A Double-blind Randomized Controlled Trial to Assess the Lot-to-lot Consistency of Sci-B-Vac™ in Adults (CONSTANT)
Phase: PHASE3
Conditions: Hepatitis B Vaccines
Sponsor: VBI Vaccines Inc.

STUDY PROTOCOL 
 
 
Official Title:  A Double-blind Randomized Controlled Trial to Assess the Lot-to-lot 
Consistency of Sci-B-Vac™ in Adults (CONSTANT) 
 
 
 
Protocol Identifying Number:  Sci-B-Vac–002  
 
 
NCT Number:  NCT03408730 
 
 
Version:  4.0  
 
 
Date of Version:  May 9, 2018  
 
 
Study Sponsor:  
VBI Vaccines Inc.  
310 Hunt Club Road East Ottawa, ON K1V 1C1 Canada  
Telephone: (613) 749-4200  
 
 
 

 
 
TITLE: 
A Double-blind Randomized Controlled Trial to Assess the Lot-to-lot  
Consistency of Sci-B-Vac™ in Adults (CONSTANT) 
 
 
Protocol Identifying Number: 
Sci-B-Vac–002 
 
EudraCT Number: 2017-001820-22  
 
 Version: 4.0 
Amendment 3 
Date of version: 
 
 May 09, 2018 
 
 
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. 

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Sponsor Signature Page  
Sponsor Signatory:  
 
 
 
 
 
 
 
 
 
 
 
 
09/05/2018 
Francisco Diaz-Mitoma    
Chief Medical Officer 
VBI Vaccines Inc. 
310 Hunt Club Road East 
Ottawa, ON K1V 1C1 
Canada  
Telephone: (613) 749-4200 
 
          Date (dd/mm/yyyy)  
 
 
F
i
Di
 
 
 
Mit

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Table of contents 
List of figures ....................................................................................................................... vii 
List of tables ........................................................................................................................ vii 
List of abbreviations ............................................................................................................ viii 
Statement of Compliance ..................................................................................................... ix 
PROTOCOL SUMMARY ........................................................................................................... x 
SCHEMATIC OF STUDY DESIGN............................................................................................. xix 
PROTOCOL AMENDMENTS Sci-B-Vac-002 .............................................................................. xx 
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 
Primary objective ................................................................................................................3 
2.2 
Secondary objectives ...........................................................................................................4 
2.3 
Exploratory objectives .........................................................................................................4 
3 
STUDY DESIGN AND ENDPOINTS ..................................................................................... 5 
3.1 
Study design .......................................................................................................................5 
3.2 
Immunogenicity endpoints ..................................................................................................5 
3.3 
Safety endpoints .................................................................................................................6 
4 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................................... 6 
4.1 
Subjects population .............................................................................................................6 
4.1.1 
Inclusion criteria .................................................................................................................... 7 
4.1.2 
Exclusion criteria ................................................................................................................... 7 
4.2 
Enrollment procedures ........................................................................................................9 
4.3 
Subject withdrawal .............................................................................................................9 
4.3.1 
Subject withdrawal from the study ...................................................................................... 9 
4.3.2 
Subject withdrawal from investigational product .............................................................. 10 
4.4 
Termination of study or suspension of study ...................................................................... 10 
5 
STUDY AGENTS ............................................................................................................. 11 
5.1 
Sci-B-Vac™ ........................................................................................................................ 11 
5.1.1 
Acquisition........................................................................................................................... 11 
5.1.2 
Formulation and Labelling .................................................................................................. 11 
5.1.3 
Product Storage .................................................................................................................. 11 
5.2 
Comparator Engerix-B® ..................................................................................................... 12 

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5.2.1 
Acquisition........................................................................................................................... 12 
5.2.2 
Formulation and Labelling .................................................................................................. 12 
5.2.3 
Product Storage .................................................................................................................. 12 
5.3 
Dosage, preparation administration of study vaccines ........................................................ 12 
5.4 
Accountability procedures for the study vaccines ............................................................... 12 
5.5 
Destruction of unused products ......................................................................................... 13 
5.6 
Rescue medications, treatments, and procedures .............................................................. 13 
5.6.1 
Safety Follow-up and management of reactions to vaccines ............................................. 13 
5.6.2 
Management of non-responders ........................................................................................ 14 
6 
STUDY PROCEDURES ..................................................................................................... 14 
6.1 
Detailed description .......................................................................................................... 14 
6.1.1 
Informed consent ................................................................................................................ 14 
6.1.2 
Check inclusion and exclusion criteria ................................................................................ 14 
6.1.3 
Collect demographic data ................................................................................................... 14 
6.1.4 
Medical history.................................................................................................................... 14 
6.1.5 
Physical examination........................................................................................................... 14 
6.1.6 
Vital signs ............................................................................................................................ 14 
6.1.7 
Treatment allocation ........................................................................................................... 15 
6.1.8 
Study product administration ............................................................................................. 15 
6.1.9 
Check and Record Concomitant Medication and Intercurrent Medical Conditions ........... 15 
6.1.10 
Recording of adverse events ............................................................................................... 16 
6.2 
Laboratory evaluations ...................................................................................................... 17 
6.2.1 
Urine pregnancy test ........................................................................................................... 17 
6.2.2 
Screening laboratory evaluations ....................................................................................... 17 
6.2.3 
Immunogenicity .................................................................................................................. 18 
6.2.4 
Clinical laboratory sub-study .............................................................................................. 18 
6.2.5 
Biological samples handling, storage and analysis ............................................................. 19 
6.3 
Study schedule of events ................................................................................................... 19 
6.3.1 
Screening ............................................................................................................................. 19 
6.3.2 
Vaccination visits ................................................................................................................. 20 
6.3.3 
Safety follow-up .................................................................................................................. 21 
6.3.4 
Supplemental visit(s) ........................................................................................................... 21 
6.3.5 
Immunogenicity and safety visit post third vaccination ..................................................... 21 
6.3.6 
Sub-study additional visits .................................................................................................. 21 
6.3.7 
End of study visit ................................................................................................................. 21 
7 
ASSESSMENT OF SAFETY ............................................................................................... 22 
7.1 
Specification of safety parameters ..................................................................................... 22 
7.1.1 
Adverse Events .................................................................................................................... 22 
7.1.2 
Serious Adverse Events ....................................................................................................... 22 
7.1.3 
Pre-existing conditions ........................................................................................................ 23 
7.1.4 
Procedures .......................................................................................................................... 23 
7.1.5 
Laboratory test abnormalities and other abnormal assessments ...................................... 23 
7.1.6 
Grading of AEs ..................................................................................................................... 23 
7.1.7 
Assessment of the outcomes ............................................................................................. 24 
7.1.8 
Causality .............................................................................................................................. 24 

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7.1.9 
Unexpectedness.................................................................................................................. 25 
7.1.10 
Suspected adverse reaction ................................................................................................ 25 
7.2 
Methods and timing for assessing, and recording safety parameters .................................. 25 
7.2.1 
AEs ....................................................................................................................................... 25 
7.2.2 
Vital signs and vaccine reactions ........................................................................................ 26 
7.2.3 
Laboratory test abnormalities............................................................................................. 26 
7.2.4 
SAEs, Medically Significant Event and New Onset of Chronic Illness ................................. 26 
7.3 
Expedited reporting procedures to study sponsor and pharmacovigilance agent ................. 27 
7.3.1 
Serious Adverse Events ....................................................................................................... 27 
7.3.2 
Reporting of pregnancy....................................................................................................... 27 
7.4 
Reporting to regulatory authorities .................................................................................... 27 
7.5 
Institutional Reporting of AEs and SAEs ............................................................................. 28 
7.6 
Type and duration of follow-up of subjects after AEs .......................................................... 28 
7.7 
Unblinding ........................................................................................................................ 28 
7.8 
Stopping Rules .................................................................................................................. 29 
7.9 
Safety oversight ................................................................................................................ 29 
8 
MONITORING ............................................................................................................... 30 
9 
STATISTICAL CONSIDERATIONS ..................................................................................... 31 
9.1 
Sample size ....................................................................................................................... 31 
9.2 
Randomization .................................................................................................................. 31 
9.3 
Analysis Sets ..................................................................................................................... 32 
9.3.1 
All Enrolled Set .................................................................................................................... 32 
9.3.2 
Safety Set ............................................................................................................................ 32 
9.3.3 
Full Analysis Set (FAS) ......................................................................................................... 32 
9.3.4 
Per Protocol Set (PPS) ......................................................................................................... 32 
9.3.5 
Sub Groups .......................................................................................................................... 32 
9.4 
Analysis of Demographic and Baseline Characteristics ........................................................ 33 
9.5 
Primary Objective.............................................................................................................. 33 
9.5.1 
Primary Hypothesis ............................................................................................................. 33 
9.5.2 
Statistical Methods for Primary Immunogenicity Analysis ................................................. 33 
9.6 
Secondary Objective .......................................................................................................... 34 
9.6.1 
Secondary Hypothesis ......................................................................................................... 34 
9.6.2 
Statistical Methods for Secondary Immunogenicity Analysis ............................................. 34 
9.7 
Exploratory Analyses ......................................................................................................... 34 
9.8 
Analysis of Safety Objectives ............................................................................................. 35 
9.8.1 
Analysis of Extent of Exposure ............................................................................................ 35 
9.8.2 
Analysis of Solicited Local, Systemic and Other Adverse Events ........................................ 35 
9.8.3 
Analysis of Vital Signs and Laboratory Parameters ............................................................. 36 
9.9 
Planned Interim Report ..................................................................................................... 36 
10 
DATA HANDLING AND RECORD KEEPING ................................................................... 36 
10.1 
Data management responsibilities ..................................................................................... 36 
10.2 
Data capture methods ....................................................................................................... 37 
10.3 
Types of data .................................................................................................................... 37 
10.4 
Study records retention ..................................................................................................... 37 

