĞƚĂƌŐĞƚĞĚ
enrollment to the ш 45 year old age groups, to ensure adequate 
power to establish superiority of Sci-B-Vac™ in adults шϰϱ years 
old (co-primary objective) according to the parameters 
detailed in Section 9.5.1 
The subjects, the study center staff performing outcome 
measurement and the sponsor will be blinded to vaccine 
allocation. Study vaccines will be administered by qualified 
unblinded study center staff. 
Upon confirmation of enrollment, each subject will be asked to 
come for a total of 6 visits (denoted V1, V2, V3, V4, V5, and 
End of Study visit, V6). Subjects will be followed a minimum of 
48 weeks after the first vaccination on Study Day 0, with at 
least 24 weeks of follow-up safety assessments after the third 
dose. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xiv | P a g e 
CONFIDENTIAL 
 
 
 
 
 
Each subject will receive one injection of 1 mL of Sci-B-Vac™ or 
Engerix-B® in the deltoid muscle at 0, 4 weeks (on Study Day 
28), and 24 weeks (on Study Day 168), as per the current 
recommended HBV immunization schedule in adults. 
There will be a safety follow-up by telephone 7 days after each 
vaccination to inquire about local and systemic reactions. 
Based on these follow up assessments, subjects may be asked 
to come for supplemental visits for clinical assessment if 
warranted. 
Immunogenicity will be assessed at baseline (Study Day 0) and 
on Study Days 28, 56, 168, 196 and 336. Immunogenicity 
endpoints will be evaluated using a validated quantitative 
hepatitis B surface antibody [anti-HBs] test (see below primary 
endpoint). Anti-pre-S1 and anti-pre-S2 investigations will be 
exploratory. 
Safety evaluations will include standardized methods for local 
and systemic vaccine reactions, repeated vital signs and 
physical examinations, 48 weeks follow-up for serious adverse 
events (SAE), medically significant events or new onset of 
chronic illness (at least 24 weeks after the third dose of 
vaccine), and changes in concomitant medication. 
At select sites, subjects will be asked to come for 3 additional 
visits (denoted A1, A2, A3) to assess clinical laboratory 
parameters (hematology, biochemistry) one week after each 
vaccination (Study Days 7, 35 and 175), as part of a clinical 
laboratory sub-study. The clinical laboratory sub-study will 
include at least 10% of the total number of subjects enrolled 
to the trial. From this clinical laboratory sub-study, ~n=50-75 
subjects /treatment arm will also be enrolled in an optional 
sub-study on cell-mediated immunity. The total study duration 
for each subject (assuming a screening period of 28 days or 4 
weeks) is 364 days or 52 weeks. 
Intervention Description 
Each subject will receive a total of 3 injections of Sci-B-Vac™ or 
3 injections of Engerix-B® in the deltoid muscle: one injection 
of 1 mL on Study Day 0, one injection of 1 mL at 4 weeks (on 
Study Day 28), and one injection of 1 mL at 24 weeks (on Study 
Day 168) as per the current recommended HBV immunization 
schedule in adults. All injections will be done intramuscularly 
(IM). 
 
Sample Size 
The total sample size is 1,564 subjects (782 per arm). Targeted 
enrollment by age strata will be as follows: 
Age 18-44 years (20%): 312 (~ 156 per arm) 
Age 45-64 years (40%): 626 (~313 per arm) 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xv | P a g e 
CONFIDENTIAL 
 
 
 
 
 
ŐĞшϲϱǇĞĂƌƐ;ϰϬйͿ͗ϲϮϲ;ΕϯϭϯƉĞƌĂƌŵͿ 
Enrollment within each stratum will be stopped once the 
target has been met. 
Study Population: 
Subjects meeting all the inclusion criteria and none of the 
exclusion criteria below. 
Inclusion criteria 
1. 
Any gender. 
2. 
ŐĞшϭϴ years. 
3. 
In stable health as determined by a physical examination 
and laboratory tests values. Common chronic conditions such 
as, but not limited to, type 2 diabetes, high blood pressure, 
COPD and asthma will be accepted if the condition is well 
controlled, as determined by the investigator, and not meeting 
the exclusion criteria. For subjects > 65 years old, Frailty Index 
чϯ17(see  Appendix 1). 
4. 
If female: 
a) 
either is not of childbearing potential, defined as 
postmenopausal for at least 1 year or surgically sterile 
(bilateral 
tubal 
ligation, 
bilateral 
oophorectomy 
or 
hysterectomy), 
OR 
b) 
is of childbearing potential and must agree to use an 
adequate birth control method during the screening period 
and until the end of her participation in the study (effective 
birth control includes: 1) hormonal (implant, oral, vaginal, 
transdermal) contraceptives; 2) diaphragm with spermicide, 
condom (with or without spermicide); 3) intra-uterine devices; 
and 4) vasectomy of male partner; 5) abstinence from penile- 
vaginal intercourse (if the preferred and usual lifestyle of the 
subject)). 
5. 
Able and willing to give consent. 
Exclusion criteria 
1. 
Previous vaccination with any HBV vaccine (licensed or 
experimental). 
2. 
Treatment by immunosuppressant within 30 days of 
enrollment including but not limited to corticosteroids at a 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xvi | P a g e 
CONFIDENTIAL 
 
 
 
 
 
dose that is higher than an oral or injected physiological dose, 
or a prednisolone-equivalent dose > 20 mg /day (Inhaled and 
topical steroids are allowed). 
3. Known history of immunological function impairment, 
including but not limited to: 
a) 
autoimmune diseases (e.g., multiple sclerosis, type 1 
diabetes, myasthenia gravis, Crohn disease and other 
inflammatory bowel diseases, celiac disease, systemic lupus 
erythematosus, scleroderma, including diffuse systemic form 
and CREST syndrome, systemic sclerosis, dermatomyositis 
polymyositis, rheumatoid arthritis, juvenile idiopathic arthritis, 
autoimmune thyroiditis -including Hashimoto thyroiditis, 
Grave's or Basedow’s disease, immune thrombocytopenic 
purpura, autoimmune hemolytic anemia, autoimmune 
hepatitis, psoriasis, vitiligo, vasculitis, Guillain-Barré syndrome, 
Addison’s disease, Bell’s palsy and alopecia areata); 
OR 
b) 
secondary immunodeficiency disorders (e.g. resulting 
from HIV/AIDS (Acquired Immunodeficiency Syndrome caused 
by Human Immunodeficiency Virus infection), solid organ 
transplant, splenectomy); 
OR 
c) 
primary immunodeficiency disorders (e.g. common 
variable immune deficiency (CVID), Defective phagocytic cell 
function 
and 
neutropenia 
syndromes, 
complement 
deficiency). 
4. 
Pregnancy or breastfeeding. 
5. 
Immunization with attenuated vaccines (e.g. MMR) within 
4 weeks prior to enrollment. 
6. 
Immunization with inactivated vaccines (e.g. influenza) 
within 2 weeks prior to enrolment. 
7. 
Has received blood products or immunoglobulin within 90 
days of enrollment or is likely to require blood products during 
the study period. 
8. 
Subject in another clinical trial with an investigational 
drug or a biologic within 30 days of enrollment. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xvii | P a g e 
CONFIDENTIAL 
 
 
 
 
 
9. 
Has received granulocyte-macrophage colony stimulating 
factor (G/GM-CSF) or erythropoietin (EPO) within 30 days of 
enrollment or likely to require GM-CSF or erythropoietin 
during the study period. 
10. Any history of cancer requiring chemotherapy or radiation 
within 5 years of randomization or current disease. Low risk 
basal cell carcinoma will be accepted (low risk being defined by 
the following: 1) location on the trunk of the body, arms, legs, 
cheeks, forehead, temples, scalp, neck or chin and 2) less than 
2 cm, and 3) nodular or superficial, and 4) primary cancer that 
has not come back after treatment and 5) edge of the 
cancerous area is clear and smooth and 6) not located in or 
around nerves). 
11. Any skin abnormality or tattoo that would limit post- 
vaccination injection site assessment. 
12. History of allergic reactions or anaphylactic reaction to 
any vaccine component (Engerix-B® or Sci-B-Vac™). 
13. Unwilling, or unable in the opinion of the investigator, to 
comply with study requirements, including the use of an 
adequate birth control method. 
14. Immediate family members of study center staff (parents, 
sibling, children). 
15. Current or past hepatitis B infection or prior vaccination 
as evidenced by HBV markers (anti-HBc, anti-HBs, HBsAg) at 
screening. 
16. Known hepatitis C infection or positive Hepatitis C 
serology at screening, unless treated and cured (defined as 
documented sustained virologic response (SVR) or negative 
ǀŝƌĂůůŽĂĚшϭϮǁĞĞŬƐĂĨƚĞƌĐĞƐƐĂƚŝŽŶŽĨĂŶƚŝǀŝƌĂů therapy). 
17. Known human immunodeficiency virus (HIV) infection or 
positive HIV serology at screening. 
18. Renal impairment with Glomerular Filtration Rate (GFR) 
<60 mL/min/1.73m2 at screening 
19. Uncontrolled diabetes mellitus (defined as HbA1C >8.5%). 
20. Uncontrolled hypertension (defined as an average SBP 
шϭϱϬŵŵ,ŐŽƌĂŶĂǀĞƌĂŐĞWшϵϱŵŵ,ŐďĂƐĞĚŽŶƚŚĞůĂƐƚ 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xviii | P a g e 
CONFIDENTIAL 
 
 
 
 
 
three measurements in people diagnosed and treated for 
hypertension, and in people without a diagnosis of 
hypertension). 
21. Any laboratory test abnormality that would be considered 
of Grade 1 severity or above as per Appendix 4 and is 
considered as clinically significant by the investigator. Grade 3 
severity or above is exclusionary, regardless of clinical 
assessment. 
22. Diagnosis of advanced stage heart failure (New York Heart 
Association (NYHA) class III or IV – see Appendix 5) or Unstable 
Angina. 
Study Duration 
15-18 months (recruitment + 12 months follow up) 
Subject Duration 
Subjects will be followed a minimum of 48 weeks after the first 
vaccination on Study Day 0, with at least 24 weeks of follow- 
up safety assessments after the third vaccination on Study Day 
168. 
Primary Objectives 
Co-Primary Objectives: 
x 
To demonstrate that the SPR 4 weeks after completion of 
the three-dose regimen of Sci-B-Vac™ is non-inferior to a 
three-dose regimen of Engerix-ΠŝŶĂĚƵůƚƐшϭϴǇĞĂƌƐŽůĚ͖ŝ͘Ğ͘
the lower bound of the 95% two-sided confidence interval (CI) 
of the difference between the SPR in the Sci-B-Vac™ arm minus 
the SPR in the Engerix-B® arm, achieved 4 weeks after the third 
vaccination, will be > - 5%. 
And 
x 
To demonstrate that the SPR 4 weeks after completion of 
the three-dose regimen of Sci-B-Vac™ is superior to a three- 
dose regimen of Engerix-ΠŝŶĂĚƵůƚƐшϰϱǇĞĂƌƐŽůĚŝ͘Ğ͘ƚŚĞ
lower bound of the 95% two-sided CI of the difference 
between the SPR in the Sci-B-Vac™ arm minus the SPR in the 
Engerix-B® arm, achieved 4 weeks after the third vaccination, 
will be >5%. 
Secondary Objectives 
x 
To determine whether the SPR after 2 vaccinations with 
Sci-B-Vac™, evaluated 4 weeks and 20 weeks after the second 
vaccination (just prior to receiving the third vaccination), is 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xix | P a g e 
CONFIDENTIAL 
 
 
 
 
 
non-inferior to the SPR 4 weeks after receiving the third 
vaccination with Engerix-B®. 
x 
To compare the safety and reactogenicty of Sci-B-Vac™ 
and Engerix-B®. 
Exploratory Objectives 
x 
To compare the geometric mean concentration (GMC) 
of anti-HBs, 4 weeks after receiving the first vaccination, 
second vaccination and third vaccination, 20 weeks after 
receiving the second vaccination (just prior to receiving the 
third vaccination), and 24 weeks after receiving the third 
vaccination with Sci-B-Vac™ or Engerix-B®. 
x 
To compare the SPR 4 weeks after receiving the first 
vaccination and second vaccination, 20 weeks after receiving 
the second vaccination (just prior to receiving the third 
vaccination), and 24 weeks after receiving the third vaccination 
with Sci-B-Vac™ or Engerix-B® on Study Days 28, 56, 168 and 
336. 
x 
To compare the proportion of subjects who achieve anti- 
,ƐůĞǀĞůƐшϭϬϬŵ/hͬŵ>͕ĂƐĂŵĞĂƐƵƌĞŽĨĂŶĞƐƉĞĐŝĂůůǇ robust 
immune response, 4 weeks after each vaccination with Sci-B- 
Vac™ or Engerix-B®, on Study Days 28, 56, and 196 and on 
Study Days 168 and 336. 
x 
To compare the rate of non-response (defined as the 
proportion of subjects not attaining anti-,Ɛ ůĞǀĞůƐ ш ϭϬ
mIU/mL) 4 weeks after receiving the third vaccination with Sci- 
B-Vac™ or Engerix-B®. 
x 
To assess the antibody responses against Pre-S1 and 
Pre-S2 at baseline, 4 weeks after each vaccination with Sci-B- 
Vac™ or Engerix-B®, and at day 168 and 336. 
x 
To compare SPR, GMC and rate of non-response in 
subgroups of interest (e.g. BMI>30), 4 weeks after receiving 
the third vaccination with Sci-B-Vac™ or Engerix-B®. 
x 
To compare clinical laboratory parameters relative to 
baseline 1 week after each vaccination with Sci-B-Vac™or 
Engerix-B® in a subset of subjects (at least 10% of the total 
number of subjects enrolled to the trial). 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xx | P a g e 
CONFIDENTIAL 
 
 
 
 
 
x 
To compare the boost relative to baseline of the cell- 
mediated immune response, 1 week after receiving each 
vaccination with either Sci-B-Vac™ or Engerix-B®, in a small 
subset of subjects (~50-75 subjects/treatment arm). 
Primary endpoint 
x 
Seroprotection rate (SPR) achieved on Study Day 196, 4 
weeks post-third vaccination with either Sci-B-Vac™ or 
Engerix-B®. Seroprotection is defined as anti-,ƐůĞǀĞůƐшϭϬ
mIU/mL in serum. Seroprotection rate is the percentage (%) of 
subjects achieving seroprotection. 
Secondary Endpoints 
x 
SPR, 4 weeks and 20 weeks after receiving the second Sci- 
B-Vac™ vaccination (just prior to receiving the third 
vaccination), and SPR 4 weeks after receiving the third Engerix- 
B® vaccination. 
x 
Number (%) of subject-reported, solicited (on the day of 
vaccination and during the next 6 days), unsolicited adverse 
events (AE) (on the day of vaccination and during the next 27 
days), and number (%) of SAEs, medically significant events or 
new onset of chronic illness through Study Day 336. Adverse 
events will be classified by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term, 
severity, seriousness, investigator and Sponsor causality 
assessment, and time since vaccination. 
x 
Number (%) of subjects with abnormal vital signs and/or 
physical examination findings, compared to baseline. 
Exploratory endpoints 
x 
Geometric Mean Concentration (GMC) of anti-HBs in 
serum, at baseline and 4 weeks after each vaccination with 
either Sci-B-Vac™ or Engerix-B® i.e. on Study Days 28, 56, and 
196, and 20 weeks after receiving the second vaccination (just 
prior to receiving the third vaccination) on Study Day 168 and 
24 weeks after receiving the third vaccination, and on Study 
Day 336. 
x 
SPR in both study arms at baseline and on Study Days 28, 
56, 168 and on Study Day 336. 
x 
Proportion of subjects achieving anti-HBs levels 
шϭϬϬŵ/hͬŵ>ŝŶƐĞƌƵŵ͕ϰǁĞĞŬƐĂĨƚĞƌĞĂĐŚǀĂĐĐŝŶĂƚŝŽŶǁŝƚŚ 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxi | P a g e 
CONFIDENTIAL 
 
 
 
 
 
either Sci-B-Vac™ or Engerix-B®, on Study Days 28, 56, and 196, 
and on Study Days 168 and 336. 
x 
Rate of non-response on Study Day 196 (defined as the 
proportion of subjects not attaining anti-,Ɛ ůĞǀĞůƐ ш ϭϬ
mIU/mL on Study Day 196), 4 weeks after receiving the third 
vaccination with either Sci-B-Vac™ or Engerix-B®. 
x 
Geometric Mean Concentrations (GMC) of anti-pre S1 
antibody and anti pre S2 antibody in serum at baseline and 4 
weeks after each vaccination with Sci-B-Vac™ or Engerix-B® on 
Study Days 28, 56, and 196, and on Study Days 168 and 336. 
x 
Number (%) of subjects with abnormal clinical laboratory 
parameters from baseline assessments, one week after each 
vaccination with either Sci-B-Vac™ or Engerix-B® (clinical 
laboratory sub-study). 
x 
Cell-mediated immunity against HBs at baseline, 1 week 
after each vaccination with either Sci-B-Vac™ or Engerix-B® (on 
a small subset of subjects enrolled in the clinical laboratory 
sub-study). 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxii | P a g e 
CONFIDENTIAL 
 
 
 
 
 
 
 
SCHEMATIC OF STUDY DESIGN 
 
 
Figure 1: Schematic of Study Design 
 
 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxiii | P a g e 
CONFIDENTIAL 
 
 
 
PROTOCOL AMENDMENTS Sci-B-Vac-001 
Protocol Version 
Issue Date 
Original Protocol 
5 May 2017 
Amendment 1 
17 July 2017 
 
 
 
 
 
 
Amendment 1 (17 July 2017) 
 
The overall reason for the amendment: The overall reason for the amendment is to change the short- 
term clinical laboratory follow-up on the entire study population to a more intensive clinical laboratory 
follow up over the full three-dose regimen on a subset (at least 10%) of the entire study population, and 
to provide per-protocol clarifications in response to study center inquiries. Changes are listed in the 
order in which they appear in the protocol. 
 
Applicable Section(s) 
Description of Change(s) 
 
Cover page and Page 
Header 
Update to version 2.0 from version 1.0 and update of corresponding date of 
version. “Amendment 1” and a study acronym have also been added. 
 
 
Rationale: Change made to reflect the update in the protocol version under Amendment 1 and the 
addition of a study acronym for study identification. 
 
“Statement of 
Compliance” 
Site signatories now limited to the Principal Investigator. Co-investigators will 
be required to sign the Delegation of Responsibilities Log on site. 
 
 
Rationale: Change made to reduce the administrative burden during site qualification. 
 
“Protocol Summary” 
and Section 4.1 
“Subjects Population” 
Number of sites has been changed from 30-45 to ~ 30 sites. 
 
 
Rationale: Fewer sites are required than initially expected, given the recruitment potential at 
participating sites. 
 
Protocol Summary 
“Investigational 
Product” and Section 
5.1.2 Formulation 
and Labelling” 
“10 μg of Hepatitis B surface antigen with aluminum hydroxide (Al(OH)3) as an 
ĂĚũƵǀĂŶƚ ;Ϭ͘ϱ ŵŐͬŵ>Ϳ͟ ĐŚĂŶŐĞĚ ƚŽ ͞ϭϬ ʅŐ ŽĨ ŚĞƉĂƚŝƚŝƐ  ƐƵƌĨĂĐĞ ĂŶƚŝŐĞŶƐ
adsorbed onto 0.5 mg of aluminum as aluminum hydroxide” 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxiv | P a g e 
CONFIDENTIAL 
 
 
 
 
Rationale: Clarification on the amount of aluminum per 1 mL in the aluminum hydroxide adjuvant. 
 
Protocol Summary 
and “Study Design” 
Change made to reflect that clinical laboratory assessments will be carried out 
in study subset (at least 10% of the total number of subjects enrolled to the trial) 
throughout the full three-dose regimen, instead of on the full study cohort after 
only one vaccination. 
 
 
Rationale: Data on a subset (at least 10%) of the total number of subjects enrolled to the trial will provide 
information sufficient to assess clinical laboratory risks to subjects receiving the entire schedule of Sci-B- 
Vac™, while reducing the visit burden on the remaining subjects enrolled to the study. 
 