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10.5 
Protocol deviations ........................................................................................................... 37 
11 
QUALITY CONTROL AND QUALITY MANAGEMENT ..................................................... 38 
12 
STUDY REGISTRATION AND RESULTS INFORMATION ................................................. 38 
13 
ETHICAL / REGULATORY CONSIDERATIONS ................................................................ 38 
13.1 
Relevant ethical body ........................................................................................................ 38 
13.2 
Ethics Review and informed consent .................................................................................. 39 
14 
REFERENCES .............................................................................................................. 41 
15 
APPENDICES .............................................................................................................. 43 
15.1 
Appendix 1: Schedule of Events ......................................................................................... 44 
15.2 
Appendix 2: FDA guidelines for grading vaccine reactions ................................................... 46 
15.3 
Appendix 3: FDA guidelines for grading clinical laboratory abnormalities ............................ 49 
 
 
 

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List of figures  
Figure 1: Schematic of Study Design ........................................................................................................... xix 
Figure 2: Sci-B-Vac™ (left) compared to a 2nd generation HBV vaccine (right) ............................................. 2 
 
List of tables  
Table 1: Unsolicited AEs severity scale ....................................................................................................... 23 
Table 2: Injection site reactions grading ..................................................................................................... 46 
Table 3: Grading of vital signs abnormalities .............................................................................................. 47 
Table 4: Systemic reactions......................................................................................................................... 48 
 
 
 

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List of abbreviations 
aa: amino acid 
Ab: antibody 
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 
bp: base pair 
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. 
DMC: data monitoring committee 
EEA: European economic area  
EPO: erythropoietin 
E.U.: European Union 
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 
GMP: Good Manufacturing Practice 
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 
IWRS: interactive web response system 
LLN: lower limit of normal range  
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 
ђg: microgram 
PT: prothrombin time 
SAE: serious adverse event 
SBP: systolic blood pressure  
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: white blood cells count 

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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 all relevant ethical review bodies as defined in section 13 of 
this protocol. Any change to the protocol that affects subject selection, safety, or changes in the conduct 
of the trial will require written approval from all relevant ethical review bodies 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 relevant ethical review body 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) 
 

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PROTOCOL SUMMARY  
Title 
A Double-blind Randomized Controlled Trial to Assess the Lot-to-lot 
Consistency of Sci-B-Vac™ in Adults 
Clinical Trial Phase 
3 
Study sponsor 
VBI Vaccines Inc. 
Number of sites  
30-40 sites (Canada, Europe, United States) 
 Background & 
Rationale 
Hepatitis B virus (HBV) is a human double-stranded enveloped DNA virus 
that causes an acute infection that, 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 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 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 was 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. 
For Engerix-B®, the 1 mL dose containing 20 ђg of HBsAg is the formulation 
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-HBs) ш10mIU/mL, 4 weeks after the third 
injection, 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) ш10mIU/mL, is accepted as an immunological 
surrogate of clinical protection against HBV infection.  
While the SPRs elicited by currently licensed hepatitis B vaccines in children 
and adolescents are high (ш98%)6, up to 10% of all adults fail to achieve anti-

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HBs levels ш10mIU/mL 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 ђg 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 primary objective of the 
current study is to verify that the manufacturing equivalence of Sci-B-Vac™ 
is consistent and 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-dose vial (1.0 mL) contains 10 ʅg of hepatitis B surface 
antigens adsorbed onto 0.5 mg of aluminum as aluminum hydroxide 

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[Al(OH)3], sodium chloride, potassium chloride, disodium hydrogen 
phosphate dodecahydrate, potassium dihydrogen phosphate anhydrous 
and water for injection. 
Three consecutive lots of Sci-B-Vac™ will be used in this study, each 
containing 10 ʅg of hepatitis B surface antigen with aluminum hydroxide as 
an adjuvant, delivered as a 1.0 mL intramuscular injection:  
x 
Group A: Sci-B-Vac™ “Lot A”  
x 
Group B: Sci-B-Vac™ “Lot B” 
x 
Group C: Sci-B-Vac™ “Lot C” 
ACTIVE COMPARTOR 
Engerix-B® (1.0 mL single dose vials), delivered as an intramuscular 
injection. 
Each vial contains 20 ђg of hepatitis B surface antigen S adsorbed onto 0.5 
mg of aluminum as aluminum hydroxide. 
Study Design 
(see also Figure 1)  
This is a double-blind 4-arm randomized study.  Subjects age 18-45 years 
will be randomly assigned to one of 3 lots of Sci-B-Vac™ or to Engerix-B® 
with a ratio 1:1:1:1 using a web-based randomization system to be 
immunized against Hepatitis B virus (HBV) with one of three independent 
consecutive lots of Sci-B-Vac™ or Engerix-B®, according to a three-dose 
immunization schedule. Study subjects will receive 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). Subjects will be followed for 24 weeks after the 
third injection. 
Randomization will be stratified by study center. 
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 5 visits (noted V1, V2, V3, V4, and end of study visit, V5). Subjects 
will be followed a minimum of 48 weeks after the first injection on Study 
Day 0, with at least 24 weeks of follow-up safety assessments after the third 
injection. 
Immunization will consist of three single dose vaccinations with one of three 
different Sci-B-Vac™ lots or Engerix-B® injected intramuscularly (IM) 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. Subjects will remain in the clinic at least 30 minutes after each 
vaccination to be observed for rare adverse reactions. 
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 

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assessments, subjects may be asked to come for supplemental visits for 
clinical assessment if warranted.  In addition, the study center will also 
contact the subject by telephone 4 weeks after the second vaccination to 
assess the subject’s status. 
Immunogenicity will be assessed at baseline (Study Day 0) and on Study 
Days 168, 196 and 336. A validated quantitative hepatitis B surface antibody 
[anti-HBs] will be used (see below primary endpoint).  
Safety evaluations will include standardized methods for local and systemic 
vaccine reactions, repeated vital signs and physical examinations, 48 week 
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. 
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 
3,200 subjects (800 subjects per study arm) 
Study Population: 
Adults 18-45 years old, meeting all the inclusion criteria and none of the 
exclusion criteria below.  
Inclusion criteria 
Subjects must meet all the following criteria:  
1. Any gender 
2. Age 18-45 years 
3. Healthy, as determined by a physical examination and values of 
laboratory tests  
4. If female: 
a) either is not of childbearing potential, defined as postmenopausal 
(12 months with no menses without an alternative medical cause) 

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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 informed consent 
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 
doseര> 20 mg /day (Inhaled and topical steroids are allowed). 
3. 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, autommune hemolytic 
anemia, autoimmune hepatitis, psoriasis, vitiligo, vasculitis, 
Guillain-Barré syndrome, Addison’s disease, Bell’s Palsy and 
Alopecia Areata);  
b) secondary 
immunodeficiency 
disorders 
(e.g. 
Acquired 
Immunodeficiency Syndrome caused by Human Immunodeficiency 
Virus infection (HIV/AIDS), solid organ transplant, splenectomy);  