Protocol Summary 
“Study Design” 
Clarification made that subjects invited to participate in the optional sub-study 
of cell-mediated immunity will be recruited from subjects already participating 
in the clinical laboratory sub-study (select sites). 
 
 
Rationale: To clarify that only subjects at select sites will contribute to the clinical laboratory sub-study 
and be eligible to participate in the optional sub-study on cell-mediated immunity sub-study. 
 
Protocol Summary 
“Exclusion criteria” 
#2 and Section 4.1.2 
“within 30 days of enrollment” has been added to exclusion criteria #2. 
 
 
Rationale: This clarification was made to exclude subjects that have recently received 
immunosuppressants from being enrolled to the study, as this may affect response to vaccination. 
 
Protocol summary, 
“Exclusion criteria” 
#20 and Section 4.1.2 
“Exclusion criteria” 
The definition of uncontrolled hypertension (SBP шϭϱϬ mmHg or DBP шϵϱ mmHg) 
has been expanded to people without a diagnosis of hypertension. 
 
 
Rationale: This change was made to ensure that no subject with higher than grade 1 hypertension is 
enrolled to the study, for safety reasons. 
 
Protocol summary 
“Study Duration” 
Longer study duration listed. 
 
 
Rationale: To account for a potentially longer study recruitment period. 
 
Protocol Summary – 
“Exploratory 
Objectives” and 
Section 2.3 
“Exploratory 
Objectives” 
Clarification provided to distinguish between the clinical laboratory exploratory 
objectives and the exploratory objectives of the cell-mediated immune response 
sub-study. Study Days are also now provided for clarity for the SPR comparisons, 
4 weeks post vaccination. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxv | P a g e 
CONFIDENTIAL 
 
 
 
 
Rationale: To delineate the specific exploratory objectives and to clarify the timing of exploratory 
comparisons of interest. 
 
Protocol Summary – 
“Exploratory 
Endpoints” and 
Section 3.4 
“Exploratory 
Endpoints” 
Addition of SPR exploratory endpoint for consistency with exploratory endpoints 
defined in Section 3.4. Also, separation of cell-mediated immune response 
endpoint and clinical laboratory parameter endpoint, for clarity. 
 
 
Rationale: Changes made to ensure consistency within the document. 
 
Protocol summary – 
“Exploratory 
Objectives” and 
Section 2.3 
Exploratory 
Objectives 
Identifies 100mIU/mL as an important measure of an especially robust immune 
response to vaccination. 
 
 
Rationale: This clarification was provided to identify 100mIU/mL as an important measure of an 
especially robust immune response to vaccination and of long-term immunity, and therefore is an 
important exploratory objective of the study (and not a typographical error). 
 
Study Schema 
Changes made to the schema to reflect the additional visits required at select 
sites for the clinical laboratory assessments, as part of a laboratory sub-study. 
The 7-day V2 visit in the full study cohort has been replaced with a 7-day 
telephone follow up call and all subsequent visits are now reduced by one (i.e. 
V3 -> V2) in the main study. 
 
Rationale: Changes made to the schema to reflect that the additional visits and clinical laboratory 
assessments for the clinical laboratory sub-study are only being done at select sites, thereby reducing 
the number of study visits by one in the main study. 
 
Section 1.3.1 Sci-B- 
Vac™ Description 
Countries where Sci-B-Vac™is approved and marketed is now provided. 
 
 
Rationale: Providing the list of countries where Sci-B-Vac™ is marketed clarifies how product distribution 
globally has reached 500,000. 
 
Section 3.1 “Study 
Design” 
Changes made to reflect the addition of laboratory sub-study at select sites, with 
assessments at Day 0 and 7 days after each vaccination. Clarification is also 
provided on the number of visits and evaluations required for the main study 
and separately for the laboratory sub-study and the sub-study of cell-mediated 
immunity. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxvi | P a g e 
CONFIDENTIAL 
 
 
 
 
Rationale: To improve clarity and consistency within the protocol and to accurately present the main 
study visits (V1-V6) and the additional clinical laboratory visits (A1-A3) for select sites participating in the 
clinical laboratory sub-study. 
 
Sections 3.1, 6.2.4, 
6.3.2, 6.3.5 and 6.3.7 
Antibody levels and characteristics will be measured and compared between Sci- 
B-Vac™ and Engerix-B® 
 
 
Rationale: This modification was made to allow for some mechanistic studies to better characterize the 
immune responses to Sci-B-Vac™ and Engerix-B®. 
 
Section 4.3.2 
“Subject withdrawal 
from Investigational 
product’ 
The use of a concomitant medication not allowed on study as a possible reason 
for withdrawal from the investigational product (after consultation with the 
medical monitor) is now provided as an example under “Other (specify)”. 
 
 
Rationale: Given the age of the population being enrolled, it is expected that some study subjects may 
need to be removed from the investigational product because they require a concomitant medication 
not permitted while on the study. 
 
Section 5.6.1 
All subjects must record their daily temperature in their diary. The condition that 
only subjects with a low grade fever need to record their daily temperature, has 
been removed. 
 
Rationale: All subjects are required to complete all elements of the safety diary provided at each 
vaccination, including the daily temperature log. 
 
6.1.2 “Check 
Inclusion and 
Exclusion Criteria” 
Verification of eligibility against all inclusion and exclusion criteria required prior 
to randomization. Prior to vaccine administration on Study Days 0, 28, and 168, 
the investigator or qualified designee must only verify that the subject remains 
eligible to be administered the vaccine and to remain on the study. 
 
 
Rationale: Clarification provided that on the days of vaccine administration, subject must only be verified 
to be eligible to have the vaccine administered (i.e. no fever, no contraindicated medications that would 
preclude vaccination) and to continue on the study. 
 
Section 6.1.10 
“Recording of 
Adverse Events” 
Clarification is provided that the recording of solicited pain, tenderness and 
pruritus at the injection site and oral daily temperature is only required on the 
day of injection and for 6 days after the injection. Safety laboratory Visit 2 in the 
main study has been replaced with a telephone follow up, 7 days after the first 
vaccination. 
 
 
Rationale: This clarification is provided to distinguish between solicited adverse events (up to 6 days post 
injection) and unsolicited adverse events (up to 27 days post injection) and to update the 7-day 
telephone follow up after the first vaccination, for consistency with Section 3.1. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxvii | P a g e 
CONFIDENTIAL 
 
 
 
 
 
Section 6.2.1 “Urine 
pregnancy test” 
Clarification is provided that a confirmatory serum pregnancy test is required in 
the event of a positive urine pregnancy test. If the serum pregnancy test is 
positive, the subject will be withdrawn from the study (per section 4.3.1). If the 
serum pregnancy test is negative, the subject will remain in the study and 
continue to receive the study vaccine. 
 
 
Rationale: This clarification has been added to provide clear guidance on the course of action in the event 
of a positive urine pregnancy test. 
 
Section 6.2.3 “Safety 
laboratory evaluations” 
Section 6.2.3 has been removed and replaced with new section 6.2.4.1 
“Clinical laboratory sub-study”. 
 
 
Rationale: Baseline and Day 7 safety laboratories for the full study cohort have been replaced with a 
more intensive laboratory assessment in a subset of the full study cohort as part of a laboratory sub- 
study (at select sites). Laboratory parameters in the sub-study are being assessed at V1 (Study Day 0) 
and 1 week after each vaccination (Study Days 7, 35, 175). 
 
Section 6.2.4.2 – 
“Optional sub study of 
cell-mediated 
immunity” 
Modifications made to the text to reflect that subjects enrolled to the cell- 
mediated sub-study will be recruited from the clinical laboratory sub-study. 
Clarification is also provided in the text that these sub-studies will include 3 
additional assessments (A1, A2, A3), one week after each vaccination. 
 
 
Rationale: To clarify the enrollment procedures and sub-study requirements for the laboratory and cell- 
mediated immunity sub-studies. 
 
6.2.5 “Biological 
samples, handling, 
analysis and storage” 
Changes made to reflect new sample requirements for clinical laboratory 
assessments and the optional cell-mediated immunity sub-study, one week 
after each vaccination. Subjects in the clinical laboratory sub-study will be 
required to come for 3 additional visits (A1, A2, A3) and provide 4 additional 
blood samples (10 mL/visit) at V1 and at each additional visit (A1, A2, A3). 
Subjects consenting to the sub-study of cell-mediated immunity will be 
required to provide an additional 40mL at each of these timepoints (V1, A1, 
A2,A3). 
 
 
Rationale: Changes made to reflect sample requirements for the main study, the clinical laboratory sub- 
study and the sub-study of cell-mediated immunity, separately. 
 
6.2.5 “Biological 
samples, handling, 
analysis and storage. 
The sentence “A separate information and consent document will be 
provided” for biobanking has been removed. Potential study subjects will be 
provided information about biobanking and will be given the opportunity to 
consent to biobanking within the main study consent form. 
 
 
Rationale: The clinical sites requested that the optional biobanking information and consent be included 
in the main consent form to reduce the number of pages to be read by potential study participants,. A 
lack of consent to biobanking will not preclude participation in the main study. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxviii | P a g e 
CONFIDENTIAL 
 
 
 
 
Section 6.3.1 Screening Addition of Urinalysis to the list of test to be done at screening, for consistency 
with the Appendix 2 Schedule of Events and Section 6.2.2 Screening 
Laboratory Evaluations. 
 
Rationale: This addition was made to ensure internal consistency within the protocol and to make sure 
that urinalysis at screening was performed. 
 
Section 6.3.2 
“Vaccination visits” 
Clarification is provided that urine pregnancy must not only be reviewed, but 
also be confirmed to be negative prior to vaccination. 
 
 
Rationale: To provide clarity on the rationale for inclusion of this pre-vaccination test in women of 
childbearing potential. 
 
Section 6.3.2 
“Vaccination visits” 
Clarification provided that inactivated vaccines should not be received 2 weeks 
prior to 2 weeks after any study vaccination and attenuated vaccines should not 
be received 4 weeks prior to 4 weeks after any study vaccination. 
 
 
Rationale: Sentence restructured to improve clarity. 
 
Section: 6.3.3 “Safety 
follow up” 
In the main study, the safety follow up will now consist of a telephone follow up 
call 7-days after each vaccination in the full study cohort. Laboratory 
assessments 1 week after each vaccination will be carried out at select sites 
(clinical laboratory sub-study). 
 
 
Rationale: Modification made to reflect implementation of clinical laboratory sub-study and removal of 
the 7-day laboratory evaluation in the full study cohort. Follow up telephone call is now done 7 days 
after each vaccination. 
 
Section 6.3.6 “Sub- 
study additional 
visits” 
Additional study visits required for subjects enrolled at select sites for the clinical 
laboratory sub-study and optional cell-mediated sub-study are defined. 
 
 
Rationale: To clarify the additional visit requirements at select sites for the clinical laboratory and cell- 
mediated immunity sub-studies. 
 
Section 6.3.7 “End of 
study visit” 
Clarification provided that lack of seroprotection corresponds to an anti-HBs 
level <10 mIU/mL and not <10 IU/mL 
 
 
Rationale: Correction of typographical error. 
 
Section 7.2.2 “Vital 
signs and vaccine 
reactions” 
Clarification provided that 1) vital signs are recorded for 30 minutes following 
each vaccination, 2) recording of solicited reactions and temperature monitoring 
are required daily to day 6 post vaccination and 3) unsolicited adverse events 
are recorded for 27 days post vaccination. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
xxix | P a g e 
CONFIDENTIAL 
 
 
 
 
Rationale: Clarification is provided as to the nature/intensity and duration of safety monitoring required 
following vaccination. 
 
Multiple sections 
Correction made from [1 mL, 10 μg HBsAg, Al(OH)3 0.5 mg/mL without 
thimerosal] to [1 mL, 10 μg HBsAg, Aluminum 0.5 mg/mL without thimerosal] 
 
Rationale: Distinction provided regarding the adjuvant, aluminum hydroxide, and the amount of 
aluminum alone (0.5mg/mL) in the investigational product, Sci-B-Vac™. 
 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
1 | P a g e 
CONFIDENTIAL 
 
 
 
 
 
1 BACKGROUND AND RATIONALE 
1.1 Epidemiology 
Hepatitis B virus (HBV) is a human double-stranded enveloped DNA virus that causes an acute infection 
which, in some cases, may develop into a chronic disease. 
Approximately 260 million people are chronically infected by the HBV, worldwide1. In 2013, it is estimated 
that 686,000 people of all ages died from complications of hepatitis B, such as liver cirrhosis and liver 
cancer2. The progressive implementation of universal immunization programs in infants, children and 
adolescents in a total of 184 countries1 has resulted in vaccine coverage of 82% of children, and a drop in 
the incidence of hepatitis B in these countries. However, adults who were not immunized as children 
against hepatitis B remain at risk of becoming infected with hepatitis B. According to the European Centre 
for Disease Prevention and Control, 25–34-year-olds are the most affected age group for both acute and 
chronic hepatitis B infections, accounting for 33.8% of the 22,442 cases reported in 2014 by the 30 EU/EEA 
Member States3. 
1.2 Immunogenicity of licensed vaccines 
Monovalent HBV vaccines, such as Engerix-B®, licensed in Canada, European Union (E.U), and the United 
States (U.S.) are second-generation vaccines using recombinant DNA technology to express the HBV DNA 
sequence coding for the small hepatitis B surface antigen (HBsAg) in yeasts. The 1 mL dose of Engerix-B® 
containing 20 μg of HBsAg is the form approved for the immunization of healthy adults. In adults, the most 
commonly recommended immunization schedule consists of three injections of vaccine: two injections 4 
weeks apart, followed by a third injection 24 weeks after the initial injection. 
A serum concentration of hepatitis B surface antigen antibody (anti-HBs) шϭϬ mIU/mL after vaccination is 
considered protective4, and is associated with long term immunity to hepatitis B5. Therefore, the 
seroprotection rate (SPR), i.e., the percentage of subjects achieving a serum concentration of hepatitis B 
surface antigen antibody (anti-HBs) шϭϬ mIU/mL after vaccination, is widely used as a surrogate endpoint 
for evaluating anti HBV vaccines. 
While the SPRs elicited by currently licensed hepatitis B vaccines in children and adolescents are high 
;шϵϴйͿ6, up to 10% of all adults fail to achieve anti-,ƐůĞǀĞůƐшϭϬŵ/hͬŵ>ĂĨƚĞƌĂƚŚƌĞĞ-dose schedule6, 
and are considered non-responders to hepatitis B vaccination. The proportion of adult non-responders is 
even higher in individuals age 30 years and above, where there is a well-documented age-dependent 
decline in response rate to currently licensed HBV vaccines7,8. In recent phase 3 trials where Engerix-B® 
was the comparator, SPRs 4 weeks after completion of the three-dose regimen were 74%, 72% and 68%, 
in adults 40-49, 50-59 and 60-69 years old, respectively8-10. In addition to age and genetic factors, other 
factors are known are known to be associated with reduced immunogenicity of HBV, including obesity11, 
and, as recently reviewed by Yang Tian et al in 2016, male gender, smoking, diabetes, and concomitant 
disease12. 
Moreover, compliance with the primary three-dose schedule is low, with up to 40% of vaccinees missing 
the third injection, resulting in inadequate clinical protection against HBV infection13. 
The current recommendation in Canada is that non-responders are given another full three-dose 
schedule, with a rate of success of 50% to 70%18. In the U.S., recent Center for Disease Control guidelines 
for health care professionals recommend either to give another full three-dose schedule, or to utilize an 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
2 | P a g e 
CONFIDENTIAL 
 
 
 
incremental approach consisting of: 1) giving one additional vaccine dose followed by anti-HBs testing 1– 
2 months later and 2) in the individuals whose anti-HBs levels remains <10 mIU/mL giving two additional 
vaccine doses, followed by repeat anti-HBs testing 1–2 months later. Similar re-vaccination strategies are 
also used in Europe. Re-vaccination in adult non-responders has variable response, is costly and delays 
the time to protection against hepatitis B infection. A more potent hepatitis B vaccine that is safe, more 
immunogenic, protects faster and with fewer injections and eliminates the need for re-vaccination 
therefore has important public health implications. 
1.3 Sci-B-Vac™ 
1.3.1 Description 
Sci-B-Vac™ is a third-generation hepatitis B vaccine, that is produced in mammalian Chinese hamster 
ovary (CHO) cells genetically modified to produce the three HBV envelope proteins (the small S Hepatitis 
B surface antigen, and the Pre-S2 and Pre-S1 proteins), unlike the second-generation hepatitis B vaccines 
that contain only the small S Hepatitis B virus surface antigen (see Figure 2). Sci-B-Vac™ is currently 
approved and marketed in Israel, Chile, Central Africa, Ivory Coast, Ethiopia, Georgia, Gabon, Guinea 
ƋƵĂƚŽƌŝĂů͕,ŽŶŐ<ŽŶŐ͕DŽůĚŽǀĂ͕EŝŐĞƌ͕EŝŐĞƌŝĂ͕WŚŝůŝƉƉŝŶĞƐĂŶĚ^ĞŶĞŐĂů͕ŝŶϯĚŽƐĂŐĞƐ͗Ϯ͘ϱʅŐĂŶĚϱʅŐ
,ƐŐͬϬ͘ϱŵ>ĨŽƌƵƐĞŝŶŶĞŽŶĂƚĞƐ͕ŝŶĨĂŶƚƐĂŶĚĐŚŝůĚƌĞŶƵƉƚŽϭϬǇĞĂƌƐŽĨĂŐĞ͕ĂŶĚϭϬʅŐ,ƐŐͬϭŵ>ĨŽƌ
individuals age 10 years and older. 
Figure 2: Sci-B-Vac™ (left) compared to a 2nd generation HBV vaccine (right) 
 
 
1.3.2 Overview of clinical pharmacology 
As described above in Section 1.3.1, Sci-B-Vac™ not only contains the S protein present in currently 
licensed second-generation HBV vaccines, but also contains pre-S1 and pre-S2 proteins that mimic the 
hepatitis B virion. The putative biological function and incremental significance of the immune response 
to each of the envelope proteins (i.e., S, pre-S2 and pre-S1) has been described previously14. Initial studies 
have shown that the pre-S antigens, and particularly pre-S1, express highly immunogenic T and B cell 
epitopes, a feature that could influence the immunogenicity and protection following administration of 
Sci-B-Vac
TM      15,16.   Synthetic   pre-S   antigens   have   been   found   to   protect   chimpanzees   against   HBV 
challenge19. In addition, the pre-S2 protein has the following properties: 1) it binds polymerized human 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
3 | P a g e 
CONFIDENTIAL 
 
 
 
serum albumin in vitro; and 2) the pre-S2 has a domain that can also act as a B cell epitope. These 
properties may contribute to an enhanced immunogenicity of pre-S2 20,21. Pre-S2 may also help in the 
attachment of HBV to hepatocytes, which may be prevented through an adequate anti-pre-S2 response22. 
Moreover, the pre-S1 domain of the envelope protein plays a critical role in binding the virus to its 
hepatocyte receptor, which may be disrupted in the presence of anti-pre-S1 antibody23. Finally, antibody 
responses to pre-S1 and pre-S2 may also reduce the risk of HBV infection caused by virus mutants in which 
the main neutralizing “a” conformational epitope (aa 124-147), within the major hydrophilic region (MHR) 
of the S protein, may escape antibody neutralization24. 
Since its original development in 1989, Sci-B-Vac™ has undergone a number of changes in formulation, 
manufacturer and proprietary name. The original formulation used aluminum phosphate (AlPO4) as its 
adjuvant and contained thimerosal. The adjuvant was switched to aluminum hydroxide (Al(OH)3) in 1994 
and thimerosal was eliminated in 1998. Aluminum hydroxide remains the adjuvant in the current Sci-B- 
Vac™ formulation. Product distribution data globally estimates that over 500,000 infants, children and 
adults have been vaccinated with Sci-B-Vac™. 
1.3.3 Potential risks and benefits 
The potential risks and benefits are described in the Sci-B-Vac™ Investigator Brochure. 
1.4 Rationale for conducting the study 
A series of clinical trials with Sci-B-Vac™ conducted in adults, children and neonates over the past 2 
decades have found that the currently approved three-dose regimen (administered on Study Day 0, at 4 
weeks and 24 weeks) elicits very high seroprotection rates that are comparable to those elicited by 
second-generation vaccines, such as Engerix-B® or Recombivax-HB®. 
More importantly, however, antibody responses following Sci-B-Vac™ administration in both the previous 
and current formulations of Sci-B-Vac™ are generally higher and faster following the first and second 
injections and may not decrease with age. These attributes suggest that Sci-B-Vac™ may help to raise 
seroprotection rates in adults with poorer or delayed response to second-generation vaccines, including 
older adults, patients with diabetes mellitus, obese individuals, and smokers. The safety profile of Sci-B- 
Vac™ is similar to second-generation vaccines, aside from being associated with a higher frequency of 
pain at the injection site in the earlier formulations. 
The sponsor, VBI Vaccines Inc., is proposing two phase III clinical trials to generate additional safety and 
efficacy data for the current adult Sci-B-Vac™ formulation [1 mL, 10 μg HBsAg, aluminum hydroxide 
adjuvant, without thimerosal] in the adult population prior to seeking licensure in Canada, the U.S. and 
the E.U. 
The current study is being undertaken to compare the immunogenicity and safety of a three-dose regimen 
of Sci-B-Vac™ to a three-dose regimen of Engerix-B® in adults. 
2 OBJECTIVES 
2.1 Co-primary objectives 
x 
To demonstrate that the SPR 4 weeks after completion of the three-dose regimen of Sci-B- 
Vac™ is non-inferior to the SPR 4 weeks after completion of the three-dose regimen of 
Engerix-B® in adults шϭϴ years old i.e. the lower bound of the 95% two-sided confidence 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
4 | P a g e 
CONFIDENTIAL 
 
 
 
 
 
And 
interval (CI) of the difference between the SPR in the Sci-B-Vac™ arm minus the SPR in the 
Engerix-B® arm, achieved 4 weeks after receiving the third vaccination, will be > - 5%. 
 
x 
To demonstrate that the SPR 4 weeks after completion of the three-dose regimen of Sci-B- 
Vac™ is superior to the SPR 4 weeks after completion of the three-dose regimen of Engerix- 
Π ŝŶ ŽůĚĞƌ ĂĚƵůƚƐ ш ϰϱ ǇĞĂƌƐ ŽůĚ ŝ͘Ğ͘ ƚŚĞ ůŽǁĞƌ ďŽƵŶĚ ŽĨ ƚŚĞ ϵϱй ƚǁŽ-sided CI of the  
difference between the SPR in the Sci-B-Vac™ arm minus the SPR in the Engerix-B® arm, 
achieved 4 weeks after receiving the third vaccination, will be > 5%. 
2.2 
Secondary objectives 
x 
To determine whether the SPR after receiving 2 vaccinations of Sci-B-Vac™, evaluated at 4 
weeks and 20 weeks after receiving the second vaccination (just prior to receiving the third 
vaccination), is non-inferior to the SPR 4 weeks after receiving the third vaccination with 
Engerix-B® 
x 
To compare the safety and reactogenicity of Sci-B-Vac™ and Engerix-B®. 
2.3 Exploratory Objectives 
x 
To compare the geometric mean concentration (GMC) of anti-HBs 4 weeks after receiving 
the first vaccination, the second vaccination and the third vaccination, 20 weeks after 
receiving the second vaccination (just prior to receiving the third vaccination), and 24 weeks 
after receiving the third vaccination of Sci-B-Vac™ or Engerix-B®. 
x 
To compare the SPR observed 4 weeks after receiving the first vaccination and second 
vaccination, 20 weeks after receiving the second vaccination (just prior to receiving the third 
vaccination), and 24 weeks after receiving the third vaccination of Sci-B-Vac™ or Engerix-B® 
on Study Days 28, 56, 168 and 336. 
x 
To compare the proportion of subjects who achieve anti-,ƐůĞǀĞůƐшϭϬϬŵ/hͬŵ>͕ĂƐĂ
measure of an especially robust immune response, 4 weeks after each vaccination with 
either Sci-B-Vac™ or Engerix-B®, on Study Days 28, 56, and 196, and on Study Days 168 and 
336. 
x 
To compare the rate of non-response 4 weeks after receiving the third vaccination with Sci- 
B-Vac™ or Engerix-B®. 
x 
To assess the antibody responses against Pre-S1 and Pre-S2 at baseline, 4 weeks after each 
vaccination with Sci-B-Vac™ or Engerix-B® and on Study Days 168 and 336. 
x 
To compare SPR, GMC and rate of non-response in subgroups of interest (e.g. BMI>30) 4 
weeks after receiving the third vaccination with Sci-B-Vac™ or Engerix-B®. 
x 
To compare clinical laboratory parameters relative to baseline 1 week after each vaccination 
with Sci-B-Vac™or Engerix-B® in a subset of subjects (at least 10% of the total number of 
subjects enrolled to the trial) recruited at select sites. 
x 
To compare the boost, relative to baseline, of cell-mediated immune response against HBs, 
1 week after each vaccination with either Sci-B-Vac™ or Engerix-B® (in a small subset of 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
5 | P a g e 
CONFIDENTIAL 
 
 
 
subjects recruited to an optional sub study at select sites (~n=50-75 subjects/treatment 
arm). 
 
3 STUDY DESIGN AND ENDPOINTS 
3.1 Study design 
This study is a double-blind randomized controlled trial designed to establish the non-inferiority of Sci-B- 
Vac™ compared to Engerix-Π ŝŶ ĂĚƵůƚƐ ш ϭϴ ǇĞĂƌƐ ŽůĚ͘ ^ƚƵĚǇ ƐƵďũĞĐƚƐ ĂŐĞ ш ϭϴ ǇĞĂƌƐ ŽůĚ ǁŝůů ďĞ
randomized 1:1 via a web-based system to receive either a total of 3 injections of Sci-B-Vac™ or 3  
injections of Engerix-B® intra-muscularly (IM) (one injection on Study Day 0, one injection at 4 weeks 
(Study Day 28), and one injection at 24 weeks (Study Day 168)), and followed for 24 weeks after receiving 
the third vaccination. 
Randomization will be stratified by study center and age (18-44 years, 45-64 years and ш 65 years). There 
will be targeted enrollment to the шϰϱ year old age groups (80% of study population) to ensure adequate 
power to also establish superiority of Sci-B-sĂĐΡŝŶŽůĚĞƌĂĚƵůƚƐ;шϰϱǇĞĂƌƐŽůĚͿ͕ĂĐŽ-primary outcome, 
according to the parameters detailed is Section 9.5.1. There will also be equal representation (i.e. 40%) of 
study subjects in the two older age strata (45-ϲϰǇĞĂƌƐĂŶĚшϲϱǇĞĂƌƐͿƚŽĞŶƐƵƌĞŐŽŽĚƌĞƉƌĞƐĞŶƚĂƚŝŽŶ
across the spectrum of older adults. 
The study subjects, the study center staff performing outcome measurement, and the sponsor will be 
blinded to vaccine allocation. Study vaccines will be prepared by a qualified unblinded study center staff. 
Preparation of the study vaccine must be done by the unblinded study center staff/pharmacy staff behind 
a screen or in a separate room from where blinded research staff and study participants will be located. 
After visual inspection, the vaccine will be covered and immediately administered. The unblinded health 
personnel will not communicate what vaccine was administered to the subject or study centre staff 
performing the outcome measurements. 
Upon confirmation of enrollment, all subjects will be asked to come for a total of 6 visits (denoted V1, V2, 
V3, V4, V5, and end of study visit, V6). Subjects will be followed a minimum of 48 weeks after receiving 
the first vaccination on Study Day 0, with at least a 24-week follow-up safety assessments after receiving 
the third injection. 
Each subject will receive one injection of 1 mL of Sci-B-Vac™ or Engerix-B® in the deltoid muscle at 0, 4 
weeks (Study Day 28), and 24 weeks (Study Day 168), as per the current recommended HBV immunization 
schedule in adults. 
There will be a safety follow-up telephone call 7 days after each vaccination to inquire about local and 
systemic reactions. Based on these follow up assessments, subjects may be asked to come for a 
supplemental visit for clinical assessment if warranted. 
Immunogenicity (measurement of anti-HBs, pre S1 and pre S2 antibody levels and characteristics) will be 
assessed at baseline and on Study Days 28, 56, 168, 196, and 336. Immunogenicity will be evaluated using 
a validated quantitative antibody test against HBsAg. Anti pre-S1 and anti pre-S2 investigations will be 
exploratory. 
Safety evaluations will include standardized methods for local and systemic vaccine reactions, repeated 
vital signs and physical examinations, 48-week follow-up for SAE, medically significant events or new onset 
of chronic illness (at least 24 weeks after receiving the third dose of vaccine), and changes in concomitant 
medication. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
6 | P a g e 
CONFIDENTIAL 
 
 
 
At select sites, study subjects will also participate in a clinical laboratory sub-study. All subjects enrolled 
at these sites will be asked to come for three additional visits (denoted A1, A2, A3 in Appendix 2 Schedule 
of Events) 1 week after each vaccination, and to provide 4 additional blood samples, at V1 (Day 0) and at 
A1, A2 and A3, on Study Days 7, 35 and 175, respectively. The clinical laboratory sub-study will include at 
least 10% of the total number of subjects enrolled to the trial and will assess hematology and biochemistry 
laboratory parameters over the full three-dose vaccination schedule. From among the subjects 
participating in the clinical laboratory sub-study, ~50-75 subjects/treatment arm will be invited to enroll 
in a optional study on cell-mediated immunity. A separate consent form will be provided for the sub-study 
on cell mediated immunity. Subjects consenting to participate will be required to provide additional blood 
samples, on Study Days 0, and Study Days, 7, 28, 56, beyond those being collected for the clinical 
laboratory sub-study. 
 
3.2 Primary endpoint 
x 
Seroprotection rate 4 weeks after receiving third vaccination with either Sci-B-Vac™ or 
Engerix-B®, on Study Day 196. Seroprotection is defined as anti-,ƐůĞǀĞůƐшϭϬŵ/hͬŵ>
in serum. Seroprotection rate is the percentage (%) of subjects achieving seroprotection. 
A validated quantitative antibody test will be used to measure anti-HBs levels in serum. 
3.3 Secondary endpoints 
x 
SPR on Study Days, 56 and 168, 4 weeks and 20 weeks after receiving the second Sci-B- 
Vac™ vaccination (just prior to receiving the third vaccination), and the SPR on Study Day 
196, 4 weeks after receiving the third Engerix-B® vaccination 
x 
Number (%) of subjects-reported, solicited (on the day of vaccination and during the next 
6 days), unsolicited AE (on the day of vaccination and during the next 27 days), and 
number of Serious SAEs, medically significant events (condition prompting emergency 
room visit, physician visit not related to a common disease/not a routine visit or an SAE 
not related to a common disease) or new onset of chronic illness through Study Day 336. 
Adverse events will be classified by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term, severity, seriousness, investigator and Sponsor 
causality assessment, and time since vaccination. 
x 
Number (%) of subjects with abnormal vital signs, and/or physical examination findings 
compared to baseline. 
3.4 Exploratory endpoints 
x 
Geometric Mean Concentration (GMC) of anti-HBs in serum, in both study arms, at 
baseline and on Study Days 28, 56, and 196, 4 weeks after each vaccination with either 
Sci-B-Vac™ or Engerix-B®, and on Study Day 168 and 336. 
x 
SPR in both study arms at baseline and on Study Days 28, 56 and 168 and on Study Day 
336. 
x 
Proportion of subjects achieving anti-,ƐůĞǀĞůƐшϭϬϬŵ/hͬŵ>ŝŶƐĞƌum, in both study 
arms, on Study Days 28, 56, and 196, 4 weeks after each vaccination with either Sci-B- 
Vac™ or Engerix-B®, and on Study Day 168 and 336. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
7 | P a g e 
CONFIDENTIAL 
 
 
 
x 
Rate of non-response (defined as the proportion of subjects not attaining anti-HBs levĞůƐш
10 mIU/mL), on Study Day 196, 4 weeks after receiving the third vaccination with either 
Sci-B-Vac™ or Engerix-B®. 
x 
The GMC of anti pre-S1 antibody and anti pre-S2 antibody in serum, in both study arms, 
at baseline and on Study Days 28, 56, and 196, 4 weeks after each vaccination with Sci-B- 
Vac™ or Engerix-B® and on Study Day 168 and 336. 
x 
Number (%) of subjects with abnormal clinical laboratory parameters from baseline 
assessments on Study Days 7, 35 and 175, one week after each vaccination with either 
Sci-B-Vac™or Engerix-B®(Clinical laboratory sub-study, select sites) 
x 
Cell-mediated immunity against HBs at baseline (Study Day 0) and on Study Days 7, 35 
and 175 with either Sci-B-Vac™ or Engerix-B® (optional sub study in a subset of subjects 
participating in the clinical laboratory sub-study). 
4 STUDY ENROLLMENT AND WITHDRAWAL 
4.1 Subjects population 
dŚĞƐƚƵĚǇǁŝůůĞŶƌŽůůĂƉƉƌŽǆŝŵĂƚĞůǇϭ͕ϱϲϰƐƵďũĞĐƚƐ͕ĂŐĞшϭϴǇĞĂƌƐŽůĚ͕ŝŶΕϯϬƐƚƵĚǇĐĞŶƚĞƌƐŝŶƵƌŽƉĞ͕
Canada, and the U.S. Individuals of any gender, race and ethnic groups are eligible for this trial. 
In order to ensure that subjects in the older age group are adequately represented, since this age group 
may benefit the most from Sci-B-Vac™, common chronic conditions in aging populations such as, for 
instance, type 2 diabetes, high blood pressure, COPD, chronic arthritis, or asthma will be accepted if the 
condition is adequately controlled, as determined by the investigator. 
Adherence to inclusion and exclusion criteria is essential to ensure safety to the subjects and precise 
comparison of control and treatment groups. Deviations from inclusion and exclusion criteria are not 
allowed because they could jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Inclusion and exclusion criteria are defined below. 
4.1.1 Inclusion criteria 
Subjects must meet all the following criteria to be eligible: 
1. Any gender. 
2. ŐĞшϭϴ years. 
3. 
In stable health as determined by a physical examination and laboratory tests values. 
Common chronic conditions such as, but not limited to, type 2 diabetes, high blood pressure, 
COPD, asthma will be accepted if the condition is well controlled, as determined by the 
investigator, and not meeting the exclusion criteria. For subjects > 65 years old, Frailty Index 
чϯ17(see  Appendix 1). 
4. If female: 
either not of childbearing potential, defined as postmenopausal for at least 1 year or 
surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), 
OR 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
8 | P a g e 
CONFIDENTIAL 
 
 
 
is of childbearing potential and must agree to use an adequate birth control method 
during the screening period and until the end of her participation in the study (effective 
birth control includes: 1) hormonal (implant, oral, vaginal, transdermal) contraceptives; 
2) diaphragm with spermicide, condom (with spermicide); 3) intra-uterine devices; and 4) 
vasectomy of male partner; 5) abstinence from penile-vaginal intercourse (if the preferred 
and usual lifestyle of the subject)). 
5. Able and willing to give consent. 
4.1.2 Exclusion criteria 
Subjects meeting any of the following criteria will be excluded: 
1. Previous vaccination with any HBV vaccine (licensed or experimental). 
2. Treatment by immunosuppressant within 30 days of enrollment including but not limited to 
corticosteroids at a dose that is higher than an oral or injected physiological dose, or a 
prednisolone-equivalent dose > 20 mg /day (Inhaled and topical steroids are allowed. 
3. Known history of immunological function impairment, including but not limited to: 
a) 
autoimmune diseases (e.g., multiple sclerosis, type 1 diabetes, myasthenia gravis, 
Crohn disease and other inflammatory bowel diseases, celiac disease, systemic lupus 
erythematosus, scleroderma, including diffuse systemic form and CREST syndrome, 
systemic sclerosis, dermatomyositis polymyositis, rheumatoid arthritis, juvenile 
idiopathic arthritis, autoimmune thyroiditis -including Hashimoto thyroiditis, Grave's 
or Basedow’s disease, immune thrombocytopenic purpura, autoimmune hemolytic 
anemia, autoimmune hepatitis, psoriasis, vitiligo, vasculitis, Guillain-Barré syndrome, 
Addison’s disease, Bell’s palsy and alopecia areata); 
OR 
b) 
secondary immunodeficiency disorders (e.g. resulting from HIV/AIDS (Acquired 
Immunodeficiency Syndrome caused by Human Immunodeficiency Virus infection), 
solid organ transplant, splenectomy); 
OR 
c) 
primary immunodeficiency disorders (e.g. common variable immune deficiency 
(CVID), Defective phagocytic cell function and neutropenia syndromes, complement 
deficiency). 
4. Pregnancy or breastfeeding. 
5. Immunization with attenuated vaccines (e.g. MMR) within 4 weeks prior to enrollment. 
6. Immunization with inactivated vaccines (e.g. influenza) within 2 week prior to enrollment. 
7. Has received blood products or immunoglobulin within 90 days of enrollment or likely to 
require blood products during the study period. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
9 | P a g e 
CONFIDENTIAL 
 
 
 
8. Subject in another clinical trial with an investigational drug or a biologic within 30 days of 
enrollment. 
9. Has 
received 
granulocyte-macrophage 
colony 
stimulating 
factor 
(G/GM-CSF) 
or 
erythropoietin (EPO) within 30 days of enrollment or likely to require GM-CSF/erythropoietin 
during the study period. 
10. Any history of cancer requiring chemotherapy or radiation within 5 years of randomization or 
current disease. Subject with a history of low risk basal cell carcinoma will be accepted (low 
risk being defined by the following: 1) location on the trunk of the body, arms, legs, cheeks, 
forehead, temples, scalp, neck or chin and 2) less than 2 cm, and 3) nodular or superficial, 
and 4) primary cancer that has not come back after treatment and 5) edge of the cancerous 
area is clear and smooth and 6) not located in or around nerves). 
11. Any skin abnormality or tattoo that would limit post-vaccination injection site assessment. 
12. History of allergic reactions or anaphylactic reaction to any vaccine component (Engerix-B® or 
Sci-B-Vac™). 
13. Unwilling, or unable in the opinion of the investigator, to comply with study requirements, 
including the use of an adequate birth control method. 
14. Immediate family members of study center staff (parents, sibling, children). 
15. Current or past hepatitis B infection or prior vaccination as evidenced by HBV markers (anti- 
HBc, anti-HBs, HBsAg) at screening. 
16. Known hepatitis C infection or positive Hepatitis C serology at screening, unless treated and 
cured (defined as documented sustained virologic response (SVR) ŽƌŶĞŐĂƚŝǀĞǀŝƌĂůůŽĂĚш 12 
weeks after cessation of antiviral therapy). 
17. Known human immunodeficiency virus (HIV) infection or positive HIV serology at screening. 
18. Renal impairment with Glomerular Filtration Rate (GFR) <60 mL/min/1.73 m2 at screening. 
19. Uncontrolled diabetes mellitus (defined as HbA1C >8.5%). 
20. hŶĐŽŶƚƌŽůůĞĚŚǇƉĞƌƚĞŶƐŝŽŶ;ĚĞĨŝŶĞĚĂƐĂŶĂǀĞƌĂŐĞ^WшϭϱϬŵŵ,ŐŽƌĂŶĂǀĞƌĂŐĞWшϵϱ
mmHg based on the last three measurements in people diagnosed and treated for 
hypertension, and in people without a diagnosis of hypertension). 
21. Any laboratory test abnormality that would be considered of Grade 1 severity or above as per 
Appendix 4 and is considered as clinically significant by the investigator. Grade 3 severity or 
above is exclusionary, regardless of clinical assessment. 
22. Diagnosis of advanced stage heart failure (New York Heart Association (NYHA) class III or IV – 
see Appendix 5) or Unstable Angina 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
10 | P a g e 
CONFIDENTIAL 
 
 
 