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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 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.  
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.  
13. Unwilling, or unable in the opinion of the investigator, to comply with 
study requirements, including the use of adequate birth control 
methods.  
14. Immediate family members of study center staff (parents, siblings, 
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 

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virologic response (SVR) or negative viral load 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. BMI ш 35. 
20. Uncontrolled hypertension (defined as an average SBP ш 150 mmHg or 
an average DBP ш 95 mmHg based on the last three measurements in 
individuals diagnosed and treated for hypertension, and in people 
without a diagnosis of hypertension).  
21. Diagnosis of Type 1 or Type 2 diabetes or HbA1C ш 6.5% at screening. 
22. Any laboratory test abnormality that would be considered of Grade 1 
severity or above as per FDA guidelines for grading clinical laboratory 
abnormalities (see Appendix 3 in Protocol) and is considered as 
clinically significant by the investigator.  Grade 3 severity or above is 
exclusionary, regardless of clinical assessment. 
Study Duration  
~15-18 months (recruitment period + 12 month 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 Objective 
 
To 
demonstrate 
the 
manufacturing 
equivalence, 
in 
terms 
of 
immunogenicity, of three independent consecutive lots of the Sci-B-Vac™ 4 
weeks after the third vaccination on Study Day 196. This objective will be 
met if the following condition is satisfied:  
x 
The upper and lower bound of the two sided 95% confidence interval 
(CI) of the geometric mean concentration (GMC) of anti-HBs ratios 4 
weeks after the third injection, for all three pairwise comparisons (GMC 
of anti-HBs in group A/GMC of anti-HBs in group B, GMC of anti-HBs in 
group A/ GMC of anti-HBs in group C, GMC of anti-HBs in group B/ GMC 
of anti-HBs in group C), are within [0.67, 1.5] 
Secondary Objectives  
Immunogenicity 
To demonstrate that the SPR 4 weeks after completion of the three-dose 
regiment of Sci-B-Vac™ is non-inferior to a three-dose regimen of Engerix-
B®, i.e. the lower bound of the 95% two-sided confidence interval (CI) of the 

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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. 
Safety 
To assess the safety and reactogenicity of Sci-B-Vac™ compared to Engerix-
B® 
Exploratory Objectives 
x 
To assesses the Geometric Mean Concentration (GMC) of anti-HBs in 
serum after 2 vaccinations, just prior to receiving the third vaccination, 
and 24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, 
on Study Days 168 and 336, respectively.  
x 
To assesses  the seroprotection rate after 2 vaccinations, just prior to 
receiving the third vaccination, and 24 weeks after the third vaccination 
with Sci-B-Vac™ or Engerix-B®, on Study Days 168 and 336, respectively. 
Seroprotection is defined as anti-HBs levels ш 10mIU/mL in serum. 
Seroprotection Rate (SPR) is the percentage (%) of subjects achieving 
seroprotection.  
x 
To assess the proportion of subjects achieving anti-HBs levels ш 
100mIU/mL in serum, as a measure of an especially robust immune 
response, on Study Days 168 and 196, just prior to and 4 weeks after 
the third vaccination with Sci-B-Vac™ or Engerix-B®, and on Study Day 
336.  
x 
To assess the rate of non-response on Study Day 196, 4 weeks after the 
third vaccination with Sci-B-Vac™ or Engerix-B®. Rate of non-response 
is defined as the proportion of subjects not attaining anti-HBs levels ш 
10mIU/mL in serum. 
x 
To assess SPR, GMC and rate of non-response in sub-groups of interest 
(e.g. BMI > 30), 4 weeks after receiving the third vaccination with Sci-B-
Vac™ or Engerix®. 
Each of the above exploratory objectives will be assessed for each Sci-B-
Vac™ lot separately, as well as for the difference between each Sci-B-Vac™ 
lot.  In addition, they will also be assessed for all 3 lots of Sci-B-Vac™ pooled 
together, for the Engerix-B® group and for the difference between all 3 
pooled lots of Sci-B-Vac™ and Engerix-B®. 
 
Immunogenicity 
Endpoints 
x 
Geometric Mean Concentration (GMC) of anti-HBs in serum after 2 
vaccinations, just prior to receiving the third vaccination, and 4 weeks 
and 24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, 
on Study Days 168, 196, and 336, respectively. The GMC at Study Day 

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196 is the basis for assessing lot-to-lot consistency of the three 
consecutive lots of Sci-B-Vac™. 
x 
Seroprotection rate after 2 vaccinations, just prior to receiving the third 
vaccination, and 4 weeks and 24 weeks after the third vaccination with 
Sci-B-Vac™ or Engerix-B®, on Study Days 168, 196, and 336, respectively. 
Seroprotection is defined as anti-HBs levels ш 10mIU/mL in serum. 
Seroprotection rate (SPR) is the percentage (%) of subjects achieving 
seroprotection.  
x 
Proportion of subjects achieving anti-HBs levels ш 100mIU/mL in serum, 
on Study Days 168 and 196, just prior to and 4 weeks after the third 
vaccination with Sci-B-Vac™ or Engerix-B®, and on Study Day 336.  
x 
Rate of non-response on Study Day 196, 4 weeks after the third 
vaccination with Sci-B-Vac™ or Engerix-B®. Rate of non-response is 
defined as the proportion of subjects not attaining anti-HBs levels ш 
10mIU/mL in serum. 
x 
SPR, GMC and rate of non-response in sub-groups of interest (e.g. BMI 
> 30), 4 weeks after receiving the third vaccination with Sci-B-Vac™ or 
Engerix®. 
Safety endpoints 
x 
Number (%) of subject-reported, solicited (on the day of vaccination and 
during the next 6 days), number (%) of unsolicited adverse events (AE) 
(on the day of vaccination and during the next 27 days), and number (%) 
of SAEs, medically significant event or new onset of chronic illness 
(through 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; physical examination 
findings, compared to baseline. 
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). 
 
 

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SCHEMATIC OF STUDY DESIGN  
 
Figure 1: Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL AMENDMENTS Sci-B-Vac-002  
 
Protocol Version  
Issue Date 
Original Protocol 
5 May 2017 
Amendment 1 
Amendment 2  
17 July 2017 
04 December 2017 
Amendment 3  
09 May 2018 
 
Amendment 3 (09 May 2018) 
The overall reason for the amendment:  The overall reason for the amendment is to reduce the 
Glomerular Filtration Rate (GFR) threshold to <60 mL/min/1.73 m2, to allow subjects with mild loss of 
kidney function to be enrolled to the study.   
Applicable Section(s) 
Description of Change(s) 
 
 
Protocol Summary 
“Exclusion criteria” 
and Section 4.1.2 
“Exclusion criteria” 
and Section 6.2.2 
“Screening laboratory 
evaluation”. 
The glomerular Filtration Rate (GFR) threshold for exclusion criteria #18 
has been reduced from <90 to <60 mL/min/1.73 m2.  
Rationale: The Glomerular Filtration Rate (GFR) threshold was reduced to <60 mL/min/1.73 m2, 
to allow subjects with mild loss of kidney function to be enrolled to the study. 
Section 6.1.3 “Collect 
Demographic Data“ 
and Section 6.2.2 
“Screening laboratory 
evaluations“  
Weight was removed as a factor contributing to the GFR calculation.  
Race was added as a factor used to calculate GFR. 
Rationale: Clarification provided that weight is not used to calculate GFR using the CKD-EPI 
creatinine equation.  
 

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Amendment 2 (04 December 2017) 
The overall reason for the amendment: The overall reason for the amendment is to provide 
clarification in Section 6.1.9 on which medications are not permitted during the study and to specify in 
Section 7.1.9 that the reference safety information in the U.S. product insert will be used to establish 
expectedness of adverse events for the comparator, Engerix-B. Clarification on the collection and 
storage of laboratory blood samples and re-testing procedures during screening is also provided. 
Changes are listed in the order in which they appear in the protocol. 
Applicable Section(s) 
Description of Change(s) 
Protocol Summary “Inclusion 
Criteria” and Section 4.1.1 
Inclusion criteria 
Postmenopausal is now defined as 12 consecutive months with no 
menses without an alternative medical cause. 
Rationale: To improve clarity. 
Section 6.1.9 “Concomitant 
medications and intercurrent 
medical conditions” 
Section 6.1.9 has been revised to make it clear that the medications 
not permitted on study are the same as those listed in the exclusion 
criteria, and if taken may result in treatment withdrawal (per Section 
4.3.2).   
Rationale: To improve clarity of treatment withdrawal criteria “received a non-permitted medication” 
in Section 4.3.2. 
Section 6.2.5 “Biological 
samples, handling, storage and 
analysis” 
Details of blood storage and procedures for the withdrawal and 
destruction of samples is now provided. 
Rationale: Details and procedures of the storage and destruction of blood samples added to the 
protocol, for consistency with the informed consent.  
Section 6.2.5 “Biological 
samples, handling, storage and 
analysis” 
Clarification provided on the provision of a central laboratory 
manual, detailing the handling, shipping, storage and analysis of 
blood samples for immunogenicity testing. Screening and safety 
laboratory samples will be collected, processed and analyzed 
according to local standard operating procedures. 
Rationale: Clarification that a laboratory manual will only be provided for blood samples for centralized 
immunogenicity testing. 

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Section 6.3.1 “Screening” 
The re-test procedure during the screening window (-28 Days to 0) is 
now defined. 
Rationale: To improve clarity on when re-testing during screening is permitted, how it should be 
documented and the approval process. 
Section 7.1.9 “Expectedness” 
Section 7.1.9 has been revised to include that unexpectedness for 
Engerix-B will be determined based on reference safety information 
that appears in the U.S. product insert.  
Rationale: To provide clarity on the reference document used to establish the expectedness of adverse 
events of Engerix-B. 
 
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 to 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 to 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. 
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Protocol Summary 
“Investigational 
Product” and Section 
5.1.2 Formulation 
and Labelling” 
“10 ђg of Hepatitis B surface antigen with aluminum hydroxide 
(Al(OH)3) as an adjuvant (0.5 mg/mL)” changed to “10 ʅg of hepatitis 
B surface antigens adsorbed onto 0.5 mg of aluminum as aluminum 
hydroxide”.  Repeated text after each defined Lot (A, B, C) removed 
for clarity and preceding sentence revised accordingly. 
Rationale: Clarification on the amount of aluminum per 1 mL in the aluminum hydroxide 
adjuvant. 
“Protocol Summary” 
– Study Design 
Change made to reflect that clinical laboratory assessments will be 
carried out in study subset (at least 10% of the study cohort) 
throughout the full three-dose regimen (clinical laboratory sub-
study), 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” 
and Section 4.1.2 
“Exclusion Criteria” 
#21, Section 6.2.2 
Screening laboratory 
evaluations , 
Appendix 1 Schedule 
of Events 
HbA1C added as a screening test and exclusion criteria #21 expanded 
to include people with an HbA1C ш 6.5% at screening. 
Rationale: A screening test for HbA1C has been added to the list of screening laboratory tests 
in order to exclude people from the study with undiagnosed diabetes. People with an HbA1C 
ш 6.5% will not be eligible to participate in the study.  
“Protocol Summary” 
and Section 4.1.2 
“Exclusion Criteria” 
#20 
The definition of uncontrolled hypertension (SBP ш150 mmHg or DBP 
ш95 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. 

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“Protocol Summary” 
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). 
“Protocol Summary” 
and Section 3.3 
“Safety Endpoints” 
Separate safety endpoint now defined for the number (%) of subjects 
with abnormal clinical laboratory tests, from clinical laboratory sub-
study.  
Rationale: This clarification was provided to delineate this endpoint as specific to the clinical 
laboratory sub-study.  
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 laboratory assessments at Day 0 and 7 days after 
each vaccination (on Study Day 7, 35 and 175).  
Rationale: To improve clarity and consistency within the protocol and to accurately reflect the 
laboratory safety assessments in the clinical laboratory sub-study.   

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Sections 3.1, 6.2.4, 
6.3.2, 6.3.5, 6.3.6 
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 3.3 “Safety 
Endpoints”  
Urinalysis removed from the Day 7 list of safety evaluations. 
Rationale: Urinalysis removed from the list of evaluations, to be consistent with Appendix 1 
Schedule of Events. 
Section 3.3 “Safety 
Endpoints” 
Baseline values (Study Day 0) added as a reference for assessing 
abnormal clinical laboratory tests in the clinical laboratory sub-study. 
Rationale: Change from baseline in clinical laboratory values is an important measure of the 
impact of vaccination on laboratory parameters.  
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: 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 “Safety 
follow up and 
management of 
reactions” 
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.  

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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. The original safety laboratory Visit 2, seven days 
after the first vaccination, has been replaced in the main study with 
a follow up telephone call. 
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 
clarify that a follow-up telephone call will occur 7 days after each vaccination, for consistency 
with section 3.1. 
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 
vaccines. 
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 6.2.2 
“Screening Laboratory 
Evaluations”  
HbA1C has been added to the list of screening evaluations.  
Rationale: To identify and exclude people with undiagnosed diabetes from the study.  People 
meeting this criteria will be referred for follow-up care.  
Section 6.2.3 “Safety 
laboratory 
evaluations” 
Section 6.2.3 has been removed and replaced with new section 6.2.4. 
“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 
clinical 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).   

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6.2.5 “Biological 
samples, handling, 
analysis and storage” 
Changes made to reflect new sample requirements for clinical 
laboratory assessments (clinical laboratory sub-study, select sites) 
one week after each vaccination. 
Rationale: Changes made to reflect sample requirements for the main study and the clinical 
laboratory sub-study. 
Section 6.3.1 
“Screening” 
 Addition of Urinalysis to the list of tests to be done at screening.  
Rationale: Addition was made for consistency with the Appendix 1 Schedule of Events and 
Section 6.2.2 Screening Laboratory Evaluations. 
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 or 
attenuated vaccines within 4 weeks of any vaccination.  
Rationale: Sentence restructured to improve clarity. 
Section 6.3.2 
“Vaccination Visit” 
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: 6.3.3 “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 
(select sites) and removal of the 7-day laboratory evaluation in the full study cohort.  A 7-day 
follow-up telephone call is now done after each vaccination in the main study.   
New Section 6.3.6 
“Sub-study additional 
visits” added and new 
Section 6.3.7 “End of 
Study visit”  
Additional study visits for clinical laboratory sub-study at select sites 
are now defined.  End of study visit is now Section 6.3.7. 

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Rationale: To clarify the additional visit requirements for the clinical laboratory sub-study. 
Section 6.3.6 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. 
Rationale: Clarification is provided as to the nature/intensity and duration of safety 
monitoring required during the conduct of the study. 
Section 7.7 
“Unblinding” 
The word ‘serious’ was added to define Suspected, Unexpected, 
Serious, Adverse Reaction (SUSAR) 
Rationale: Correct definition of SUSAR provided.  
Appendix 1 Schedule 
of Events  
Addition of HbA1C to the list of evaluations at screening. 
Rationale: HbA1C was included as part of the screening evaluations in order to identify and 
exclude people meeting the study exclusion criteria from participating in the study.  

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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. For Engerix-B®, the 1 mL dose 
containing 20 ђg of HBsAg is the formulation 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) ш10 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) ш10 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 adolescent are high 
(ш98%)6, up to 10% of all adults fail to achieve anti-HBs levels ш10 mIU/mL 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, 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%17. 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 
incremental approach consisting of: 1) giving one additional vaccine dose followed by anti-HBs testing 1–

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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 
Equatorial, Hong Kong, Moldova, Niger, Nigeria, Philippines and Senegal, in 3 dosages: 2.5 ʅg and 5 ʅg 
HBsAg/0.5 mL for use in neonates, infants and children up to 10 years of age, and 10 ʅg HBsAg/1 mL for 
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 previously.14 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-VacTM 15,16. Synthetic pre-S antigens have been found to protect chimpanzees against HBV 
challenge18. In addition, the pre-S2 protein has the following properties: 1) it binds polymerized human 
serum albumin in vitro; and 2) the pre-S2 has a domain that can also act as a B cell epitope. These 

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properties may contribute to an enhanced immunogenicity of pre-S2 19,20. Pre-S2 may also help in the 
attachment of HBV to hepatocytes, which may be prevented through an adequate anti-pre-S2 response21. 
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 antibody22. 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 neutralization23. 
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 Days 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 ђg 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 verify that the manufacturing equivalence of Sci-B-Vac™ is 
consistent, and 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 Primary objective 
To demonstrate the manufacturing equivalence, in terms of immunogenicity, of three independent 
consecutive lots of the Sci-B-Vac™ 4 weeks after the third vaccination. This objective will be met if the 
following condition is satisfied:  

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x 
The upper and lower bound of the two sided 95% CI of the geometric mean concentration (GMC) of 
anti-HBs ratios 4 weeks after the third injection, for all three pairwise comparisons (GMC of anti-HBs 
in group A/GMC of anti-HBs in group B, GMC of anti-HBs in group A/ GMC of anti-HBs in group C, GMC 
of anti-HBs in group B/ GMC of anti-HBs in group C), are within [0.67, 1.5]; 
 
2.2 Secondary objectives  
Immunogenicity 
To demonstrate that the SPR 4 weeks after completion of the three-dose regiment of Sci-B-Vac™ is non-
inferior to a three-dose regimen of Engerix-B®, i.e. 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. 
 