4.2 Enrollment procedures 
Eligible subjects must be informed of the study, including the schedule of visits, the required evaluations, 
the risks, the alternative options, and all the regulatory aspects of consent. Written consent must be 
obtained prior to the conduct of any study-related activity. Consenting subjects will be informed that the 
study site staff will provide them with their serology results at the end of the study, after the database 
has been locked. Eligible subjects will also be asked to provide their consent to have their blood samples 
de-identified and securely stored and used for future research (bio banking) by the sponsor after the study 
is completed and the blood samples are no longer required for validation studies. De-identification is the 
process by which a coded sample is relabeled with a unique second code, as an added step to preserve 
confidentiality, with limited and restricted access to the list linking the codes. Lack of consent to the bio 
banking of blood samples will not preclude participation in the main study. 
At select study sites, study subjects will also participate in a clinical laboratory sub-study. All subjects 
enrolled at these select sites will be asked to come for three additional visits (A1, A2, A3) and to provide 
four additional blood samples, beyond those required for the main study. Blood samples for the clinical 
laboratory sub-study will be collected at V1 (Study Day 0) and one week after each vaccination, at A1 
(Study Day 7), A2 (Study Day 35) and A3 ( Study Day 175). A small subset of subjects participating in the 
laboratory sub-study will be invited to participate in an optional sub-study on cell-mediated immunity. 
Subjects consenting to the cell-mediated sub-study will be required to provide an additional blood sample 
at V1 (study Day 0) and at each of the additional visits (A1, A2, A3). Lack of consent to the optional sub- 
study on cell mediated immunity will not preclude participation in the main study or the clinical laboratory 
sub-study. . 
Assessments to confirm eligibility should be completed within 4 weeks of the first vaccination visit on 
Study Day 0. 
To complete enrollment, an investigator will confirm eligibility criteria, and a member of the study center 
staff will complete the protocol-specific eligibility checklist in the interactive web response system (IWRS). 
Access to the IWRS randomization page will be through individual login and password. 
The authorized staff will be prompted to complete the enrolment page in the IWRS including the subject’s 
age and other demographic data, and to confirm individually the presence of all inclusion criteria and the 
absence of all exclusion criteria. 
Upon confirmation that all inclusion criteria and no exclusion criteria are met, the subject will be 
randomized to one of the two study arms. A confirmation of the randomization (blinded) and the study 
ID will be sent by E-mail to the site. The confirmation of enrolment should be retained in the study files. 
The dedicated unblinded site staff and/or pharmacy (if applicable) will receive a notification, which must 
be filed in a locked area/computer folder not accessed by the blinded center staff. 
4.3 Subject withdrawal 
Subjects who are withdrawn because of SAEs/AEs must be clearly distinguished from subjects who are 
withdrawn for other reasons. Investigators will follow subjects who are withdrawn as result of a SAE/AE 
until resolution or stabilization of the event and will assess, record, and report AEs and SAEs as instructed 
in Section 7 (ASSESSMENT OF SAFETY). 
Withdrawals for any reasons will not be replaced. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
11 | P a g e 
CONFIDENTIAL 
 
 
 
4.3.1 Subject withdrawal from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did not come back 
for the concluding visit (V6) /was not available for the concluding contact foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has occurred, no follow- 
up has been performed and no further information has been collected for this subject from the date of 
withdrawal/last contact. 
Research center staff will make diligent attempts to contact those subjects who do not return for 
scheduled visits or follow-up. Attempts will be documented in source documents. A registered letter will 
be sent after four unsuccessful attempts to contact a subject by telephone. If unsuccessful, the subject 
will be considered lost to follow-up and withdrawn from the study. In order to mitigate the risk of subject 
lost to follow-up, research center staff will obtain any relevant contact details, including, when allowed 
by applicable privacy and patients’ rights laws and institutional policies, alternate contact information for 
relatives or relevant third parties (as determined by the subject) upon enrollment of the subject in the 
study. Study center staff will inquire about changes at each visit. Information will be collected and stored 
in compliance with all applicable privacy and patients’ rights laws, and institutional policies. 
Information relevant to the withdrawal will be recorded in the electronic case report form (eCRF). The 
investigator will document whether the decision to withdraw a subject from the study was made by the 
subject or by the investigator, as well as which of the following possible reasons was responsible for 
withdrawal: 
x 
SAE 
x 
Non-serious AE 
x 
Major Protocol violation warranting withdrawal of the subject from the study, after 
consultation with the medical monitor (specify) 
x 
Consent withdrawal, not due to an AE* (specify) 
x 
Moved from the study area 
x 
Lost to follow-up 
x 
Request of regulatory agency, or Sponsor or Principal Investigator 
x 
Subject is non-compliant with study procedures/study protocol 
x 
Investigator decides that withdrawal from the study is in the best interest of the subject 
x 
Any clinically significant change in subject’s medical condition. 
x 
Pregnancy 
x 
Other (specify) 
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the investigator 
will document the reason for withdrawal of consent, if specified by the subject, in the eCRF. 
4.3.2 Subject withdrawal from investigational product 
A ‘withdrawal’ from the investigational product refers to any subject who does not receive the complete 
treatment, i.e., when no further planned dose is administered from the date of withdrawal. A subject 
withdrawn from the investigational product may not necessarily be withdrawn from the study as further 
study procedures or follow-up may be performed (safety or immunogenicity) if planned in the study 
protocol. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
12 | P a g e 
CONFIDENTIAL 
 
 
 
Information relevant to premature discontinuation of the investigational product will be documented on 
the End of Study Visit (V6) screen of the eCRF. The investigator will document whether the decision to 
discontinue further injection/treatment was made by the subject or by the investigator, as well as which 
of the following possible reasons was responsible for withdrawal: 
x 
SAE 
x 
Non-serious AE 
x 
Pregnancy 
x 
Other (e.g. subject found to have received a concomitant medication not permitted on study that 
required withdrawal from the investigational product, based on consultation with the medical 
monitor) 
4.4 Termination of study or suspension of study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to the investigator, the study sponsor, and regulatory authorities. 
If the study is prematurely terminated or suspended, the investigator will promptly inform the relevant 
ethical body (see Section 13.1) and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to subjects 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, or data quality are addressed and 
satisfy the study sponsor, the relevant ethical bodies, and all regulatory authorities. 
Otherwise, the execution of the study will close after the last complete assessment of all the subjects. 
Laboratory measures, subsequent planned laboratory measures, data management and analysis will 
continue until final statistical report of the trial results. 
This trial will be conducted in compliance with the protocol, good clinical practice (GCP) and the applicable 
regulatory requirements. 
5 STUDY AGENTS 
Study agents ordering, shipping, receiving, storage and handling is detailed in the pharmacy manual. 
5.1 Sci-B-Vac™ 
5.1.1 Acquisition 
Sci-B-Vac™ will be supplied by study sponsor. 
5.1.2 Formulation and labelling 
Sci-B-Vac™ will be supplied 1 mL single-dose vials. 
Each 1.0 mL single-dose vial contains 10 ʅŐ of hepatitis B surface antigens adsorbed on 0.5 mg aluminum 
as aluminum hydroxide , sodium chloride, potassium chloride, disodium hydrogen phosphate 
dodecahydrate, potassium dihydrogen phosphate anhydrous and water for injection. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
13 | P a g e 
CONFIDENTIAL 
 
 
 
Vials and secondary packaging will be labeled as required by applicable regulations (including the use of 
the appropriate official language(s)). 
5.1.3 Product storage 
Sci-B-Vac™ should be stored at 2-8qC (36°and 46°F). 
5.2 Comparator: Engerix B 
5.2.1 Acquisition 
Engerix-B® will be purchased from commercial source(s) and supplied by study sponsor. 
5.2.2 Formulation and labelling 
For the study, Engerix-B® will be provided as 1 mL vials. 
Each 1-mL adult dose contains 20 Pg of HBsAg adsorbed on 0.5 mg aluminum as aluminum hydroxide. 
Vials and secondary packaging will be labeled as required by applicable regulations (including the use of 
the appropriate official language(s)). 
5.2.3 Product storage 
ENGERIX®-B (hepatitis B vaccine recombinant) should be stored at 2 to 8°C (36° and 46°F). 
5.3 Dosage, preparation administration of study vaccines 
This is a double-blind study. On the day study subjects are dosed, vaccine vials will be removed from the 
refrigerator. The treatment each subject will receive will be allocated by an IWRS tool. The unblinded 
study center staff/pharmacy staff will select the appropriate vial. The vial will be transported to the 
administration site by unblinded study center staff as outlined in the pharmacy manual. Vaccine vials not 
utilized on a vaccination administration day (i.e., Study Day 0, 28, or 168) will be destroyed and 
documented as per study center policy following verification of product accountability (see Section 5.5). 
Study vaccine will be administered by unblinded qualified health personnel, whose sole role is to prepare 
and administer the allocated study vaccine and to perform activities requiring vial handling. Preparation 
of the study vaccine must be done by the unblinded study center staff/pharmacy staff behind a screen or 
in a separate room from where blinded research staff and study participants will be located. The 
unblinded study center staff will thoroughly mix all study vaccines by swirling the vial for 30 seconds 
immediately before administration. The study vaccines should be visually inspected for discoloration prior 
to administration. The study vaccine should not be used if the vaccine appears discolored. After visual 
inspection a syringe will be used to withdraw the vaccine from the vial and then it will be covered and 
immediately administered to the subject. The needle length used for the vaccine administration must be 
adjusted to the subjects BMI to ensure intramuscular administration and to avoid subcutaneous vaccine 
leakage. The unblinded health personnel will have no other role in the study and will not communicate 
what vaccine was administered to the subject or study centre staff performing the outcome 
measurements. As such, subjects and all study personnel will not be aware of treatment assignment. 
The first injection will be given in the deltoid of the non-dominant arm using the IM route by the unblinded 
health personnel. Subsequent injections will be administered IM in the deltoid but will be alternated 
between the non-dominant and dominant arms. The injection site will be recorded at each vaccination. 
The study vaccine should be administered immediately after withdrawing the 1-mL dose of vaccine from 
the single-dose vial. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
14 | P a g e 
CONFIDENTIAL 
 
 
 
5.4 Accountability procedures for the study vaccines 
The site investigator is responsible for ensuring that all study vaccines received at the center are 
inventoried and accounted for throughout the study. Site staff must not combine contents of the study 
vaccine containers. 
Study vaccine must be handled in strict accordance with the protocol and the container label and will be 
stored in a limited access area under appropriate environmental conditions as outlined in the pharmacy 
manual. 
Study vaccine will be administered at the study center by qualified health personnel. Study vaccines will 
be supplied only to subjects participating in the study. Study vaccines may not be relabeled or reassigned 
for use by other subjects. The investigator agrees to ensure appropriate storage requirements and 
product accountability and to administer the study vaccine only at the centers agreed upon with the study 
sponsor. 
5.5 Destruction of unused products 
As outlined in the pharmacy manual, all empty vials will be destroyed and documented as per study center 
policy following verification of product accountability by the unblinded Clinical Research Associate (CRA). 
If a vial is compromised, such as unreadable label or presence of particles in the study product, the study 
sponsor should be notified immediately. The vial should be photographed, if possible, and placed in a 
labelled container. Following verification and product accountability by the unblinded CRA, all 
compromised vials will be destroyed and documented as per study center policy. At the end of the study 
all unused products will also be destroyed and documented as per study center policy, following 
verification and product accountability by the unblinded CRA. 
5.6 Rescue medications, treatments, and procedures 
5.6.1 Safety Follow-up and management of reactions to vaccines 
The following safety observation procedures will be performed immediately following vaccination with 
the study vaccine and during the 4 weeks following vaccine visits for all subjects: 
x 
Subjects will remain in the clinic for at least 30 minutes post vaccination. The observation period 
will include an assessment for rare adverse reactions. 
x 
Any unusual signs or symptoms reported during the initial 30 minutes of observation will prompt 
continued close monitoring. 
x 
Based on their condition, subjects may be asked to remain in the clinic for more than 30 minutes 
after the vaccination (reason will be recorded in source data). 
x 
All data (including assessment of solicited local and systemic reactions) will be recorded in the 
source document during and after the post-observation period. 
During the vaccination visits, subjects will be given 28-day diary cards. A measurement device template 
(in mm) for measuring solicited local reactions (erythema [redness] and swelling), and an oral 
thermometer for recording daily temperature (in ºC or in ºF) will be provided at the first vaccination at 
visit V1 (Study Day 0). 
Subjects will be contacted by study center staff over the telephone 7 days (+/- 2 days) after each 
vaccination visit to inquire about local or systemic adverse reactions and may be asked to come to the 
clinic for a clinical assessment, if warranted. Subjects will be advised to record their temperature daily in 
the diary, on the day of vaccination and for the next six days. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
15 | P a g e 
CONFIDENTIAL 
 
 
 
Refer to Sections 6.1.10 and 7 for further details on the recording, assessment, and reporting of AE and/or 
local and systemic reactions. 
5.6.2 Management of non-responders 
After the database has been locked individual serology results will be communicated to the study sites 
and subjects will be informed of their results by the study site staff. Study subjects that are found not to 
be seroprotected (anti-HBs levels < 10mIU/mL in serum) after completing the three-dose regimen of the 
study vaccine will be offered re-immunization with Engerix-B® according to local guidelines. Engerix-B® 
will be supplied by the study sponsor. 
6 STUDY PROCEDURES 
6.1 Detailed description 
6.1.1 Informed consent 
The signed informed consent must be obtained before conducting any study-related activity. 
6.1.2 Check inclusion and exclusion criteria 
Verification of eligibility must be completed by the investigator or qualified designee prior to 
randomization. Prior to vaccine administration on Study Days 0, 28, and 168, eligibility for vaccine 
administration and continued participation in the study must be verified by the investigator or qualified 
designee. 
6.1.3 Collect demographic data 
Record demographic data such as age, gender at birth, race, ethnicity, height, weight, smoking history, 
tobacco use and average daily alcohol consumption in the subject’s eCRF. Height (inches or cm) and 
weight (pounds or kg) will be measured at screening for automatic calculation of body mass index and 
GFR. 
The age at randomization will be required to randomize the subjects according to their age at enrollment 
(i.e., 18-44 years , 45-ϲϰǇĞĂƌƐŽƌшϲϱǇĞĂƌƐ ). 
6.1.4 Medical history 
Obtain the subject’s medical history by interview and/or review of the subject’s medical records and 
record any pre-existing conditions or signs and/or symptoms present in a subject prior to the first study 
injection in the eCRF. 
6.1.5 Physical examination 
Full physicals will be done at the screening visit or at Study Day 0 (Visit 1) prior to injection; history- 
directed physical examination can be completed at subsequent visits. If the investigator determines that 
the subject’s health on the day of vaccination temporarily precludes injection, the visit will be rescheduled 
within the allowed interval for the visit. Collected information will be recorded in the eCRF. 
6.1.6 Vital signs 
Oral temperature, blood pressure (systolic/diastolic), heart rate, and respiratory rate will be assessed at 
baseline and at each vaccination visit and recorded in the eCRF. Any abnormal vital sign after injection 
should be reassessed. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
16 | P a g e 
CONFIDENTIAL 
 
 
 
The oral body temperature of all subjects will be measured prior to any study product administration. 
The subject should be instructed to refrain from eating or drinking 30 minutes prior to obtaining the 
ƚĞŵƉĞƌĂƚƵƌĞ͘/ĨƚŚĞƐƵďũĞĐƚŚĂƐĂĨĞǀĞƌ;ĚĞĨŝŶĞĚĂƐƚĞŵƉĞƌĂƚƵƌĞшϯϴ͘0°C/100.4°F oral) on the day of 
injection, the vaccination visit will be rescheduled within the allowed interval for the visit. 
6.1.7 Treatment allocation 
Treatment allocation will be done through IWRS. Access to the IWRS will be through individual login and 
password. To enroll a new subject, the authorized staff at the site will be prompted to complete a 
randomization page including the subject’s age, and other demographic information and to confirm 
individually the presence of all inclusion criteria, and the absence of all exclusion criteria. Upon 
confirmation that all inclusion criteria and no exclusion criteria are met the subject will be randomized. 
Blinded confirmation of the randomization will be sent by E-mail to the site and should be retained in the 
study files. The site pharmacy and/or unblinded study center staff will receive a notification, which must 
be filled in a locked area/computer folder not accessible by blinded study center staff. 
6.1.8 Study product administration 
After completing all prerequisite procedures prior to vaccination, one dose of study vaccine will be 
administered IM in the deltoid of the non-dominant arm. Subsequent injections will be administered IM 
in the deltoid but will be alternated between dominant and non-dominant arms. The site of injection will 
be recorded at each vaccination visit. Reasons for subject refusal for site rotation will be documented in 
the eCRF. If the investigator or qualified designee determines that the subject’s health on the day of 
administration temporarily precludes administration, the visit will be rescheduled within the allowed 
interval for this visit. 
Subjects will be observed for 30 minutes following the administration of their injection for rare adverse 
reactions. Appropriate medical treatment will be readily available in case of anaphylaxis. 
6.1.9 Check and Record Concomitant Medication and Intercurrent Medical Conditions 
Concomitant medication, including administration of a vaccine, must be checked and recorded in the 
eCRF. 
The use of the following concomitant medications/products/vaccines will not require withdrawal of the 
participant from the study but may determine a subject’s evaluability in the per protocol set analysis. 
Subsequent study vaccinations in a subject that is found to have received any of the following concomitant 
medications/products/vaccines will be determined on an individual basis, after consultation with the 
medical monitor. 
x 
Any investigational or non-registered product (drug or vaccine) other than the study product(s) 
used during the study period 
x 
Any inactivated vaccine received 2 weeks prior to 2 weeks after a study vaccination. 
x 
Any attenuated vaccine received 4 weeks prior to 4 weeks after a study vaccination. 
x 
Immunosuppressant corticosteroids > 20mg/day prednisolone equivalent administered during 
the study 
x 
Blood products, immunoglobulin, or GMCSF/EPO received during the study 
 
Intercurrent medical conditions must be checked and recorded in the eCRF. Subjects may be eliminated 
from the per protocol set for immunogenicity if, during the study, they incur a condition that has the 
capability of altering their immune response or if they become diagnosed with an immunological disorder. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
17 | P a g e 
CONFIDENTIAL 
 
 
 
 
 
6.1.10 Recording of adverse events 
x 
The subjects will be instructed to contact the investigator/study center staff immediately should 
they manifest any signs or symptoms they perceive as significant. 
x 
During the vaccination visits (on Study Days 0, 28, and 168), the subject will be provided 28-day 
diary cards. On Study Day 0 they will also be provide with a measurement device template (in 
mm) for measuring the largest diameter of solicited local reactions (erythema [redness], swelling), 
and an oral thermometer for recording daily temperature (in ºC or in ºF) on the day of vaccination 
and for the next 6 days. 
x 
Subjects will be asked to record daily the maximum pain, tenderness and pruritus [itchiness] they 
experience at the injection site on a scale from 0 to 3 (0: no pain 1: Mild discomfort to touch 2: 
Discomfort with movement 3: Significant discomfort at rest) on the day of vaccination and for the 
next 6 days. 
x 
The subject will record body temperature (oral) and any local/systemic AEs (i.e., on the day of 
vaccination and during the next 6 days) or any solicited or unsolicited AEs (i.e., on the day of 
vaccination and during the next 27 days occurring after injection) on the 28-day diary card. The 
study center will contact the subject 7 days (+/-2 days) after each vaccination to assess subject 
status and to remind the subject to complete the diary cards and return them at the next study 
visit. 
 
x 
The subject will be: 
x 
Trained on how to complete the diary. 
x 
Requested to record their individual data in their diary cards, as described above. 
x 
Asked to provide a telephone contact, so the study center staff can contact them for the 
safety follow-up 7 days (+/- 2 days) after each vaccination. 
x 
Advised that they will be asked about the occurrence of any symptoms or events requiring 
medical attention (i.e., requiring a doctor or emergency room visit) and the use of 
concomitant medication up to Study Day 336. 
x 
Instructed to bring their diary cards to clinic visit on Study Days 28, 56, and 196 as follows: 
the diary card provided on Study Day 0 will be collected on Study Day 28; the diary card 
provided on day 28 will be collected on Study Day 56, and the diary card provided on day 
168 will be collected on Study Day 196. The staff will review the diary cards entries with the 
subject. 
x 
Advised on how to contact study center staff. Subjects will be advised to immediately 
contact the investigator (or his/her designee) in the event of a SAE or change in health. 
x 
Informed to notify their health care professional(s) (e.g., primary care physician) that they 
are participating in a clinical research study of HBV vaccine. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
18 | P a g e 
CONFIDENTIAL 
 
 
 
x 
Be informed of the appointments (date and time) for the next planned visits to the study 
center (Study Days 28, 56, 168, 196, and 336). At select sites, subjects will also be required 
to come for 3 additional visits one week after each vaccination (Study Days 7, 35 and 175) 
to provide a blood sample for the clinical laboratory sub-study. 
x 
Any unreturned diary cards will be sought from the subject through telephone call(s) or any 
other convenient procedure. 
Diary cards will be available in all official languages of participating countries. The investigator/study 
center staff will transcribe the collected information into the eCRF in English. AEs from the diary card 
transcribed to English from another language will be verified for accuracy during the site monitoring visit. 
x 
Diary cards are considered source documents. 
6.2 Laboratory evaluations 
6.2.1 Urine pregnancy test 
In females of childbearing potential urine pregnancy tests must be confirmed negative at screening, and 
prior to study vaccines administration on Study Days 0, 28, and 168. A confirmatory serum pregnancy test 
will be required in the event of a positive urine pregnancy test. A positive serum pregnancy test will result 
in withdrawal of the subject from the study (per Section 4.3.1). A negative serum pregnancy test will 
permit the subject to continue on the study and to continue to receive the study vaccines. In women 
whose urine pregnancy tests is positive, no study vaccine will be administered until the confirmatory 
serum pregnancy tests is found to be negative. 
6.2.2 Screening laboratory evaluations 
The following laboratory evaluations will be done at screening: 
x 
All potential subjects will be tested for HIV infection, HCV infection and past or current HBV 
infection prior to enrollment. A positive test is exclusionary, except in the case of HCV, if the 
subject was treated and cured (defined as documented sustained virologic response (SVR) or 
ŶĞŐĂƚŝǀĞǀŝƌĂůůŽĂĚшϭϮǁĞĞŬƐĂĨƚĞƌĐĞƐƐĂƚŝŽŶŽĨĂŶƚŝǀŝƌĂů therapy). 
x 
Hematology 
o White blood cell count with differential 
o Red blood cell count 
o Hematocrit (HCT) 
o Mean cell hemoglobin (MCH) 
o Mean cell hemoglobin concentration (MCHC) 
o Mean corpuscular volume (MCV) 
o Hemoglobin 
o Platelet count 
x 
Biochemistry: 
o Blood urea nitrogen (BUN) 
o Serum creatinine 
x 
GFR: will be automatically calculated upon input of serum creatinine value, age, gender and 
weight in the eCRF using the CKD-EPI Creatinine Equation (2009)25 
 
'&ZчϲϬŵ>ͬŵŝŶͬϭ͘ϳϯŵ2 is exclusionary 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
19 | P a g e 
CONFIDENTIAL 
 
 
 
o Alkaline phosphatase (AP), alanine transaminase (ALT: SGPT), aspartate transaminase 
(AST: SGOT), total and conjugated bilirubin, gamma-glutamyl-transferase (GGT) 
o HbA1C will be tested in subjects with a known type 2 diabetes if a previous HbA1C test 
result is unavailable and/or is > 3 months old, in order to verify that diabetes is 
controlled. HbA1C >8.5 % is exclusionary. 
x 
Urinalysis: 
o A urine sample will be tested for: pH, gravity, glucose, ketones, nitrites, bilirubin 
urobilirubin, blood, protein, red blood cell count, white cell count. 
Any anomaly that would be considered of Grade 1 severity (or more) according to Appendix 4 will be 
interpreted within the subject’s specific context (subject’s medical history, physical examination, other 
laboratory tests) by the investigator to determine whether the subject still meets inclusion criterion # 3. 
Grade 3 severity or above is exclusionary, regardless of clinical assessment. One repeat testing 
assessment will be permitted. 
6.2.3 Immunogenicity 
Immunogenicity (measurement of anti-HBs, anti pre-S1 and anti pre-S2 levels and characteristics) will be 
assessed at baseline (V1), on Study Days 28 (V2), 56 (V3), 168(V4), 196 (V5), and on Study Day 336 (End of 
Study Visit – V6) in all subjects. 
A validated quantitative antibody test will be utilized to measure anti-HBs levels in serum. 
The assay to measure anti pre-S1 antibody and anti pre-S2 antibody is currently under development and 
will be validated prior to its use in the phase 3 trial. 
In study subjects that have agreed for their unused blood samples to be used for future research by the 
study sponsor (bio banking), de-identified frozen serum aliquots will be stored in a secure biorepository 
held by the study sponsor for future use. De-identification is the process by which a coded sample is 
relabeled with a unique second code, as an added step to preserve confidentiality, with limited and 
restricted access to the list linking the codes. No genetic testing will be performed. 
6.2.4 Sub-Studies 
6.2.4.1 
Clinical laboratory sub-study 
At select study sites, clinical laboratory parameters (hematology, biochemistry) will be assessed one week 
after each vaccination with either Sci-B-Vac or Engerix-B® and compared to baseline (pre-vaccination) 
values, as part of a clinical laboratory sub-study. All subjects enrolled at these select sites will be required 
to come for three additional visits and to provide four additional blood samples, beyond those required 
for the main study. The clinical laboratory sub-study will include at least 10% of all subjects enrolled to 
the entire trial. 
Blood samples for the clinical laboratory sub-study will be collected at baseline (Day 0, Visit 1) prior to 
receiving any study vaccine, and at each of the three additional visits (additional visits A1, A2 and A3 in 
Appendix 2 Schedule of Events), to be scheduled 1 week after each vaccination with Sci-B-Vac™or Engerix- 
B® on Study Day 7 (-3/+7 days), Study Day 35 (-3/+7 days) and Study Day 175 (-3/+7 days), respectively.The 
following clinical laboratory parameters will be evaluated: 
x 
Hematology 
o White blood cell count with differential 
o Red blood cell count 
o Hematocrit (HCT) 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
20 | P a g e 
CONFIDENTIAL 
 
 
 
o Mean cell hemoglobin (MCH) 
o Mean cell hemoglobin concentration (MCHC) 
o Mean corpuscular volume (MCV) 
o Hemoglobin 
o Platelet count 
x 
Biochemistry: 
o Blood urea nitrogen (BUN), serum creatinine. 
o Alkaline phosphatase (AP), alanine transaminase (ALT), aspartate transaminase (AST), 
total and conjugated bilirubin, gamma-glutamyl-transferase (GGT) 
 
Safety laboratory evaluations may be repeated if indicated (e.g. follow-up of a clinically significant 
laboratory abnormality (from baseline assessment)) 
 
6.2.4.2 
Optional sub study of cell-mediated immunity directed against HBs 
Cell-mediated immunity directed against HBs and related mechanistic studies will also be studied on a 
small subset of subjects (~50-75 subjects/treatment arm), recruited from among the subjects participating 
in the clinical laboratory sub-study (see 6.2.4.1 above). Participation in the sub-study of cell-mediated 
immunity is optional, and will require a separate consent. 
Subjects who agree to participate in the sub-study of cell-mediated immunity will be asked to provide 4 
additional blood samples, beyond those required for the clinical laboratory sub-study, at V1 (Study Day 0) 
prior to vaccination and at each of three additional visits (A1, A2, A3) 1 week after each vaccination with 
either Sci-B-Vac™ or Engerix-B® (Study Days 7, 35, 175). 
Lack of participation in the optional sub-study of cell-mediated immunity will not preclude participation 
the clinical laboratory sub-study or the main study. 
6.2.5 Biological samples handling, analysis and storage 
For the main study, the total amount of blood will not exceed 15 mL at any given visit. For select sites 
participating in the clinical laboratory sub-study, an additional 10 mL of blood will be required at V1 (Study 
Day 0) and at each of the additional study visits (A1, A2, A3) on Study Days 7, 35, and 175, respectively. 
For the clinical laboratory sub-study participants who also consent to participate in the optional sub-study 
of cell-mediated immunity, an additional 40 mL will be required at V1 (Study Day 0) and at each of the 
additional study visits (A1, A2, A3) on Study Days 7, 35, and 175, respectively. 
Samples and accompanying documentation will not be labeled with information that directly identifies 
the subject but will be coded with the identification number for the subject (subject number). 
Unused blood samples will be stored until the Sci-B-Vac™ has been approved, for confirmation purposes 
only, for a maximum of 60 months (5 years) after the study has been completed. No genetic testing will 
be performed. 
 
Study subjects will be offered the possibility to donate any unused stored blood samples for use in 
future research projects in HBV testing and vaccine development. De-identified bio banked frozen serum 
aliquots from consenting study subjects will be stored in a secure biorepository held by the study 
sponsor for future research. No genetic testing will be performed. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
21 | P a g e 
CONFIDENTIAL 
 
 
 
If the study subject does not agree to donate unused stored blood samples, they will not be used in other 
research projects and they will be destroyed once the vaccine is approved in Canada, the U.S. and Europe 
or after a maximum period of 5 years after the end of the study, whichever comes first. 
Detailed information on biological sample handling and analysis is provided in the laboratory manual. 
6.3 Study schedule of events 
A schedule of events is available in Appendix 2. 
6.3.1 Screening 
The screening will be conducted within 28 days (4 weeks) of Visit 1. After obtaining informed consent in 
accordance with ICH GCPs, inclusion/exclusion criteria will be assessed and the following data/samples 
will be obtained: 
x 
Medical History/ Demographics 
x 
Physical Examination (or at Visit 1 prior to injection) 
x 
Height and weight 
x 
Concomitant medications 
x 
Urine Pregnancy test (in females of childbearing potential) 
x 
Blood sampling for screening hematology, blood chemistry and serology tests (HIV, 
Hepatitis C and B) 
x 
Urinalysis 
If the subject is eligible, the study staff will proceed to complete the enrollment procedures and to 
schedule the first vaccination visit. Study subjects will be requested not have any inactivated vaccines (e.g. 
influenza) 2 weeks prior to 2 weeks after each study vaccination and not to have attenuated vaccines (e.g. 
MMR) 4 weeks prior to 4 weeks after each study vaccination. 
6.3.2 Vaccination visits 
Vaccination will be done at Visit 1, 2 and 4 (Study Day 0, Study day 28 (-3 days/+7 days), and Study day 
168 (+/- 7 days, respectively). 
On Day 0 (Visit 1), subjects will have a blood sample collection prior to vaccine administration. 
At subsequent vaccination visits (on Study Days 28 and 168), and prior to study vaccine administration, 
there will be a review of ongoing eligibility to receive the study vaccine and continue on the study. Diary 
cards will be collected (Study Day 28) and there will be a review of any local and systemic reactions. There 
will also be a blood sample collection prior to each vaccine administration. 
Subject will remain at least 30 minutes after each vaccination to be observed for rare adverse reactions. 
At each vaccination visit the following will be done: 
x 
Concomitant medications will be recorded, including other vaccines. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
22 | P a g e 
CONFIDENTIAL 
 
 
 
x 
A urine pregnancy test will be done in females of childbearing potential and reviewed prior 
to vaccination. Pregnancy test must be confirmed negative prior to study vaccine 
administration. 
x 
Blood samples for Immunogenicity tests (measurement of anti-HBs, anti pre-S1 and anti 
pre-S2 levels and characteristics), on Study Day 0, Study Day 28 and Study Day 168 will be 
taken, prior to vaccination. 
x 
Blood samples for assessment of clinical laboratory parameters will be taken on Study Day 
0, prior to vaccination (select sites). 
x 
Vital signs will be assessed before and after the injection of study vaccine. Any abnormal 
vital sign after injection should be reassessed. 
x 
Physical/History-directed physical examination will be done. 
x 
Eligibility for receiving treatment will be reviewed by the investigator. 
x 
Study vaccine will be administered. 
x 
Subject will be monitored for 30 minutes after the injection. 
x 
A diary card will be provided at each vaccination visit. In addition, at Visit 2 (Study Day 28), 
the diary card provided at Visit 1 will be collected and reviewed. Adverse events will be 
recorded in the eCRF. 
x 
The next visit will be scheduled. 
x 
Subjects will be reminded that they should return the diary card at the next visit and that 
they should not receive any inactivated vaccine 2 weeks prior to or 2 weeks following the 
first, second or third vaccination. Subjects will also be reminded not to have an attenuated 
vaccine between V1 (Study Day 0) and V2 (Study Day 28), or for 4 weeks after V2 or within 
4 weeks of the third vaccination on V4 (Study Day 168). 
6.3.3 Safety follow-up 
The study center will contact the subject by telephone 7 days (+/- 2 days) after each vaccination to assess 
subject’s status and to remind the subject to complete the diary cards and return them at their next study 
visit. A scripted set of questions will be asked over the telephone to determine health status and safety 
clinical markers. 
6.3.4 Supplemental visit(s) 
Subjects may be asked to come for a supplemental visit for clinical assessment of an adverse event if 
warranted, as determined by the investigator. The supplemental visit will be recorded in the eCRF. 
6.3.5 Immunogenicity visits 
Additional immunogenicity visits will be scheduled on V3 Study Day 56 (-3/+7 days) and V5 Study Day 196 
(+/-7 days). At these clinical visits, the following will also be done: 
x 
Physical/History-directed physical examination. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
23 | P a g e 
CONFIDENTIAL 
 
 
 
x 
Blood samples for measurement of anti-HBs, anti pre-S1 and anti pre-S2 levels and 
characteristics will be taken on Study Day 56 and Study Day 196. 
x 
V3 should be scheduled at least 3 weeks after V2 
x 
Diary card provided at the previous vaccination visit will be reviewed. 
x 
Adverse events and the use of concomitant medications will be recorded in the eCRF. 
x 
The next visit will be scheduled. 
x 
At V3 (on day 56) subjects will be reminded that they should not receive inactivated vaccines 
2 weeks prior or attenuated vaccines 4 weeks prior to the next vaccination at V4 (on Study 
Day 168). 
x 
V5 should be scheduled at least 3 weeks after V4 
6.3.6 Sub-study additional visits 
At select sites, study subjects will also participate in a clinical laboratory sub-study. All subjects enrolled 
at these sites will be asked to come for three additional visits (denoted A1, A2, A3 in Appendix 2 Schedule 
of Events) beyond those required for the main study and to provide 4 additional blood samples, at V1 
(Study Day 0) and at A1, A2 and A3, on Study Day 7 (-3/+7 days), Study Day 35 (-3/+7 days) and Study Day 
175 (-3/+7 days), respectively. These blood samples will be used to investigate and compare clinical 
laboratory parameters (hematology, biochemistry) following vaccination with Sci-B-Vac™ and Engerix-B®. 
Subjects recruited from the clinical laboratory sub-study to participate in the optional sub-study of the 
cell-mediated immune response, will be asked to provide an additional blood sample on Study Day 0 (Visit 
1) and at A1, A2 and A3 on Study Day 7 (- 3/+7 days) and Study Day 35 (-3/+7 days) and Study Day 175 (- 
3/+7 days) to investigate and compare cell-mediated immune response following vaccination with either 
Sci-B-Vac™ or Engerix-B®. 
6.3.7 End of study visit 
The end of study visit will be performed on Study Day 336 (+/-14 days) or earlier in case of withdrawal. 
x 
Physical/History-directed physical examination. 
x 
Blood samples for measurement of anti-HBs, anti pre-S1, and anti pre-S2 levels and 
characteristics will be taken. 
x 
SAE, AE requiring medical attention and the use of concomitant medications will be 
recorded in the eCRF 
x 
In case of withdrawal: reason for withdrawal will be documented in the eCRF 
x 
Subject will be advised that the study center staff may need to contact them in case new 
information, such as lack of seroprotection (anti-HBs levels <10 mIU/mL), becomes 
available. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
24 | P a g e 
CONFIDENTIAL 
 
 
 
7 ASSESSMENT OF SAFETY 
7.1 Specification of safety parameters 
7.1.1 Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have to have a causal relationship 
with this treatment. 
An AE can therefore be: 
භ 
Any unfavorable and unintended sign (including an abnormal laboratory finding); 
භ 
Symptom or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product; 
භ 
Preexisting symptoms or conditions which worsen during a study. 
7.1.2 Serious Adverse Events 
A Serious Adverse Event (SAE): 
භ 
Results in death 
භ 
Is life threatening 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, had it been more severe. 
භ 
Requires subject hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the subject has been admitted at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in the physician’s office or 
in an out-patient setting. Hospitalizations for routine procedures and investigations are not considered a 
SAE in this protocol. 
භ 
Results in persistent or significant 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. 
x 
Is a congenital anomaly/ birth defect 
x 
Is another medically important event 
Note: Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
subject or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Should the investigator feel that an adverse event may jeopardize the subject or may 
require intervention to prevent more serious outcomes, then the adverse event should be treated as 
serious. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
25 | P a g e 
CONFIDENTIAL 
 
 
 
7.1.3 Preexisting conditions 
In this trial, a preexisting condition (i.e., a disorder present before the adverse event reporting period 
started) should not be reported as an adverse event unless the condition worsens during the adverse 
event reporting period. 
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 are not considered as AE. 
7.1.4 Procedures 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be reported 
as AE. However, the medical condition for which the procedure was performed should be reported if it 
meets the definition of an AE. For example, an acute appendicitis that begins during the adverse event 
reporting period should be reported as an adverse event and the resulting appendectomy noted under 
Comments. 
7.1.5 Laboratory test abnormalities and other abnormal assessments 
In subjects participating in the clinical laboratory sub-study, laboratory test value abnormalities and other 
abnormal assessment will be reported as AE, if they satisfy one or more of the following conditions for 
clinical significance: 
භ 
accompanied by clinical symptoms 
භ 
requiring a change in concomitant therapy (e.g. addition of, interruption of, discontinuation of, or 
any other change in a concomitant medication, therapy or treatment). 
භ 
In absence of clinical symptoms or change in concomitant therapy if the investigator judges it to 
be clinically significant 
භ 
Clinically significant abnormal laboratory findings and other abnormal assessment present at 
baseline and significantly worsening following the start of the study 
The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal 
laboratory finding is clinically significant. 
7.1.6 Grading of AEs 
7.1.6.1 
Unsolicited Adverse Events 
These adverse event will be graded according to the severity scale in Table 1. 
 