Safety 
x 
To assess the safety and reactogenicity of Sci-B-Vac™ compared to Engerix-B® 
2.3 Exploratory objectives  
The following are exploratory objectives: 
x 
To assess the Geometric Mean Concentration (GMC) of anti-HBs in serum after 2 vaccinations, just 
prior to receiving the third vaccination, and 24 weeks after the third vaccination with Sci-B-Vac™ or 
Engerix-B®, on Study Days 168 and 336, respectively.  
x 
To assess  the seroprotection rate after 2 vaccinations, just prior to receiving the third vaccination, 
and 24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, on Study Days 168 and 336, 
respectively. Seroprotection is defined as anti-HBs levels ш 10mIU/mL in serum. Seroprotection Rate 
(SPR) is the percentage (%) of subjects achieving seroprotection.  
x 
To assess the Proportion of subjects achieving anti-HBs levels ш 100mIU/mL in serum, as a measure of 
an especially robust immune response, on Study Days 168 and 196, just prior to and 4 weeks after the 
third vaccination with Sci-B-Vac™ or Engerix-B®, and on Study Day 336.  
x 
To assess the rate of non-response on Study Day 196, 4 weeks after the third vaccination with Sci-B-
Vac™ or Engerix-B®. Rate of non-response is defined as the proportion of subjects not attaining anti-
HBs levels ш 10mIU/mL in serum. 
x 
To assess SPR, GMC and rate of non-response in sub-groups of interest (e.g. BMI > 30), 4 weeks after 
receiving the third vaccination with Sci-B-Vac™ or Engerix®. 
Each of the above exploratory objectives will be assessed for each Sci-B-Vac™ lot separately, as well as for 
the difference between each Sci-B-Vac™ lot.  In addition, they will also be assessed for all 3 lots of Sci-B-
Vac™ pooled together, for the Engerix-B® group and for the difference between all 3 pooled lots of  Sci-B-
Vac™ and Engerix-B®. 
 

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3 STUDY DESIGN AND ENDPOINTS  
3.1 Study design  
This is a double-blind 4-arm randomized study.  Subjects age 18-45 years will be randomly assigned to one 
of 3 lots of Sci-B-Vac™ or to Engerix-B® with a ratio 1:1:1:1 using a web-based randomization system to 
be immunized against the Hepatitis B virus (HBV), according to a three-dose immunization schedule, and 
followed for 24 weeks after the third vaccination.  
Randomization will be stratified by study center. 
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 5 visits (noted V1, V2, 
V3, V4, and end of study, V5). 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. 
Immunization will consist of three single dose treatments with one of three different Sci-B-Vac™ lots or 
Engerix-B®. Each subject will receive one injection of 1 mL of Sci-B-Vac™ or Engerix-B® injected 
intramuscularly (IM) in the deltoid muscle at 0, 4 weeks (Study Day 28), and 24 weeks (Study Day 168).  
Subjects will remain in the clinic at least 30 minutes after each vaccination for rare adverse reactions. 
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 a 
supplemental visit for clinical assessment if warranted. In addition, the study center will also contact the 
subject 4 weeks after the second vaccination to assess the subject’s status. 
Immunogenicity (measurement of anti-HBs levels and characteristics) will be assessed on Study Days 0, 
168, 196 and 336. A validated quantitative hepatitis B surface antibody (anti-HBs) test will be used to 
measure the level of anti-HBs (see below primary endpoint).  
Safety evaluations will include standardized methods for local and systemic vaccine reactions, repeated 
vital signs and physical examinations, 48 week follow-up for SAEs, medically significant event or new onset 
of chronic illness (at least 24 weeks after the third dose of vaccine), and changes in concomitant 
medication.  
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 1 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.  
The total study duration for each subject (assuming a screening period of 28 days) is 364 days. The 
schedule of assessments and timelines are detailed in section 6.3 and in Appendix 1: Schedule of Events . 
3.2 Immunogenicity endpoints 
x 
Geometric Mean Concentration (GMC) of anti-HBs in serum after 2 vaccinations, just prior to receiving 
the third vaccination, and 4 weeks and 24 weeks after the third vaccination with Sci-B-Vac™ or 
Engerix-B®, on Study Days 168, 196, and 336, respectively. The GMC at Study Day 196 is the basis for 
assessing lot-to-lot consistency of the three consecutive lots of Sci-B-Vac™. 

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x 
Seroprotection rate after 2 vaccinations, just prior to receiving the third vaccination, and 4 weeks and 
24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, on Study Days 168, 196, and 336, 
respectively. Seroprotection is defined as anti-HBs levels ш 10mIU/mL in serum. Seroprotection rate 
is the percentage (%) of subjects achieving seroprotection. 
x 
Proportion of subjects achieving anti-HBs levels ш 100mIU/mL in serum after 2 vaccinations, just prior 
to receiving the third vaccination, and 4 weeks and 24 weeks after the third vaccination with Sci-B-
Vac™or Engerix-B® on Study Days 168, 196, and 336, respectively.   
x 
Rate of non-response on Study Day 196, 4 weeks after the third vaccination with Sci-B-Vac™ or 
Engerix-B®.  Rate of non-response is defined as the proportion of subjects not attaining anti-HBs levels 
ш 10mIU/mL in serum.  
x 
SPR, GMC and rate of non-response in sub-groups of interest (e.g. BMI > 30), 4 weeks after receiving 
the third vaccination with Sci-B-Vac™ or Engerix®. 
3.3 Safety endpoints  
Standard clinical parameters for evaluating the safety of a biologic or vaccine product will be used, 
including the following: standardized methods for local and systemic vaccine reactions classified by 
severity within predefined categories, repeated vital signs and physical examinations, 48-week follow-up 
for SAE (at least 24 weeks after the third vaccination), 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.  
x 
Number (%) of subjects who reported solicited AEs (on the day of vaccination and during 
the next 6 days), number (%) of unsolicited AEs (on the day of vaccination and during the 
next 27 days), and number (%) of SAEs, 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) 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; physical examination findings compared 
to baseline. 
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) 
 
4 STUDY ENROLLMENT AND WITHDRAWAL  
4.1 Subjects population 
The study will enroll approximately 3,200 subjects, 18-45 years old, in at least 30 study centers in the E.U., 
Canada and the U.S. Both men and women of all races and ethnic groups are eligible for this trial.  

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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. Age 18-45 years. 
3. Healthy, as determined by a physical examination and values of laboratory tests. 
4. If female: 
a) either not of childbearing potential, defined as postmenopausal (12 months with no 
menses without an alternative medical cause) 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 informed 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 > 20 mg /day 
prednisolone equivalent (Inhaled and topical steroids are allowed). 
3. 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);  

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b) secondary immunodeficiency disorders (e.g. Acquired Immunodeficiency Syndrome caused by 
Human Immunodeficiency Virus infection (HIV/AIDS), solid organ transplant, splenectomy);  
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 prior to study entry or 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.  
9. Has received granulocyte-macrophage 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 an 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.  
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 infection 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 viral load 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) of <60 mL/min/1.73m2 
19. Body mass index (BMI) ш 35. 
20. Uncontrolled hypertension (defined as an average SBP ш 150 mmHg or an average DBP ш 95 mmHg 
based on the last three measurements in people diagnosed and treated for hypertension, and in 
people without a diagnosis of hypertension).  
21. Diagnosis of Type 1 or Type 2 diabetes or HbA1C ш 6.5% at screening. 