Table 1: Unsolicited AEs severity scale 
 
Grade 1 (Mild) 
No interference with daily activity 
Grade 2 (Moderate) 
Some interference with daily activity but not 
requiring medical intervention 
Grade 3 (Severe) 
Prevents daily activity and requires medical 
intervention 
Grade 4 (Potentially life threatening) 
Requiring Emergency 
hospitalization 
Room (ER) visit or 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
26 | P a g e 
CONFIDENTIAL 
 
 
 
7.1.6.2 
Solicited Adverse events 
Reactions at the site of injection (redness/erythema, pain, tenderness, swelling/edema, pruritus), 
systemic reactions (nausea/vomiting, diarrhea, headache, fatigue, myalgia) and vital signs abnormalities 
(fever, tachycardia, bradycardia, hypertensions, hypotension, changes in respiratory rate) will be graded 
according to the FDA Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007) - see Appendix 3. 
7.1.6.3 
Laboratory tests abnormalities 
Laboratory tests abnormalities will be graded according to the FDA Guidance for Industry Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007) - 
see Appendix 4. 
7.1.7 Assessment of the outcomes 
The investigator will assess the outcome of all AEs (including SAEs) recorded during the study as: 
x 
Ongoing 
x 
Recovered/resolved to pre-immunization health status 
x 
Recovered/Resolved with sequelae 
x 
Recovering/Improving 
x 
Stabilized 
x 
Unknown/Lost to Follow-up 
x 
Fatal (SAE) 
7.1.8 Causality 
Relationship of all AE and SAE to the study interventions (causality) should be assessed by the investigator 
and the sponsor according to the criteria below: 
භ 
Very likely/Certain: A clinical event with a plausible time relationship to vaccine administration 
and which cannot be explained by concurrent disease or other drugs or chemicals. 
භ 
Probable: A clinical event with a reasonable time relationship to vaccine administration; and is 
unlikely to be attributed to concurrent disease or other drugs or chemicals. 
භ 
Possible: A clinical event with a reasonable time relationship to vaccine administration, but which 
could also be explained by concurrent disease or other drugs or chemicals. 
භ 
Unlikely: A clinical event whose time relationship to vaccine administration makes a causal 
connection improbable, but which could be plausibly explained by underlying disease or other 
drugs or chemicals. 
භ 
Unrelated: A clinical event with an incompatible time relationship and which could be explained 
by underlying disease or other drugs or chemicals. 
භ 
Unclassifiable: A clinical event with insufficient information to permit assessment and 
identification of the cause. 
7.1.9 Unexpectedness 
Adverse events and SAE will also be assessed according to the following categories: 
• 
Expected (anticipated): the event is identified in nature, severity, and frequency in the 
investigator brochure or in the protocol. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
27 | P a g e 
CONFIDENTIAL 
 
 
 
• 
Unexpected (unanticipated): the event is not identified in nature, severity, or frequency in the 
investigator brochure or in the protocol. 
7.1.10 Suspected adverse reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the drug caused 
the AE. For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug. 
7.2 Methods and timing for assessing, and recording safety parameters 
Unless specified otherwise all AE occurring between obtaining the subject’s written consent to participate 
in the study and subject’s last study visit will be documented in the eCRF at all visits. All AE data and clinical 
laboratory data will be included in the study report. 
Clinical investigators and ultimately the Site Principal Investigator have the primary responsibility for AE 
identification, documentation, grading, assignment of attribution and reporting to the sponsor. 
7.2.1 AEs 
All new AE or abnormal laboratory test values considered as clinically significant, expected or unexpected 
related or unrelated experienced after the subject received the study treatment should be recorded in 
the eCRF. AEs (any untoward medical occurrence in trial subject) do not necessarily have to have a causal 
relationship with treatment. 
As a consistent method of collecting AEs, the subjects will be asked a non-leading question. 
The investigator or delegates will record all directly observed AE, and all AE solicited or spontaneously 
reported by the subject, or reported in the subject’s diary. 
In addition to solicited AE following vaccination, unsolicited AE will be defined as follows: 1) AE, 2) serious 
AE (SAE), 3) medically significant event (condition prompting emergency room visit, physician visit not 
related to a common disease/not a routine visit or an SAE not related to a common disease), 4) 
investigator-determined new onset of chronic illness (NOCI). Any AE/SAE spontaneously reported at any 
study visit will be classified accordingly and reported in the eCRF. 
AEs will be recorded in terms of medical diagnosis using the Medical Dictionary for Regulatory Activities 
(MedDRA). When this is not possible, the AE will be documented in terms of signs and symptoms observed 
by the investigator or as reported by the subject. In this case, each sign or symptom will be coded  
separately using MedDRA. 
In addition, information provided for each AE will include: start date, treatment required if any assessment 
of the outcome at the time of reporting, causality, severity, and seriousness. 
For each symptom the subject experiences, the subject will be asked if the subject 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. 
7.2.2 Vital signs and vaccine reactions 
Vital signs will be assessed before and for 30 minutes following each vaccination. Study subjects will be 
provided with a 28-day diary card to record vaccine reactions. Study subjects will be asked to record daily 
body temperature and local and systemic solicited adverse events on the day of vaccination and for the 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
28 | P a g e 
CONFIDENTIAL 
 
 
 
next 6 days. Study subjects will also be asked to record unsolicited adverse events in their diary card, on 
the day of vaccination and for the next 27 days. Vaccine reactions will be assessed at each visit and 
recorded in the eCRF for the corresponding visit. If a vaccine reaction meets the criteria of an SAE, the 
investigator or delegates will complete and submit an SAE report form (see also section SAE reporting). 
For the recording of local vaccine reactions: 
 
The largest diameter of redness or swelling at the injection site will be measured daily on the day 
of vaccination and for the next 6 days and recorded in the eCRF 
 
Subjects will be asked to indicate the maximum pain, tenderness and pruritus (itchiness) they 
experience at the injection site on a scale from 0 to 3 (0: no pain 1: Mild discomfort to touch 2: 
Discomfort with movement 3: Significant discomfort at rest) on the day of vaccination and for the 
next 6 days. 
In addition, subjects will be asked to record local or general AE in the diary card that will be reviewed at 
each visit. AEs reported in the diary cards will be transcribed in English by the study center staff (if 
applicable) prior to recording in the eCRF. AEs transcribed to English from the diary card will be verified 
for accuracy during the site monitoring visit. 
7.2.3 Laboratory test abnormalities 
In subjects participating in the clinical laboratory sub-study, abnormal laboratory test values will be 
recorded individually in an AE form if they qualify as AE (see Section 7.1.5) and are not part of the data 
supporting a medical diagnosis already reported as an AE. Any Grade 4 potentially life-threatening 
laboratory abnormality (see Appendix 4) within 7 days after a study injection will stop any further study 
vaccinations in the subject, irrespective of the study vaccine relationship, as defined in Section 7.8. 
7.2.4 SAEs, Medically Significant Event and New Onset of Chronic Illness 
All SAE, expected or unexpected, medically significant event or new onset of chronic illness occurring 
between obtaining the subject’s written consent to participate in the study and the last study visit will be 
documented in the eCRF, first in an AE form. For SAE, upon completion of the AE form, and confirmation 
that the AE is an SAE, the investigator or delegates will be prompted to complete and submit a SAE report 
form. Follow-up SAE forms may be completed and submitted as needed e.g., if the event outcome, 
treatment and resolution are not known at the time of the initial report. The follow-up information should 
contain sufficient detail to allow for a complete medical assessment of the case and an independent 
determination of possible causality, such as concomitant medications, or other conditions possibly 
explaining the SAE if any (must be consistent with the medical history recorded at baseline), relevant 
diagnostic tests, and autopsy report if applicable. All copies of source data attached with the SAE report 
form will be de-identified to protect subject subjects’ privacy. 
In addition, the reports should record: subject unique study ID, age, gender, weight, initial or follow-up 
report, date of the event, date of report, and individual completing the report. 
7.3 Expedited reporting procedures to study sponsor and pharmacovigilance agent 
7.3.1 Serious Adverse Events 
SAEs require prompt or immediate reporting to the site Principal Investigator or designates. The site 
Principal Investigator will be responsible for reporting the SAEs to study sponsor/pharmacovigilance agent 
as per protocol, and to the IRB/REB if/as required by institutional policies and procedures. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
29 | P a g e 
CONFIDENTIAL 
 
 
 
The site Principal Investigator or delegates will complete and submit a SAE form in the eCRF, within 24 
hours of becoming aware of the SAE. An E-mail notification of the SAE will be sent automatically to the 
Medical 
Monitor/pharmacovigilance 
agent 
appointed 
by 
study 
sponsor. 
The 
Medical 
Monitor/pharmacovigilance agent will assess the SAE report and proceed to report to the appropriate 
regulatory bodies as described in section 7.4. 
Once additional relevant information is received, the report should be updated WITHIN 24 HOURS. 
7.3.2 Reporting of pregnancy 
Female subjects, if not post-menopausal or surgically sterile are required to use adequate contraception 
methods as part of the entry criteria. 
If any study subject becomes or is found to be pregnant during the treatment period or within 4 weeks of 
the last injection of study vaccines, the pregnancy will be reported in the same way as SAE to study 
sponsor using the SAE Report Form, including an estimated date of conception (EDC), and the date of last 
study vaccine dose. Pregnancies will be followed by the investigator until completion of the pregnancy to 
learn the outcome, as congenital anomaly/birth defect is a SAE. Spontaneous abortion, ectopic pregnancy 
and stillbirth will also be considered as a SAE. At the end of the pregnancy, whether full-term or 
premature, information on the status of the mother and child will be forwarded to the study sponsor. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
7.4 
Reporting to regulatory authorities 
The study sponsor will appoint a Medical Monitor/pharmacovigilance agent who will report adverse 
events to the appropriate regulatory authorities as outlined below. 
The study sponsor or delegates will report any unexpected fatal or life-threatening suspected adverse 
reactions to the appropriate regulatory authorities as soon as possible but no later than 7 calendar days 
of initial receipt of the information. 
The study sponsor is also responsible for reporting to the appropriate regulatory authorities and to all 
investigators no later than 15 calendar days after determining that the information qualifies for reporting, 
any: 
x 
suspected adverse reaction that is both serious and unexpected, reported by any study center 
irrespective of the location. 
x 
suspected adverse reaction that is both serious and unexpected occurring in any of the subjects 
of the clinical trial, which are identified by or come to the attention of the sponsor after the end 
of the clinical trial 
x 
findings from clinical, epidemiological, or pooled analysis of multiple studies or any findings from 
animal or in vitro testing that suggest a significant risk in humans exposed to the drug 
x 
clinically important increase in the rate of a serious suspected adverse reaction over that listed in 
the protocol or investigator brochure. 
If the regulatory authority requests any additional data or information, the study sponsor or delegates 
must submit it as soon as possible, but no later than 15 calendar days after receiving the request. 
The study sponsor or delegates will submit periodic reports of the progress of the trial, if and as, requested 
by the regulatory authorities. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
30 | P a g e 
CONFIDENTIAL 
 
 
 
7.5 Institutional Reporting of AEs and SAEs 
The investigator will be responsible for reporting all SAEs directly to the relevant ethical review body 
(IRB/REB) according to institutional policies. 
In addition, the investigator will be responsible for reporting AEs directly to the relevant ethical review 
body (IRB/REB) if and as requested by institutional policies, and will also provide the ethical review body 
with any safety reports prepared by/on behalf of the study sponsor. 
7.6 Type and duration of follow-up of subjects after AEs 
All AEs and SAEs will be followed until they are resolved (return to normal or baseline values), unless: 1) 
they are judged by the investigator to be no longer clinically significant, 2) the investigator attributes the 
AE/SAEs to a cause other than the study drug or assesses them as chronic or stable, or 3) the subject is 
lost-to follow-up. Supplemental measurements and/or evaluations may be necessary to fully investigate 
the nature and/or causality of an AE or SAE. This may include laboratory tests, diagnostic procedures or 
consultation with other healthcare professionals. If the subject dies, any post-mortem findings (including 
histopathology) must be provided to the Sponsor or designee. In addition, the designated Medical 
Monitor may request blood tests, diagnostic imaging studies or specialist physician consultations in order 
to further evaluate any AE or abnormality considered to be potentially clinically significant. 
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached. 
7.7 Unblinding 
Unblinding procedure (which incorporates ICH E2A guidance, EU Regulations on clinical trials on medicinal 
products for human use and US Federal Regulations) is to unblind the report of any SAE that is unexpected 
and attributable/suspected to be attributable to the investigational product/product, prior to regulatory 
reporting. Causality will be determined by the investigator. 
The IRB/REB will receive blinded or unblinded safety reports in keeping with local requirements. 
Suspected unexpected serious adverse reactions (SUSAR) reports will be distributed to the investigator 
and IRB/REB in compliance with local regulations. 
The Medical Monitor will be responsible for the unblinding of events that meet the study stopping rules, 
if this is determined to be necessary for evaluation purposes by the data monitoring committee. 
The blind should ordinarily be broken for regulatory submission. 
Unblinding in case of an emergency is described below. However, it should be noted that is not anticipated 
that such occurrence will be encountered in the conduct of the study since it is unlikely that the knowledge 
of the vaccine received by the subject will affect his/her medical management. 
The investigator may unblind a subject’s treatment assignment only in the case of an emergency, when 
knowledge of the study treatment is essential for the appropriate clinical management or welfare of the 
subject. The unblinding should be formally completed in IWRS. Whenever possible, the investigator must 
first discuss options with the Study Medical Monitor or appropriate VBI study personnel before unblinding 
the subject’s treatment assignment in IWRS. If this is impractical, the investigator must notify the Contract 
Research Organization (CRO) and sponsor as soon as possible, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the safety of subjects 
currently in the study. The date and reason for the unblinding must be recorded in the appropriate data 
collection tool. If the Investigator does not have access to IWRS or is having technical issues, the 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
31 | P a g e 
CONFIDENTIAL 
 
 
 
investigator can contact unblinded staff at the site for the treatment but this must be clearly documented 
in the source notes and should only be used as a back-up option. 
For all other cases, the Medical Monitor will determine on a case-by-case basis if it is necessary to break 
the blind for safety purposes. The blind will be broken by the Medical Monitor or his designee for the 
specific subject. In the event that the blind is broken for a subject, the blind will be maintained for the 
clinical study team members to the extent possible to minimize the potential for introducing bias in 
evaluating the subject’s data. 
7.8 Stopping Rules 
Stopping criteria for further study vaccinations in individual subjects: 
 
The investigator will notify the sponsor (and/or sponsor representative) if any of the below conditions 
occur and will stop any further study vaccinations in an individual subject if they experience any of the 
following: 
x 
Grade 4* post-injection reaction within 7 days after any study injection 
x 
Clinically significant systemic reaction (i.e., angioedema, generalized urticaria) within 7 days after any 
study injection 
x 
Grade 4** potentially life-threatening laboratory abnormality within 7 days after a study injection, 
irrespective of the study vaccine relationship (in clinical laboratory sub-study subjects) 
x 
Grade 3 or 4* hypotension within 24 hours after any study injection 
x 
Grade 3 or 4* respiratory reaction occurring within 24 hours after any study injection 
x 
Any life-threatening event within 7 days after any study injection, regardless of relationship to study 
vaccine 
*FDA Grading of Vaccine Reactions and FDA Grading of Vital Sign Abnormalities (Appendix 3) 
**FDA Grading of Clinical Laboratory Abnormalities (Appendix 4) 
 
7.9 Safety oversight 
An independent Data Monitoring Committee (DMC) for this study will monitor human subject safety and 
consider study-specific data as well as relevant background information about the study vaccines, and 
target population under study. 
The DMC will comprise of a minimum of 3 members. The DMC will operate under procedures that will be 
developed at the organizational meeting of the DMC. At this time, each data element that the DMC needs 
to assess will be clearly defined. The DMC will meet before the study starts or as soon thereafter as 
possible to discuss the protocol, set triggers for data review, define a quorum, establish guidelines for 
monitoring the study, and designate a DMC Chair. 
All discussions and decisions will be documented in writing. The DMC will advise the study sponsor of its 
findings in writing. 
In the event that a stopping rule for an individual subject is triggered (Section 7.8), the data monitoring 
committee will meet on an ad hoc basis to review the data and determine whether the clinical trial should 
be stopped or requires modification in order to proceed safely. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
32 | P a g e 
CONFIDENTIAL 
 
 
 
The DMC will only meet if a stopping rule for an individual subject is triggered. In the event that a stopping 
rule is triggered, the DMC will make every reasonable attempt to meet as soon as possible, preferably 
within three (3) to five (5) business days of the Sponsor being notified of the event, but no later than ten 
(10) business days. During this period, the DMC will be provided the relevant information regarding the 
event(s) that triggered the stopping rule in the subject. 
 
In the event that adequate information is not available in the timeframe noted above, the DMC may 
schedule a second meeting to review additional information regarding the event(s) triggering a stopping 
rule in an individual subject. 
8 MONITORING 
Study center monitoring, including monitoring by designated unblinded personnel, is conducted to ensure 
that the rights and well-being of human subjects are protected, that the reported trial data are accurate, 
complete, and verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
Monitoring for this study will be performed by a CRO appointed by the study sponsor. Details of study 
center monitoring will be documented in the Clinical Monitoring Plan (CMP) developed by the CRO and 
approved by the study sponsor. 
The monitor will ensure that all subjects have been enrolled according to the protocol and that informed 
consent has been obtained prior to any study procedure. Monitors will review the study files, the subject 
files, source documents, eCRF, any SAE forms, as well as the product logs and laboratory records to ensure 
that the study is being conducted according to the protocol and GCP. eCRFs will be reviewed by the 
monitor according to the CMP 
The study will be monitored once the first subject has been enrolled, during the study at appropriate 
intervals, and after the last subject has completed the study. The monitoring visit schedule will be 
determined by the monitor and investigator, based on the frequency of enrollments and follow-up visits. 
Audits and inspections may be conducted by IRB/IEC or regulatory authorities and to ensure that the study 
is conducted in accordance to the protocol, and applicable ethics norms, ICH GCPs, and all applicable 
regulations. 
9 
STATISTICAL CONSIDERATIONS 
The statistical analysis of the data obtained from this study will be the responsibility of the designee of 
the sponsor. 
The statistical considerations summarized in this section outline the plan for data analysis of this study. If, 
after the study has begun, but prior to any un-blinding, changes are made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be amended 
(consistent with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they occurred, will 
be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
33 | P a g e 
CONFIDENTIAL 
 
 
 
9.1 Sample size 
The overall sample size for the study is driven by the superiority co-primary analysis in study subjects ш 45 
years old. Assuming an SPR of 0.81 for Engerix-B® and 0.96 for Sci-B-Vac™, a minimum of 540 subjects 
(270 per treatment group) provides 90% power to demonstrate superiority of SPR, assuming a 5% margin 
with a two-sided type 1 error of 0.05, i.e., to rule out a <5% difference in SPR based on the lower limit of 
the two-sided 95% confidence interval. Based on a targeted enrollment of 80% of study subjects age шϰϱ
years-old, an additional 180 (20%) 18-44 year old study subjects would be required, for a total of at least 
ϲϴϬƐƵďũĞĐƚƐŝŶƚŚĞĨƵůůƐƚƵĚǇ͘ƐĂŵƉůĞƐŝǌĞŽĨϲϴϬǁŽƵůĚƉƌŽǀŝĚĞшϵϬйƉŽǁĞƌƚŽĚĞŵŽŶƐƚƌĂƚĞŶŽŶ- 
inferiority with a 5% margin if the Sci-B-Vac™ SPR is as low as 0.88, with the same SPR for Engerix-B® 
(0.81), and the two-sided alpha is 0.05. A 5% margin of non-inferiority is justified by the > 90% SPR of 
Engerix-B® in young adults. In older adults, a 5% margin of superiority represents a clinically meaningful 
improvement at both the individual level and from a public health perspective, given the reduced 
immunogenicity of Engerix-B® in this population. 
Given the desire to have robust immunogenicity estimates of SPR in the adult population following a 
three-dose regimen of Sci-B-Vac™ and to guard against a better than expected SPR for Engerix-B® (up to 
84% in subjects шϰϱ years old), a total of 1,564 subjects will be enrolled to the trial. There will be targeted 
enrollment, with 80% (~n=1252) of the study population being ш 45 years old and 20% (~n=312) being 18- 
44 years old. This sample size will provide >90% power to establish the superiority of Sci-B-Vac™ over 
Engerix-ΠŝŶŽůĚĞƌĂĚƵůƚƐ;шϰϱǇĞĂƌƐŽůĚͿĂŶĚŶŽŶ-ŝŶĨĞƌŝŽƌŝƚǇŝŶĂĚƵůƚƐшϭϴǇĞĂƌƐŽůĚ͕ŐŝǀĞŶƚŚĞĂďŽǀĞ
statistical parameters. 
Given the desire to have good representation across the spectrum of older adults, the targeted enrollment 
of adults ш 45 years old (80%) will be divided equally between the 45-64 year old and ш 65 year old strata. 
Targeted enrollment by age strata will be as follows: 
Age 18-44 years (20%): 312 (~ 156 per arm) 
Age 45-64 years (40%): 626 (~313 per arm) 
ŐĞшϲϱǇĞĂƌƐ;ϰϬйͿ͗ϲϮϲ;ΕϯϭϯƉĞƌĂƌŵͿ 
Enrollment within each stratum will be stopped once the target has been met. 
9.2 Randomization 
This is a double blind 2-arm study. A statistician who is not involved in the clinical aspects of the study will 
generate a permuted blocked randomization list for each site and inside each site for each of the 3 
following strata: 18-44 years, 45-ϲϰǇĞĂƌƐĂŶĚшϲϱǇĞĂƌƐŽůĚĂƚƚŚĞĚĂƚĞŽĨĞŶƌŽůŵĞŶƚ͘ZĂŶĚŽŵŝǌĂƚŝŽŶ
will be via a web-based IWRS. The site pharmacy and/or unblinded study center staff will receive a 
notification of the randomization and the treatment allocation for the subject, which should be filed in a 
locked area/ computer folder not accessed by blinded study center staff. The IWRS will track and supply 
appropriate medication to the study subjects. 
Randomization within an age stratum will stop after the target sample size has been reached. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
34 | P a g e 
CONFIDENTIAL 
 
 
 
9.3 Analysis Sets 
9.3.1 All Enrolled Set 
The All Enrolled Set will be defined as all screened subjects who provide informed consent and provide 
demographic and/or baseline screening assessments, regardless of the subject’s randomization and 
treatment status in the study. 
9.3.2 Safety Set 
All subjects in the All Enrolled Set who receive a study vaccination. 
9.3.3 Intent-to-Treat (ITT) 
All subjects in the All Enrolled Set who were randomized. 
9.3.4 Full Analysis Set (FAS) 
All subjects in the All Enrolled Set who receive at least one vaccination and provide at least one evaluable 
serum sample both before and after baseline. The FAS will be analyzed “as randomized” (i.e., according 
to the vaccine a subject was randomized to receive, which may be different from the vaccine the subject 
actually received). A FAS will be defined for each relevant time point. 
9.3.5 Per Protocol Set (PPS) 
All subjects in the FAS who: 
x 
received all 3 vaccinations 
x 
have an evaluable serum sample at the time point of interest 
x 
are sero-negative at baseline 
x 
had no major protocol violations, which will be identified prior to unblinding. 
 
A major protocol violation for the purpose of exclusion from the PPS is defined as a protocol violation that 
is considered to have a significant impact on the immunogenicity result of the subject. These will be 
identified prior to unblinding and analysis and may include: 
x 
subjects enrolled who did not meet study entry criteria 
x 
subjects who did not receive the correct treatment 
x 
subjects who attended visits outside the allowed windows 
x 
subjects who developed withdrawal criteria but were not withdrawn 
x 
subjects who received a prohibited concomitant medication [as per exclusion criteria], if the 
medication and the timing of its administration is considered to have a significant impact on the 
reliability of subject immunogenicity result 
x 
subjects with a deviation identified through monitoring visits or otherwise, where the deviation 
is judged to impact the reliability of subject immunogenicity result 
9.3.6 Sub Study Analysis Set (SSA) 
All subjects in the All Enrolled Set who actually receive at least one dose of study vaccination, participated 
in the sub-study, and provide data at baseline and at least one post baseline visit for cell mediated 
immunity. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
35 | P a g e 
CONFIDENTIAL 
 
 
 
9.3.7 Sub Groups 
The following key sub-groups of interest will be pre-specified: 
x 
Gender (male vs female) 
x 
BMI (<= 30 vs > 30) 
x 
Smoking Status (current vs past or non-smoker) 
x 
Age cohort (18-44 years, 45-ϲϰǇĞĂƌƐ͕шϲϱ years) 
x 
Diabetes (Diabetic vs non-diabetic) 
x 
ĂŝůǇĂůĐŽŚŽůĐŽŶƐƵŵƉƚŝŽŶ;шϰĚƌŝŶŬƐͬĚĂǇǀƐϮ-3 drinks/day vs 0-1 drink/day) 
x 
Non–study licensed vaccines (no vaccination vs vaccination) 
x 
Race and Ethnicity 
9.4 Analysis of Demographic and Baseline Characteristics 
All demographic and baseline characteristics will be summarized overall and by treatment group using 
appropriate descriptive statistics. Continuous data will be summarized using the number of observations, 
mean, standard deviation, median, minimum and maximum. Categorical data will be summarized using 
frequency counts and percentages. No statistical hypothesis testing will be conducted. 
9.5 Co-Primary Objectives 
9.5.1 Co-Primary Hypotheses 
The two co-ƉƌŝŵĂƌǇĂŶĂůǇƐĞƐǁŝůůďĞƚĞƐƚĞĚŝŶƐĞƋƵĞŶĐĞ͕ƚŚĞƚĞƐƚĨŽƌƐƵƉĞƌŝŽƌŝƚǇŝŶƚŚĞƐƵďŐƌŽƵƉ;шϰϱ
year-olds) can only be conducted after non-ŝŶĨĞƌŝŽƌŝƚǇŝŶƚŚĞŽǀĞƌĂůůƉŽƉƵůĂƚŝŽŶ;шϭϴǇĞĂƌŽůĚƐͿŚĂƐ
already been shown. 
1) Non-Inferiority of Sci-B-Vac™ compared to Engerix-B® will be assessed using the PPS for the entire 
ƐƚƵĚǇƉŽƉƵůĂƚŝŽŶ;ŝ͘Ğ͕͘ĂĚƵůƚƐшϭϴǇĞĂƌƐŽůĚͿ͘dŚĞŶŽŶ-inferiority margin is set at 5%. The null and 
alternative hypotheses are as follows; 
Null Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) <= -5% 
Alternative Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) > -5% 
Non-inferiority will be assessed using the lower bound of the two-sided 95% confidence interval. If the 
lower bound is greater than -5%, Sci-B-Vac™ will be declared non-inferior to Engerix-B®, and the study 
will be considered a success. 
2) Superiority of Sci-B-Vac™ compared to Engerix-B® will be assessed using the FAS for the study 
ƉŽƉƵůĂƚŝŽŶŽĨĂĚƵůƚƐшϰϱǇĞĂƌƐŽůĚ͘/ŶŽůĚĞƌĂĚƵůƚƐ͕ĂϱйŵĂƌŐŝŶŽĨƐƵƉĞƌŝŽƌŝƚǇƌĞƉƌĞƐĞŶƚƐĂĐůŝŶŝĐĂůůǇ
meaningful improvement at both the individual level and from a public health perspective, given the 
reduced immunogenicity of Engerix-B® in this population. Therefore a superiority margin is set at 5%. 
The null and alternative hypotheses are as follows; 
Null Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) <= 5% 
Alternative Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) > 5% 
Superiority will be assessed using the lower bound of the two-sided 95% confidence interval. If the 
lower bound is greater than 0%, Sci-B-Vac™ will be declared statistically superior to Engerix-B®. If the 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
36 | P a g e 
CONFIDENTIAL 
 
 
 
lower bound is greater than 5%, Sci-B-Vac™ will be declared clinically superior to Engerix-B®, and the 
study will be considered a success. 
9.5.2 Statistical Methods for Co-Primary Analyses 
For the primary endpoint of SPR at day 196, 4 weeks following the third vaccination, data from all centers 
will be pooled for the primary analysis. The difference in adjusted proportions and two-sided 95% Cis, 
calculated using the Miettnen and Nurminen method, will be reported. For immunogenicity data, it may 
be reasonable to consider missing immunogenicity values as missing completely at random (MCAR), i.e., 
not informative. Therefore, the primary analysis will comprise a complete case analysis only without 
introducing any bias. Imputation methods will not be used. The co-primary non-inferiority analysis will 
use the PPS. For the co-primary superiority analysis, only subjects in the FAS who are sero-negative will 
be used. 
The impact of center will be investigated through funnel plots. 
Sensitivity analyses using the same modeling approach outlined above will also be conducted using the 
FAS, for the non-inferiority co-primary analysis. These analyses will be reported both with and without 
patients in the FAS who are seropositive at baseline. Sensitivity analyses using the ITT analysis set will be 
conducted for the superiority co-primary analysis. For these ITT analyses, patients with missing data at 
day 196 (4 weeks following the third vaccination) will be included and treated as failures. These analyses 
will be reported both with and without patients who are seropositive at baseline. Additonal sensitivity 
analyses will be conducted using a Log Linear model, to adjust for age group. Factors for treatment and 
age group will be included in the model. 
 
Analyses of the co-primary endpoints will also be conducted and reported by key sub-groups using the 
sub-groups identified in Section 9.3.7. 
9.6 Secondary Immunogenicity Objectives 
9.6.1 Secondary Immunogenicity Hypotheses 
If the co-primary hypotheses are significant, the following secondary hypotheses will be tested in the 
following pre-specified order, with each hypothesis using a two-sided 5% significance level. 
1) Non-Inferiority of Sci-B-Vac™, 20 weeks following the second vaccination, compared to Engerix-B®, 4 
weeks following the third vaccination, will be assessed using the PPS3 analysis set for the entire study 
ƉŽƉƵůĂƚŝŽŶ;ŝ͘Ğ͕͘ĂĚƵůƚƐшϭϴǇĞĂƌƐŽůĚͿ͘dŚĞŶŽŶ-inferiority margin is set at 5%. The null and alternative 
hypotheses are as follows; 
Null Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) <= -5% 
Alternative Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) > -5% 
Non-inferiority will be assessed using the lower bound of the two-sided 95% confidence interval. If the 
lower bound is greater than -5%, Sci-B-Vac™20 weeks following the second vaccination will be declared 
non-inferior to Engerix-B® 4 weeks following the third vaccination, and the next secondary hypothesis will 
be tested. 
2) Non-Inferiority of Sci-B-Vac™ 4 weeks following the second vaccination compared to Engerix-B® 4 
weeks following the third vaccination will be assessed using the PPS for the entire study population (i.e., 
ĂĚƵůƚƐшϭϴǇĞĂƌƐŽůĚͿ͘dŚĞŶŽŶ-inferiority margin is set at 5%. The null and alternative hypotheses are as 
follows; 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
37 | P a g e 
CONFIDENTIAL 
 
 
 
Null Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) <= -5% 
Alternative Hypothesis: SPR(Sci-B-Vac™) –SPR(Engerix-B®) > -5% 
Non-inferiority will be assessed using the lower bound of the two-sided 95% confidence interval. If the 
lower bound is greater than -5%, Sci-B-Vac™ 4 weeks following the second vaccination will be declared 
non-inferior to Engerix-B® 4 weeks following the third vaccination. 
9.6.2 Statistical Methods for Secondary Immunogenicity Analyses 
The secondary endpoints of SPR 4 weeks following the second vaccination with Sci-B-Vac™ and 20 weeks 
following the second vaccination Sci-B-Vac™, each compared with SPR 4 weeks following the third 
vaccination with Engerix-B® will be analyzed using data from all centers will be pooled together. The 
difference in adjusted proportions and two-sided 95% Cis, calculated using the Miettnen and Nurminen 
method, will be reported. will be calculated based on these models. For immunogenicity data, it may be 
reasonable to consider missing immunogenicity values as missing completely at random (MCAR), i.e., not 
informative. Therefore, the analysis will comprise a complete case analysis only without introducing any 
bias. Imputation methods will not be used. These analyses will be conducted using the PPS. 
The impact of center will be investigated through funnel plots. 
Sensitivity analyses using the same modeling approach outlined above will be conducted using the FAS, 
for both secondary analyses. These analyses will be reported both with and without patients in the FAS 
who are seropositive at baseline. Additonal sensitivity analyses will be conducted using a Log Linear 
model, to adjust for age group. Factors for treatment and age group will be included in the model. 
Analyses of the above secondary endpoints will also be conducted and reported by key sub-groups using 
the sub-groups identified in Section 9.3.7. 
 
9.7 Exploratory Immunogenicity Endpoints 
Analysis of all exploratory immunogenicity endpoints will be based on the PPS, unless otherwise indicated. 
Geometric Mean Concentration (GMC) 
All statistical analyses will be performed on the logarithmically (base 10) transformed values. Individual 
titers below the detection limit will be set to half the limit. 
Adjusted estimates of GMCs and their associated 95% CIs at day 28, day 56, day 168, day 196 and day 336 
will each be determined using an analysis of covariance (ANCOVA) model with factors for treatment, age 
group, and a covariate for the log transformed pre-vaccination (baseline) titer. Antibody GMCs, associated 
standard errors, two-sided 95% CIs and median, minimum, and maximum titer values will be determined 
and presented by treatment group. The median, minimum, and maximum values will be reported on the 
actual titer values, rather than the log scale. The difference in GMCs between the two treatment groups, 
and associated two-sided 95% CIs will also be presented. For immunogenicity data, it may be reasonable 
to consider missing immunogenicity values as missing completely at random (MCAR), i.e., not informative. 
Therefore, this analysis will comprise a complete case analysis only, without introducing any bias. 
Imputation methods will not be used. 
dŚĞĂďŽǀĞĂŶĂůǇƐĞƐǁŝůůďĞĐŽŶĚƵĐƚĞĚĂŶĚƌĞƉŽƌƚĞĚĨŽƌĂůůƐƵďũĞĐƚƐĂŐĞшϭϴǇĞĂƌƐŽůĚĂŶĚĨŽƌƐƵďũĞĐƚƐĂŐĞ 
ш45 years old. Analyses of GMC in both age cohorts will also be reported by sub-group using the sub- 
groups identified in section 9.3.7. Sub-group analyses will include additional factors in the model, a factor 
for the sub-group of interest and the interaction between the sub-group and treatment. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
38 | P a g e 
CONFIDENTIAL 
 
 
 
Binary Data 
All binary data will be summarized using frequency counts and percentages, by time point. Data from all 
centers will be pooled for these analyses. The difference in adjusted proportions and two-sided 95% CIs, 
calculated using the Miettnen and Nurminen method, will be reported. Additonal sensitivity analyses will 
be conducted using a Log Linear model, to adjust for age group. Factors for treatment and age group will 
be included in the model. For immunogenicity data, it may be reasonable to consider missing 
immunogenicity values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
analysis will comprise a complete case analysis only without introducing any bias. Imputation methods 
will not be used. 
The above analyses will be conducted ĂŶĚƌĞƉŽƌƚĞĚĨŽƌĂůůƉĂƚŝĞŶƚƐĂŐĞшϭϴǇĞĂƌƐŽůĚĂŶĚĨŽƌƉĂƚŝĞŶƚƐĂŐĞ 
шϰϱǇĞĂƌƐŽůĚ͘ŶĂůǇƐĞƐŽĨďŝŶĂƌǇĚĂƚĂŝŶďŽƚŚĂŐĞĐŽŚŽƌƚƐǁŝůůĂůƐŽďĞƌĞƉŽƌƚĞĚďǇƐƵď-group using the 
sub-groups identified in section 9.3.7. 
Sub Study 
Cell mediated immunity data collected in the sub-study will be summarized for the Sub Study Analysis Set 
using descriptive statistics. 
9.8 Analysis of Safety Objectives 
There are no statistical hypotheses associated with the safety objectives. All safety data will be analyzed 
using descriptive statistics. All safety analyses will be presented by severity for each age group and for 
each treatment group using the Safety Analysis Set. 
9.8.1 Analysis of Extent of Exposure 
The number of subjects actually receiving the first, second and the third vaccination will be summarized 
by treatment group. 
9.8.2 Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited AEs will be summarized according to defined severity grading scales. Reactions at the site of 
injection (redness/erythema, pain, tenderness, swelling/edema, pruritus), systemic reactions 
(nausea/vomiting, diarrhea, headache, fatigue, myalgia) and vital signs abnormalities (fever, tachycardia, 
bradycardia, hypertensions, hypotension, changes in respiratory rate) will be graded according to the FDA 
Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (2007) - see Appendix 3. Frequencies and percentages of subjects 
experiencing each AE will be presented by treatment group for each symptom overall and by dose and 
severity for each age group and by time point (i.e., after each vaccination). 
9.8.3 Analysis of Spontaneously Reported Adverse Events 
The original verbatim terms used by investigators to identify AEs in the eCRFs will be mapped to preferred 
terms using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. The AEs will then be 
grouped by MedDRA preferred terms into frequency tables according to system organ class. These 
summaries will be presented by treatment group and by interval of study observation. When an AE occurs 
more than once for a subject, the maximal severity and strongest relationship to the treatment group will 
be counted. Separate summaries will be produced for the following categories: 
- 
SAEs 
- 
Unexpected AEs 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
39 | P a g e 
CONFIDENTIAL 
 
 
 
- 
AEs that are very likely, probably or possibly related to vaccine 
- 
AEs of special interest 
- 
AEs leading to vaccine/study withdrawal 
 
9.8.4 Analysis of Vital Signs and Laboratory Parameters 
All vital sign data and laboratory (e.g., hematology, chemistry) data (clinical laboratory sub-study) will be 
summarized using descriptive statistics. Data will be reported by treatment group. Summaries will be 
provided for the observed values and changes from baseline at each scheduled visit. In addition, absolute 
and change from baseline values will be categorized according to the toxicity scales (See Appendix 3 for 
vital signs and Appendix 4 for laboratory parameters). 
9.9 Interim Analysis 
Not applicable. 
 
10 DATA HANDLING AND RECORD KEEPING 
Data handling, record-keeping, reporting, study record retention and protocol deviations will be managed 
in accordance with FDA regulations and ICH GCP and will be described in detail in study-specific SOPs. 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data 
reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is recommended to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the change. DO 
NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each subject enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
Study sponsor and/or it designee will provide guidance to investigators on making corrections to the 
source documents and eCRF. 
10.1 Data management responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data entry staff, 
who will ensure that they are accurate and complete. Adverse events must be graded, assessed for 
severity and causality, and reviewed by the site Principal Investigator or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
During the study, the investigator must maintain complete and accurate documentation for the study. 
10.2 Data capture methods 
Clinical data (including AEs, concomitant medications, and vaccine reaction data) and clinical laboratory 
data will be entered into a 21 CFR Part 11-compliant eCRF. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
40 | P a g e 
CONFIDENTIAL 
 
 
 
10.3 Types of data 
Data for this study will include safety (vital signs, clinical signs and symptoms, concomitant medications 
and clinical laboratory tests), and efficacy outcome measures (immunogenicity). 
10.4 Study records retention 
Following closure of the study, the investigator must maintain all center study records (except for those 
required by local regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible, when needed (e.g., audit or inspection), and must be available for review in 
conjunction with assessment of the facility, supporting systems, and staff. Where permitted by applicable 
laws/regulations or institutional policy, some or all of these records can be maintained in a validated 
format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions are legible and 
are a true and accurate copy of the original and meet accessibility and retrieval standards, including re- 
generating a hard copy, if required. Furthermore, the investigator must ensure that an acceptable back- 
up of the reproductions exists and that there is an acceptable quality control procedure in place for making 
these reproductions. 
The investigator/institution should seek the written approval of the Sponsor before proceeding with the 
disposal of these records after the indicated time period for record retention. 
The minimum retention time will meet the strictest standard applicable to a particular study center, as 
dictated by ICH GCP, any institutional requirements, applicable laws or regulations; otherwise, the 
minimum retention period will default to 25 years. 
The investigator/institution must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to archival at an off- study center facility, transfer of ownership of the records 
in the event the investigator leaves the study center. 
10.5 Protocol deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice (GCP), or 
Manual of Procedures requirements. The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly. 
These practices are consistent with ICH E6:4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 Quality Assurance and Quality Control, Section 5.1.15.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations to the local 
Trial Coordinator within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity. All deviations must be promptly reported to the study 
sponsor or its designees according to the Study Manual of Operating Procedures. 
All deviations from the protocol must be addressed in study subject source documents. A Protocol 
Deviation Form should be completed in the eCRF. Protocol deviations must be reported to the local IRB 
according to institution policies. The site PI/study center staff is responsible for knowing and adhering to 
their institution policies. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
41 | P a g e 
CONFIDENTIAL 
 
 
 
11 QUALITY CONTROL AND QUALITY MANAGEMENT 
SOPs for quality management will be developed, used to train appropriate personnel, and kept on file 
with documentation of training. Data will be evaluated for compliance with protocol and accuracy in 
relation to source documents. The study will be conducted in accordance with procedures identified in 
the protocol. The types of materials to be reviewed, the personnel responsible, and the schedule for 
reviews will be referenced in the SOPs. Study-specific training will be provided for all staff prior to the 
commencement of the trial. 
SOPs will be used at all clinical and laboratory sites. Regular monitoring and an independent audit will be 
performed according to GCP/ICH (e.g., data monitoring). Following written standard operating 
procedures, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements. Reports will be submitted to study sponsor on monitoring activities. 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the study sponsor, and inspection by local and 
regulatory authorities. 
The Data Management Center will implement quality control procedures according to the Data 
Management Plan. 
12 STUDY REGISTRATION AND RESULTS INFORMATION 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a trial 
registration policy as a condition for publication. This policy requires that all clinical trials be registered in 
a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. 
 
It is the responsibility of study sponsor to register this trial in ClinicalTrial.gov before any subject 
enrolment and to comply with the requirements for the submission of results information as per US 42 
CFR Part 11 [Clinical Trials Registration and Results Information Submission]. 
 