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22. Any laboratory test abnormality that would be considered of Grade 1 severity or above as per FDA 
guidelines for grading clinical laboratory abnormalities (see Appendix 3 in Protocol) AND is 
considered as clinically significant by the investigator. Grade 3 severity or above is exclusionary, 
regardless of clinical assessment. 
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 enrollment. Consenting subjects will be informed that the study site staff will provide 
them with their serology results at the end of the study, once the database has been locked.  
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 an authorized 
member of the study team will access the enrollment page in the interactive web response system (IWRS). 
The authorized staff will be prompted to complete the enrolment page in the IWRS, including the subject’s 
year of birth 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 four study arms. A confirmation of the 
randomization (blinded) 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 confirmation notification, which must be filed in a locked area/computer folder not accessed by blinded 
study 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 evaluate, record and report AEs and SAEs as instructed 
in Section 7 (ASSESSMENT OF SAFETY). 
Withdrawals will not be replaced. 
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 end of study visit (V5)/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 enquire about changes in contact information at each visit. Information will 

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be collected and stored in compliance with all applicable privacy and patients’ rights laws and institutional 
policies.  
Information relevant to the withdrawal will be documented in the eCRF. The investigator will document 
whether the decision to withdraw a subject from the study was made by the subject, the investigator or 
the medical monitor, 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 
immunization schedule, 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. 
Information relevant to premature discontinuation of the investigational product will be documented on 
the Study Exit 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 by the sponsor, a regulatory agency, 
the data monitoring committee or an ethical body. 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 

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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:  
x 
Determination of unexpected, significant, or unacceptable risk to subjects ͒ 
x 
Insufficient compliance to protocol requirements ͒ 
x 
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, relevant ethical body and regulatory agencies. ͒ 
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  
Details concerning the ordering, shipping, receiving, storage and handling of study agents are detailed in 
the pharmacy manual.  
5.1 Sci-B-Vac™ 
5.1.1 Acquisition  
Sci-B-Vac™ will be supplied by the study sponsor. 
5.1.2 Formulation and Labelling 
Sci-B-Vac™ will be supplied as 1.0 mL single-dose vial containing 10 ʅg of hepatitis B surface antigen 
adsorbed onto 0.5 mg of aluminum as aluminum hydroxide (Al(OH)3), sodium chloride, potassium 
chloride, disodium hydrogen phosphate dodecahydrate, potassium dihydrogen phosphate anhydrous and 
water for injection. 
Three independent consecutive lots of Sci-B-Vac ™ will be used in the trial, each containing 10 ђg of 
hepatitis B surface antigen with aluminum hydroxide (Al(OH)3) as an adjuvant, delivered as a 1.0 mL 
intramuscular injection: 
x 
Group A:   
Sci-B-Vac™ “Lot A” 
x 
Group B:   
Sci-B-Vac™ “Lot B” 
x 
Group C:   
Sci-B-Vac™ “Lot C” 
All 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).  

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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.  Engerix-B® will be delivered as an intramuscular 
injection.  
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  
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 an 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 an unblinded qualified health personnel, whose sole role is to 
prepare for, and administer the allocated study vaccine, and to perform related activities that require 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 unblinded health personnel 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. The study subject will not be told whether the study product is Sci-B-Vac™ or Engerix-
B®.  
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. 

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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). 
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. 
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 and stored separately 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. 
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: 
Subjects will remain in the clinic for at least 30 minutes after vaccination. The observation period will 
include an assessment of immediate solicited local and systemic reactions. Any unusual signs or symptoms 
reported during the initial 30 minutes of observation will prompt continued close monitoring. 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). 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).  
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. In addition, the study center will contact the 
subject on Day 56 (+/- 3 days), 4 weeks after the second vaccination to assess subject’s status. 
Subjects will be advised to record their temperature daily in the diary, on the day of vaccination and for 
the next six days.   
Refer to Sections 6.1.9 and 7 for further details on the recording, assessment, and reporting of adverse 
events and/or local and systemic reactions. 

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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 to not 
be seroprotected after completing the three-dose regimen (anti-HBs levels < 10mIU/mL in serum) 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 any study-related procedures.  
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, height, weight, race, ethnicity, 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.  
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 injection temporarily precludes injection, the visit will be rescheduled. 
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 (Study Day 0) and at each vaccination visit and recorded in the eCRF. Any abnormal vital sign 
after injection should be reassessed. 
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 
temperature. If the subject has a fever (defined as temperature ш38.0°C/100.4°F oral) on the day of 
injection, the vaccination visit will be rescheduled within the allowed treatment interval. 

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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 of the 
randomization, which must be filed in a locked area/computer folder not accessed by blinded study center 
staff. 
6.1.8 Study product administration  
After completing all prerequisite procedures, 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. This 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 the 
study 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 other licensed vaccines, must be checked and 
recorded in the eCRF.  
The use of the concomitant medications/products/vaccines listed below are not permitted on study and 
may result in withdrawal from the investigational product (see Section 4.3.2). The use of these 
concomitant medications 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 concomitant medications/products/vaccines listed below 
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 (inhaled and topical steroids are allowed). 
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 analysis 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. 

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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] and 
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.  
 Subjects will be asked to record the maximum pain, tenderness and pruritus 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.  
 The subject will record daily body temperature (oral) and any solicited local and systemic AEs 
(i.e., on the day of injection and during the next 6 days) and any unsolicited AEs (i.e., on the day 
of injection and during the next 27 days). The study center will also contact the subject by 
telephone 7 days after each vaccination to assess subject status and to remind the subject to 
complete the diary card and return it 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, and 4 weeks (+/- 7 days) after 
the second 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 Day 336. 
x 
Instructed to bring their diary cards to clinic visit on Study Days 28, 168, and 196 as follows: 
the diary card provided on Study Day 0 will be collected on day 28; the diary card provided 
on Study Day 28 will be collected on Study Day 168, and the diary card provided on Study 
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 an HBV vaccine. 
x 
Be informed of the appointments (date and time) for the next planned visits to the study 
center (Days 28, 168, 196, and 336). At select sites, subjects will also be required to come 

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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 transcribed to English 
from the diary card 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 vaccine 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 
negative viral load ш 12 weeks after cessation of antiviral 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  
 
GFR: will be automatically calculated upon input of serum creatinine value, age, 
gender and race in the eCRF using CKD-EPI Creatinine Equation (2009)24 
 
GFR < 60 mL/min/1.73 m2 is exclusionary  
o Alkaline phosphatase (AP), alanine transaminase (ALT), aspartate transaminase (AST), 
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o HbA1C will be tested at screening to identify people with undiagnosed diabetes.  
HbA1C ш 6.5% is exclusionary.  People found to have HbA1C ш 6.5% will be referred for 
follow up care.  
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 3 will be 
interpreted within the subject’s specific context (e.g. subject’s medical history, physical examination, 
other laboratory tests) by the investigator to determine whether the subject still meets the 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 hepatitis B surface antibody (anti-HBs) levels and characteristics) will 
be assessed on Study Day 0 (V1), on Day 168 (V3) just before the third vaccination, and 4 weeks and 24 
weeks after the third vaccination on Days 196 (V4) and on Day 336 (V5 end of study visit), respectively. 
A validated quantitative hepatitis B surface antibody test will be utilized to measure anti-HBs levels in 
serum.  
6.2.4 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 (Study 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 1 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) 
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)  

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Safety laboratory evaluations may be repeated if indicated (e.g. follow-up of a clinically significant 
laboratory abnormality (from baseline assessment)) 
6.2.5 Biological samples handling, storage and analysis  
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. 
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 up to 60 months (5 years) after the study has been completed for 
re-testing purposes, after which the samples will be destroyed. 
If consent is withdrawn after a blood sample has been taken, but before the samples are sent for testing, 
the study doctor will arrange to have the samples destroyed.  If consent is withdrawn after the samples 
have been sent for testing, the Sponsor and the study doctor will ensure that the sample is destroyed.  
However, if the testing has been performed, the Sponsor is not obliged to destroy the results of this 
research.  In this case, only the sample will be destroyed.  
A central laboratory manual will be provided to the clinical sites detailing the handling, analysis, storage 
and shipping of blood samples for immunogenicity testing.  Screening and safety laboratory blood samples 
will be collected, processed and analyzed according to local standard operating procedures.  Each clinical 
site will be provided with the conversion factors to SI (International System of units) to facilitate the 
grading of blood chemistry and hematology abnormalities, according to the FDA guidelines.  
 
6.3 Study schedule of events  
A schedule of events is available in Appendix 1. 
6.3.1 Screening  
The screening will be conducted within 28 days (4 weeks) of Visit 1 (V1).  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 V1 prior to injection) 
x 
Height and weight 
x 
Concomitant medications  
x 
Urine Pregnancy test (in females of childbearing potential) 
x 
Blood sampling for safety laboratory tests and serology testing (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. 