The sponsor will also register the trial in the EudraCT database, which shares information with the 
publicly available European Union Clinical Trial Register and will comply with applicable regulations and 
guidelines with respect of the posting of results-related information. 
13 ETHICAL / REGULATORY CONSIDERATIONS 
13.1 Relevant ethical body 
A relevant ethical body is either and Institutional Review Board (IRB) or an Independent Ethics committee 
(IEC). 
An Independent Ethics committee (IEC) is: 
An independent body (a review board or a committee, institutional, regional, national, or supranational), 
constituted of medical professionals and non-medical members, whose responsibility it is to ensure the 
protection of the rights, safety and well-being of human subjects involved in a trial and to provide public 
assurance of that protection, by, among other things, reviewing and approving/providing favorable 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
42 | P a g e 
CONFIDENTIAL 
 
 
 
opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material 
to be used in obtaining and documenting informed consent of the trial subjects. 
The legal status, composition, function, operations and regulatory requirements pertaining to 
Independent Ethics Committees may differ among countries, but an Independent Ethics Committee 
should act in agreement with ICH Good Clinical Practice guidance document. 
 
An Institutional Review Board (IRB) is: 
An independent body constituted of medical, scientific, and non-scientific members, whose responsibility 
is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, 
among other things, reviewing, approving, and providing continuing review of trial protocol and 
amendments and of the methods and material to be used in obtaining and documenting informed consent 
of the trial subjects. 
 
It is the responsibility of the site Principal Investigator to identify the relevant ethical body that has the 
responsibilities described in the Section 3 of the ICHGCP with respect of trials conducted at the site. 
Note: There could be more than one relevant ethical body e.g. if the investigator has a cross appointment 
with a hospital and a university and both institutions require the trial to be reviewed by their respective 
ethics committees. In that case, it the Investigator’s responsibility to identify all the relevant ethical 
bodies. The singular form will be used in this document for simplification purposes. However it should be 
understood that if more than one ethical body has the responsibilities described in the section 3 of the 
ICHGCP with respect of clinical trials conducted at the site, then all obligations /procedures described in 
this section and in Sections 7, 8 and 10.5 of this protocol apply for all relevant ethical bodies. 
13.2 Ethics Review and informed consent 
The investigator or designate will be responsible for presenting a full description of the research project 
including risks/benefits and how personal health information may be used and disclosed in research. A 
written informed consent/authorization will then be obtained from the subject prior to the screening 
procedures and injection. The investigator or designate will also be responsible for maintaining up-to-date 
records of the consent forms and providing a copy to the subject. 
Subjects will be encouraged and will have ample opportunity to have their questions answered before 
and after consenting to participate. 
The Principal Investigator must receive a copy of the letter of approval from any relevant ethical body, 
which specifically approves the protocol and informed consent, before beginning or continuing subject 
enrollment. 
The relevant ethical body must also approve any significant changes to the protocol and documentation 
of this approval must be sent to the Principal Investigator. 
Records of all study review and approval documents must be kept on file by the Investigator and are 
subject to inspection by regulatory authorities during or after completion of the study. SAEs must be 
reported to the relevant ethical body. Other AEs should be reported according to modalities defined in 
the ethical body policies and procedures. The relevant ethical body should receive notification of 
completion of the study and final report within 3 months of study completion and termination. The 
Investigator will maintain an accurate and complete record of all submissions made to the IRB/IEC, 
including a list of all reports and documents submitted. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
43 | P a g e 
CONFIDENTIAL 
 
 
 
14 REFERENCES 
1. 
Hepatitis 
B 
Factsheet 
World 
Health 
Organization, 
2016. 
at 
http://www.who.int/mediacentre/factsheets/fs204/en/.) 
2. 
Collaborators GMaCoD. Global, regional, and national age-sex specific all-cause and cause-specific 
mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 
2013. The Lancet 2015;385:117-71. 
3. 
Control ECfDPa. Annual Epidemiological Report 2016 – Hepatitis B. Stockholm: European Centre 
for Disease Prevention and Control; 2016 
4. 
Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis B antibody is protective? 
J Infect Dis 1999;179:489-92. 
5. 
Leuridan E, Van Damme P. Hepatitis B and the need for a booster dose. Clin Infect Dis 2011;53:68- 
75. 
6. 
Coates T, Wilson R, Patrick G, Andre F, Watson V. Hepatitis B vaccines: assessment of the 
seroprotective efficacy of two recombinant DNA vaccines. Clin Ther 2001;23:392-403. 
7. 
Williams RE, Sena AC, Moorman AC, et al. Hepatitis B vaccination of susceptible elderly residents 
of long term care facilities during a hepatitis B outbreak. Vaccine 2012;30:3147-50. 
8. 
Janssen JM, Jackson S, Heyward WL, Janssen RS. Immunogenicity of an investigational hepatitis B 
vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B 
vaccine in subpopulations of healthy adults 18-70 years of age. Vaccine 2015;33:3614-8. 
9. 
Heyward WL, Kyle M, Blumenau J, et al. Immunogenicity and safety of an investigational hepatitis 
B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B 
vaccine in healthy adults 40-70 years of age. Vaccine 2013;31:5300-5. 
10. 
Sablan BP, Kim DJ, Barzaga NG, et al. Demonstration of safety and enhanced seroprotection 
against hepatitis B with investigational HBsAg-1018 ISS vaccine compared to a licensed hepatitis B vaccine. 
Vaccine 2012;30:2689-96. 
11. 
Fan W, Chen XF, Shen C, Guo ZR, Dong C. Hepatitis B vaccine response in obesity: A meta-analysis. 
Vaccine 2016;34:4835-41. 
12. 
Yang S, Tian G, Cui Y, et al. Factors influencing immunologic response to hepatitis B vaccine in 
adults. Sci Rep 2016;6:27251. 
13. 
Nelson JC, Bittner RC, Bounds L, et al. Compliance with multiple-dose vaccine schedules among 
older children, adolescents, and adults: results from a vaccine safety datalink study. Am J Public Health 
2009;99 Suppl 2:S389-97. 
14. 
Neurath A.R. KSBH. Antigenic structure of human hepatitis viruses. In: van Regenmantel M.H.V. 
NAR, ed. Immunochemistry of Viruses: The Basis for Serodiagnosis and Vaccines Amsterdam: Elsevier 
Science Publishers 1985:325-66. 
15. 
Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H, Gerlich WH. Large surface 
proteins of hepatitis B virus containing the pre-s sequence. J Virol 1984;52:396-402. 
16. 
Milich DR, Thornton GB, Neurath AR, et al. Enhanced immunogenicity of the pre-S region of 
hepatitis B surface antigen. Science 1985;228:1195-9. 
17. 
Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly 
people. CMAJ: Canadian Medical Association Journal 2005;173:489-95. 
18. 
Canadian Immunization Guide: Part 4 - Active Vaccines-Hepatitis B Vaccine 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
44 | P a g e 
CONFIDENTIAL 
 
 
 
Updated: February 2015. at http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/4- 
canadian-immunization-guide-canadien-immunisation/index-eng.php?page=7 - p4c6a5j.) 
19. 
Pride MW, Bailey CR, Muchmore E, Thanavala Y. Evaluation of B and T-cell responses in 
chimpanzees immunized with Hepagene, a hepatitis B vaccine containing pre-S1, pre-S2 gene products. 
Vaccine 1998;16:543-50. 
20. 
Stephenne J. Development and production aspects of a recombinant yeast-derived hepatitis B 
vaccine. Vaccine 1990;8 Suppl:S69-73; discussion S9-80. 
21. 
Neurath AR, Kent SB, Strick N, Taylor P, Stevens CE. Hepatitis B virus contains pre-S gene-encoded 
domains. Nature 1985;315:154-6. 
22. 
Itoh Y, Takai E, Ohnuma H, et al. A synthetic peptide vaccine involving the product of the pre-S (2) 
region of hepatitis B virus DNA: protective efficacy in chimpanzees. Proceedings of the National Academy 
of Sciences 1986;83:9174-8. 
23. 
Yerushalmi B, Raz R, Blondheim O, Shumov E, Koren R, Dagan R. Safety and immunogenicity of a 
novel mammalian cell-derived recombinant hepatitis B vaccine containing Pre-S1 and Pre-S2 antigens in 
neonates. Pediatr Infect Dis J 1997;16:587-92. 
24. 
Coppola N, Onorato L, Minichini C, et al. Clinical significance of hepatitis B surface antigen 
mutants. World J Hepatol 2015;7:2729-39. 
25. 
National       Kidney       Foundation.       CKD-EPI     Creatinine      Equation. 
[available 
at: 
https://www.kidney/org/content/ckd-epi-creatinine-equation-2009, accessed on March 16, 2017] 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
45 | P a g e 
CONFIDENTIAL 
 
 
 
 
 
15 APPENDICES 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
46 | P a g e 
CONFIDENTIAL 
 
 
 
 
15.1 Appendix 1: CHSA* FRAILTY SCALE17 
 
Table 2: CHSA Frailty Scale 
 
Index 
Description 
1 
Very fit — robust, active, energetic, well motivated and fit; these people commonly 
exercise regularly and are in the most fit group for their age 
2 
Well — without active disease, but less fit than people in category 1 
3 
Well, with treated comorbid disease — disease symptoms are well controlled 
compared with those in category 4 
4 
Apparently vulnerable — although not frankly dependent, these people commonly 
complain of being “slowed up” or have disease symptoms 
5 
Mildly frail — with limited dependence on others for instrumental activities of daily 
living 
6 
Moderately frail — help is needed with both instrumental and non-instrumental 
activities of daily living 
7 
Severely frail — completely dependent on others for the activities of daily living, or 
terminally ill 
*: CSHA = Canadian Study of Health and Aging. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
47 | P a g e 
CONFIDENTIAL 
 
 
 
15.2 Appendix 2: Schedule of Events 
Table 3: Schedule of Events (main study and sub-studies) 
 
 
Screening 
V1 
Phone Safety 
Follow-up 
V2 
Phone Safety 
Follow-up 
V3 (i) 
V4 
Phone Safety 
Follow-up 
V5 (j) 
V6 
End of Study 
Visit 
Timelines (days) 
-28 
0  
28  
56 
168  
196 336(a) 
Range (days) 
-28 
to 0 
 
V1 
+ 5-9 
-3/+7 
V2 
+ 5-9 
-3/+7 +/-7 
V4 
+ 5-9 
+/-7 +/-14 
Screening 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X  
 
 
 
 
 
 
 
 
Inclusion & Exclusion Criteria 
X  
 
 
 
 
 
 
 
 
Physical Examination (b) 
X 
X  
X 
 
X 
X  
X 
X 
Medical History 
X  
 
 
 
 
 
 
 
 
Height and weight 
X  
 
 
 
 
 
 
 
 
Medications 
X  
 
 
 
 
 
 
 
 
HBV serology 
X  
 
 
 
 
 
 
 
 
HIV and HCV serology 
X  
 
 
 
 
 
 
 
 
Urine Pregnancy test 
X 
X  
X 
 
 
X  
 
 
Blood tests: CBC, liver and renal 
function, HbA1C if indicated 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X  
 
 
 
 
 
 
 
 
Randomization 
 
X  
 
 
 
 
 
 
 
Vaccination 
 
X  
X 
 
 
X  
 
 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
Anti-HBs 
X(c)  
X(c)  
X 
X(c)  
X 
X 
Anti pre-S1, anti pre-S2 
X(c)  
X(c)  
X 
X(c)  
X 
X 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X X(d)  
X(d)  
 
X(d)  
 
 
Subject instructed to complete 
diary 
 
X 
X 
X 
X 
 
X 
X 
 
 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
48 | P a g e 
CONFIDENTIAL 
 
 
 
 
Recording Local & Systemic 
Reactions 
 
X 
X(e) 
X 
X(e) 
 
X 
X(e) 
 
 
Recording Concomitant 
Medications 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Unsolicited AEs
X 
X 
X(g) 
X(g) 
X(g) 
X(f) X(g) 
X(g) 
X(g) 
X(f) 
SAEs, medically significant event,
NOCI (h)
Continuous 
Sub-Studies (only at select sites) 
 
 
A1* 
 
A2*  
 
A3* 
 
 
Serum chemistry , Hematology 
X(c) 
x(k) 
 
x(k)  
 
x(k) 
 
 
Cell-mediated immunity 
X(c) 
x(k) 
 
x(k)  
 
x(k) 
 
 
 
(a) Or earlier in case of withdrawal 
(b) Full physicals to be done at screening or pre-vaccination at
Day 0. History-directed physicals can be completed at
subsequent visits. 
(c) Blood sample at V1, V2 & V4 will be taken before vaccination 
(d) Vital signs will be recorded before and 30 minutes after each 
vaccination. 
(e) Subjects will be instructed to record solicited and unsolicited
AES. There will be a telephone call 1 week after each
vaccination to inquire about reaction to vaccine. If there is a
reaction the subject may be asked to come for a
supplemental visit (not represented in this table) to assess
severity at the discretion of the investigator. Follow-up until
resolution. 
(f) Only AEs requiring medical attention 
(g) All AEs 
(h) NOCI: new onset of chronic illness 
(i) V3 should be scheduled at least 3 weeks after V2 
(j) V5 should be scheduled at least 3 weeks after V4 
(k) Blood sample collected 7 days (-3/+7 days) after vaccination 
* Additional visits (A1, A2 and A3) required for study subjects at
select sites participating in the clinical laboratory sub-study. A small
subset of subjects participating in the clinical laboratory sub-study
will be eligible to participate in an optional sub-study on cell-
mediated immunity. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
49 | P a g e 
CONFIDENTIAL 
 
 
 
15.3 Appendix 3: FDA guidelines for grading vaccine reactions 
 
Table 4: FDA Grading of Injection site reactions 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Pain (pain without 
touching) 
 
Does not 
interfere with 
activity 
Repeated use of 
non- 
narcotic pain 
reliever 
Any use of 
narcotic pain 
reliever or 
prevents daily 
 
Emergency room (ER) 
visit or 
hospitalization 
Tenderness 
(pain when area is 
touched) 
 
Mild discomfort 
to touch 
 
Discomfort with 
movement 
 
Significant 
discomfort at rest 
 
ER visit or 
hospitalization 
 
Pruritis associated 
with injection 
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized 
to injection site 
AND Relieved 
spontaneously 
or with< 48 
hours 
treatment 
Itching beyond the 
injection site but 
not generalized OR 
Itching localized to 
injection site 
ƌĞƋƵŝƌŝŶŐшϰϴ
hours treatment 
Generalized itching 
causing inability to 
perform usual 
social & 
functional 
activities 
 
 
 
NA 
Erythema/Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative dermatitis 
 
Induration/Swelling 
** 
2.5 – 5 cm and 
does not 
interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
 
Necrosis 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
50 | P a g e 
CONFIDENTIAL 
 
 
 
Table 5: FDA Grading of vital signs abnormalities 
 
Vital Signs * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
(°F) * 
38.0 – 38.4 
00.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
A 
39.0 – 40 
B 102.1 – 104 
> 40 
> 104 
Tachycardia - beats 
per minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats 
per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension 
(systolic) - mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension 
(diastolic) - mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension (systolic) 
– mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 - 100 beats per minute. Use clinical judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
51 | P a g e 
CONFIDENTIAL 
 
 
 
Table 6: FDA Grading of systemic reactions 
 
Systemic 
(General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 
- 2 episodes/24 
hours 
Some 
interference with 
activity or > 2 
episodes/24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 - 3 loose stools 
or < 400 g/24 
hours 
4 - 5 stools or 
400 - 800 g/24 
hours 
6 or more 
watery stools or 
> 800gms/24 
hours or 
requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic 
pain reliever > 24 
hours or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
52 | P a g e 
CONFIDENTIAL 
 
 
 
15.4 Appendix 4: FDA guidelines for grading clinical laboratory abnormalities 
The laboratory values provided in the tables below serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
Conversion factors to SI units will be provided in the laboratory manual. 
 
Table 7: FDA Grading of blood chemistry abnormalities 
 
Serum * 
Mild (Grade 1) Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 4)** 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 < 125 
Sodium – Hypernatremia mEq/L 
144 – 145 
146 – 147 
148 – 150 > 150 
Potassium – Hyperkalemia 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 
Glucose – Hypoglycemia mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia Fasting – 
mg/dL 
Random – mg/dL 
100 – 110 110 – 
125 
111 – 125 126 
– 200 
 
>125 >200 Insulin requirements or 
hyperosmolar coma 
Blood Urea Nitrogen BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 
12.0 
> 12.0 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x 
ULN 
3.1 –10 x 
ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
53 | P a g e 
CONFIDENTIAL 
 
 
 
Serum * 
Mild (Grade 1) Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 4)** 
Alkaline phosphate – increase by 
factor 
1.1 – 2.0 x ULN 2.1 – 3.0 x 
ULN 
3.1–10 
xULN 
> 10 x ULN 
Liver Function Tests –ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 2.6 – 5.0 x 
ULN 
5.1 – 10 x 
ULN 
> 10 x ULN 
Bilirubin – when accompanied 
by any increase in Liver Function 
Test increase by factor 
1.1 – 1.25 x 
ULN 
1.26 – 1.5 x 
ULN 
1.51 – 
1.75 x ULN 
 
> 1.75 x ULN 
Bilirubin – when Liver Function Test 
is normal; increase by factor 
1.1 – 1.5 x ULN 1.6 – 2.0 x 
ULN 
2.0 – 3.0 x 
ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, 
lipase 
1.1 – 1.5 x ULN 1.6 – 2.0 x 
ULN 
2.1 – 5.0 x 
ULN 
> 5.0 x ULN 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they 
are appropriate. ** The clinical signs or symptoms associated with laboratory abnormalities might result 
in characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, 
a low sodium value that falls within a grade 3 parameter (125-129 mEq/L) should be recorded as a grade 
4 hyponatremia event if the subject had a new seizure associated with the low sodium value. 
***ULN” is the upper limit of the normal range. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
54 | P a g e 
CONFIDENTIAL 
 
 
 
Table 8: FDA Grading of hematology tests abnormalities 
 
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening (Grade 4) 
Hemoglobin (Female) - 
gm/dL 
11.0 – 
12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from baseline 
value - gm/dL 
Any 
decrease 
– 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - 
gm/dL 
12.5 – 
13.5 
10.5 – 12.4 
8.5 – 10.4 < 8.5 
Hemoglobin (Male) 
change from baseline 
value – gm/dL 
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 2,500 – 
3,500 
1,500 – 
2,499 
1,000 – 
1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm3 
750 – 
1,000 
500 – 749 
250 – 499 < 250 
Neutrophils Decrease - 
cell/mm3 
1,500 – 
2,000 
1,000 – 
1,499 
500 – 999 < 500 
Eosinophils - cell/mm3 
650 – 
1500 
1501 - 5000 > 5000 
Hypereosinophilic 
Platelets Decreased - 
cell/mm3 
125,000 – 
140,000 
100,000 – 
124,000 
25,000 – 
99,000 
< 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 
x ULN** 
1.11 – 1.20 
x ULN 
1.21 – 
1.25 x 
ULN 
> 1.25 ULN 
PTT – increase by factor 
(partial thromboplastin 
time) 
1.0 – 1.2 x 
ULN 
1.21 – 1.4 x 
ULN 
1.41 – 1.5 
x ULN 
> 1.5 x ULN 
Fibrinogen increase - 
mg/dL 
400 – 500 501 – 600 
> 600 
-- 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
55 | P a g e 
CONFIDENTIAL 
 
 
 
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening (Grade 4) 
Fibrinogen decrease - 
mg/dL 
150 – 200 125 – 149 
100 – 124 < 100 or associated with gross 
bleeding or disseminated intravascular 
coagulation (DIC) 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they 
are appropriate. 
** “ULN” is the upper limit of the normal range. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
56 | P a g e 
CONFIDENTIAL 
 
 
 
Table 9: FDA Grading of urinalysis abnormalities 
 
Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for hyperglycemia 
Blood (microscopic) – 
red blood cells per 
high power field 
(rbc/hpf) 
 
1 - 10 
 
11 – 50 
 
> 50 and/or 
gross blood 
 
Hospitalization or packed red 
blood cells (PRBC) transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they 
are appropriate. 

Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) 
Version 2.0– July 17, 2017, Amendment 1 
57 | P a g e 
CONFIDENTIAL 
 
 
 
15.5 Appendix 5: NYHA functional classification 
 
Table 10: NYNA Classification of physical activity 
 
 
 
Class Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. 
If any physical activity is undertaken, discomfort increases.