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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.  For tests conducted during screening to 
establish eligibility, one re-test will be permitted during the screening window (-28 Days to 0). If a re-test 
is performed, the second result of the test will be used to establish subject eligibility for study 
participation. The reason for the re-test (e.g., suspected hemolysis of a blood sample; inadequate urine 
specimen) will be recorded in the eCRF.  Approval from the Sponsor or their delegate should be sought 
before performing the re-test. 
6.3.2 Vaccination visits 
Vaccination will be administered at Visit 1, 2 and 3 (Study Day 0, Study Day 28 (-3 days/+7 days), and Study 
Day 168 (+/- 7 days, respectively)).   
On Day 0 (V1), 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 and there will be a review of any local and systemic reactions. There will also be a 
blood sample collection prior to the third vaccine administration (Study Day 168). 
Subject will remain in the clinic at least 30 minutes after each vaccination to be observed for rare adverse 
reactions.  
The following will be done at each vaccination visit: 
x 
Concomitant medications and any adverse reactions will be recorded  
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 will be taken prior to vaccination on Study Days 0 and 168, for baseline 
anti-HBs levels and characteristics (Study Day 0) and measurement of anti-HBs 
measurement levels and characteristics just prior to the third vaccination (Study Day 168).  
x 
Blood samples for assessment of clinical laboratory parameters will be taken on Study Day 
0, prior to vaccination (select sites). 
x 
Physical/History-directed physical examination will be done. 
x 
Vital signs will be assessed before and after the injection of study vaccine.  Any abnormal 
vital sign after injection should be reassessed. 
x 
Eligibility for receiving treatment will be reviewed by the investigator.  
x 
Study vaccine will be administered  
x 
Subject will be observed for 30 minutes after the injection  
x 
A new diary will be provided  
x 
The next visit will be scheduled  

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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 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), 4 weeks following the second 
vaccination or within 4 weeks of the third vaccination.   
6.3.3 Safety follow-up  
The study center will contact the subject by telephone 7 days after each vaccination to assess subject’s 
status and to remind the subject to complete the diary cards.  A scripted set of questions will be asked 
over the telephone to determine health status and safety clinical markers. 
In addition, the study center will contact the subject 4 weeks (+/- 3 days) after the second vaccination to 
assess subject’s status. 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 additional visit(s) for clinical assessment of an AE if warranted based 
on the telephone follow up safety assessment. The supplemental visit will be recorded in the eCRF.  
6.3.5 Immunogenicity and safety visit post third vaccination 
An immunogenicity visit (V4) will be scheduled 4 weeks after the third vaccination, on Day 196 (+/- 7 days): 
x 
Physical/History-directed physical examination 
x 
Blood samples for measurement of anti-HBs levels and characteristics will be taken.  
x 
Diary will be reviewed.  
x 
Adverse events and the use of concomitant medications will be recorded in the eCRF 
x 
Visit 4 should be scheduled at least 3 weeks after the third vaccination (Visit 3) 
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 1 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®. 
6.3.7 End of study visit  
The end of study visit (V5) will be performed on Day 336 +/-14 days or earlier in case of withdrawal. 
x 
Physical/History-directed physical examination 
x 
Blood samples for measurement of anti-HBs levels and characteristics will be taken.  
x 
Serious Adverse Events, AE requiring medical attention and the use of concomitant 
medications will be recorded in the eCRF 

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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 an anti-HBs levels <10 mIU/mL, becomes available. 
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  
Pre-existing symptoms or conditions which worsen during a study. 
7.1.2 Serious Adverse Events 
A Serious Adverse Event:  
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. 
භ  
Is a congenital anomaly/ birth defect. 
භ  
Is an important medical event 

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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 AE may jeopardize the subject or may require 
intervention to prevent more serious outcomes, then the AE should be treated as serious.  
7.1.3 Pre-existing conditions 
In this trial, a pre-existing condition (i.e. a disorder present before the AE reporting period started) should 
not be reported as an AE unless the condition worsens during the AE 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 non-invasive and invasive procedures, such as surgery, should not be reported 
as an 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 AE reporting 
period should be reported as an AE 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 AE 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 

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Grade 3 (Severe) 
Prevents daily activity and requires medical 
intervention 
Grade 4 (Potentially life threatening) 
Requiring Emergency Room (ER) visit or 
hospitalization 
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 2.  
7.1.6.3 
Laboratory tests abnormalities  
Laboratory tests abnormalities will be graded according to the FDA guidelines for grading clinical 
laboratory abnormalities (Appendix 3).  
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 
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7.1.9 Unexpectedness 
Adverse events and SAEs will also be assessed according to the following categories: 
For Sci-B-Vac ™ 
•  
Expected (anticipated): the event is identified in nature, severity, and frequency in the 
investigator brochure or in the protocol. 
• 
Unexpected (unanticipated): the event is not identified in nature, severity, or frequency in the 
investigator brochure or in the protocol. 
For Engerix-B® 
• 
Expected (anticipated): the event is identified in nature, severity, and frequency in the reference 
safety information in the U.S. product insert. 
• 
Unexpected (unanticipated): the event is not identified in nature, severity, or frequency in the 
reference safety information in the U.S. product insert. 
 
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 AE. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any AE caused by a drug. 
7.2 Methods and timing for assessing, and recording safety parameters 
Unless specified otherwise all AE occurring between obtaining written subject’s consent 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 has provided written consent 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.  

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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 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 
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 and recorded 
daily on the day of vaccination and for the next 6 days in the eCRF. 
 
Subjects will be asked to indicate the maximum pain, tenderness and pruritus 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 3) 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 SAEs, expected or unexpected, medically significant event and new onset of chronic illness occurring 
between the time the subject provides written consent and the last study visit will be documented in the 
eCRF, first in an AE form. For SAEs, upon completion of the AE form, and confirmation that the AE is an 
SAE, the investigator or delegate 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 

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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. 
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 of child-bearing potential 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 SAEs 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 (or delegate) 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.  

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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 delegate) 
must submit it as soon as possible, but no later than 15 calendars days after receiving the request.  
The study sponsor (or delegate) will submit periodic reports of the progress of the trial, if and as, 
requested by the regulatory authorities. 
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  
The blind should ordinarily be broken for regulatory submission.  
When reporting a Suspected Unexpected Serious Adverse Reaction (SUSAR) to regulatory authorities the 
sponsor shall only unblind the treatment allocation of the affected subject to whom the SUSAR relates.  
If an event is potentially a SUSAR the blind shall be broken for that subject only by the sponsor. The blind 
shall be maintained for other persons responsible for the ongoing conduct of the clinical trial (such as the 
management, monitors, investigators) and those persons responsible for data analysis and interpretation 
of results at the conclusion of the clinical trial, such as biometrics personnel.  
Unblinded information shall be accessible only to persons who need to be involved in the safety reporting 
to regulatory authorities, to the data monitoring committee, or to persons performing ongoing safety 
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Unblinding of sites in case of an emergency is not anticipated in this study since it is very unlikely that the 
knowledge of the vaccine or vaccine lot 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, 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 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 
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 
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 2) 
**FDA Grading of Clinical Laboratory Abnormalities (Appendix 3) 
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.   

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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, and then as often as necessary.  
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. 
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 for 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 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 clinical 
site 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 according to 
the defined monitoring plan. 
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 the relevant ethical body 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.  

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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. 
9.1 Sample size  
The sample size for this study is driven by the lot-to-lot consistency requirement. A total of 800 subjects 
in each of the three Sci-B-Vac™ lots will provide at least 90% power to ensure that the 95% confidence 
interval for each pairwise difference (GMC of anti-HBs in group A/GMC of anti-HBs in group B, GMC of 
anti-HBs in group A/ GMC of anti-HBs in group C, GMC of anti-HBs in group B/ GMC of anti-HBs in group 
C) in normalized log10 (GMC) will have a lower bound that is >-0.176 and an upper bound that is <0.176 if 
the true standard deviation is ч0.9; this corresponds to the true GMC ratio falling between 2/3 and 3/2. 
With an active comparator arm of Engerix-B® of equal size (n=800), the total sample size of the study is 
3,200. 
If lot-to-lot consistency is demonstrated, all three Sci-B-Vac™ lots will be pooled together to  test that the 
Seroprotection Rate (SPR) four weeks after completion of the three-dose regimen of Sci-B-Vac™ is non-
inferior to a three-dose regimen of Engerix-B®.  Assuming 10% of the subjects are non-evaluable (i.e., 2880 
are evaluable, with 2160 randomized to Sci-B-Vac™ and 720 to Energix-B®), a two-sided 5% significance 
level and a non-inferiority margin of – 5%, the non-inferiority test will have > 90% power.  The following 
table provides the estimated power under different assumptions of the SPR four weeks after completion 
of the three-dose regimens. 
Response in Energix-B® 
(N=720) 
Response in Sci-B-VacTM 
(N=2160) 
Power 
80% 
85% 
99% 
85% 
85% 
92% 
90% 
95% 
99% 
 
9.2 Randomization  
This is a double blind 4-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.  Randomization will be via a web-based 
IWRS, stratified by study center.  The site pharmacy and/or unblinded study center staff will receive a 
notification of the randomization, which should be filed in a locked area/ computer folder not accessed 
by blinded study center staff.   

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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 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. 
9.3.4 Per Protocol Set (PPS) 
All subjects in the FAS who: 
x 
received all 3 vaccinations 
x 
have an evaluable serum samples at baseline and at the time point of interest 
x 
are seronegative 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 that is judged to impact the 
reliability of subject immunogenicity results 
x 
Subjects with a deviation identified through monitoring visits or otherwise, where the deviation 
is judged to impact the reliability of subject immunogenicity results 
9.3.5 Sub Groups 
The following key sub-groups of interest will be pre-specified:  
x 
Gender (male vs female) 
x 
BMI (ч 30 vs > 30) 
x 
Smoking Status (current vs past or non-smoker) 
x 
Daily alcohol consumption (ш4 drinks/day vs 2-3 drinks/day vs 0-1 drink/day) 
x 
Non-study licensed vaccine (no vaccination vs vaccination) 
x 
Race and ethnicity 

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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.  Data will be 
summarized by Sci-B-Vac™ lot, Sci-B-Vac™ treatment group and Engerix-B® treatment group.  
9.5 Primary Objective  
9.5.1 Primary Hypothesis 
The lot-to-lot equivalence, in terms of immunogenicity, of three independent consecutive lots of the Sci-
B-Vac™ will be demonstrated if the following condition is satisfied:  
The upper and lower bound of the two sided 95% CI of the geometric mean concentration (GMC) of anti-
HBs ratios 4 weeks after the third injection, for all three pairwise comparisons (GMC of anti-HBs in group 
A/GMC of anti-HBs in group B, GMC of anti-HBs in group A/ GMC of anti-HBs in group C, GMC of anti-HBs 
in group B/ GMC of anti-HBs in group C), are within [0.67, 1.5] 
 
The analysis will use a two-sided 5% significance level. The PPs will be used to test the primary hypothesis.  
9.5.2 Statistical Methods for Primary Immunogenicity Analysis 
Missing Data 
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 immunogenicity analysis will 
comprise a complete case analysis only, without introducing any bias. Imputation methods will not be 
used.  
Geometric mean concentration (GMC) of anti-HBs ratios 4 weeks after the third injection  
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 will each be determined using an analysis of 
covariance (ANCOVA) model with a factor for vaccine lot group, and a covariate for the log transformed 
pre-vaccination (baseline) titer. Data from all centers will be pooled. For each vaccine lot, anti-HBs GMCs, 
associated standard errors, two-sided 95% CIs and median, minimum, and maximum titer values will be 
determined and presented by lot group. The median, minimum, and maximum values will be reported on 
the actual titer values, rather than the log scale. The ratio in GMCs between each vaccine lot group (GMC 
of anti-HBs in group A/ GMC of anti-HBs in group B, GMC of anti-HBs in group A/ GMC of anti-HBs in group 
C, GMC of anti-HBs in group B/ GMC of anti-HBs in group C), and their associated two-sided 95% CIs will 
also be presented.  
Sensitivity analyses using the same modeling approach outlined above will be conducted using the FAS. 
These analyses will be reported both with and without patients in the FAS who are seropositive at 
baseline. 
If this condition is satisfied, then manufacturing equivalence (lot-to-lot consistency) will be demonstrated.  
If consistency is demonstrated, then the data from the three lots will be combined to address the 
secondary immunogenicity non inferiority-hypothesis. 

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9.6 Secondary Objective  
9.6.1 Secondary Hypothesis 
If the primary hypothesis test is successful, the secondary hypothesis will be tested.  The secondary 
hypothesis is 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-B®. Seroprotection is defined as anti-HBs levels ш 
10mIU/mL in serum. Seroprotection rate (SPR) is the percentage (%) of subjects achieving seroprotection. 
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%.” 
The analysis will use a two-sided 5% significance level. The PPs will be used to test the secondary 
hypothesis.  
9.6.2 Statistical Methods for Secondary Immunogenicity Analysis 
For the secondary endpoint of SPR at day 196, 4 weeks following the third vaccination, data from all 
centers will be pooled and data from all 3 lots of Sci-B-Vac™ will be pooled. The difference in proportions 
and two-sided 95% CIs, will be calculated using the Miettnen and Nurminen method. For immunogenicity 
data, it may be reasonable to consider missing immunogenicity values as missing completely at random 
(MCAR), i.e., not informative. Therefore, this primary analysis will comprise a complete case analysis only 
without introducing any bias. Imputation methods will not be used. This analysis will use the PPS.  
The impact of center will be investigated through funnel plots. 
Sensitivity analyses using the same approach outlined above will also be conducted using the FAS. These 
analyses will be reported both with and without patients in the FAS who are seropositive at baseline.   
 
9.7 Exploratory Analyses 
Analysis of all exploratory immunogenicity endpoints will be based on the PPS, unless otherwise indicated. 
No adjustment for multiplicity will be made. All analyses will comprise a complete case analysis only.  Data 
from all centers will be pooled. 
The following exploratory immunogenicity endpoints will be summarized: 
x 
Geometric Mean Concentration (GMC) of anti-HBs in serum after 2 vaccinations, just prior to receiving 
the third vaccination, and 24 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, on Study 
Days 168 and 336, respectively.  
x 
Seroprotection rate after 2 vaccinations, just prior to receiving the third vaccination, and 24 weeks 
after the third vaccination with Sci-B-Vac™ or Engerix-B®, on Study Days 168 and 336, respectively. 
Seroprotection is defined as anti-HBs levels ш 10mIU/mL in serum. Seroprotection rate (SPR) is the 
percentage (%) of subjects achieving seroprotection.  
x 
Proportion of subjects achieving anti-HBs levels ш 100mIU/mL in serum, on Study Days 168 and 196, 
just prior to and 4 weeks after the third vaccination with Sci-B-Vac™ or Engerix-B®, and on Study Day 
336.  

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x 
Rate of non-response on Study Day 196, 4 weeks after the third vaccination with Sci-B-Vac™ or 
Engerix-B®. Rate of non-response is defined as the proportion of subjects not attaining anti-HBs levels 
ш 10mIU/mL in serum. 
x 
SPR, GMC and rate of non-response in sub-groups of interest (e.g. BMI > 30), 4 weeks after receiving 
the third vaccination with Sci-B-Vac™ or Engerix®. 
Each of the above endpoints will be summarized for each Sci-B-Vac™ lot separately, as well as for the 
difference between each Sci-B-Vac™ lot.  Analysis of GMC endpoints will use the same methods as 
described above for the primary endpoint. For binary data, proportions and two-sided 95% CIs will be 
reported.  The difference in proportions and two-sided 95% CIs, will be calculated using the Miettnen and 
Nurminen method. 
In addition, each of the above endpoints will be summarized with data from all 3 lots of Sci-B-Vac™ pooled 
together.  Summaries will be presented for Sci-B-Vac™, Engerix-B® and for the treatment difference.  
Adjusted estimates of GMCs and their associated 95% CIs will each be determined using an analysis of 
covariance (ANCOVA) model with a factor for treatment group, and a covariate for the log transformed 
pre-vaccination (baseline) titer. For each treatment group, anti-HBs 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 ratio in GMCs between treatment groups (GMC of anti-HBs in Sci-B-
Vac™ / GMC of anti-HBs in Engerix-B®), and their associated two-sided 95% CIs will also be presented.  For 
binary data, proportions and two-sided 95% CIs will be reported.  The difference in proportions and two-
sided 95% CIs, will be calculated using the Miettnen and Nurminen method. 
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. For all safety summaries, data from each Sci-B-Vac™ lot will be presented both 
individually as well as pooled together, while data from Engerix-B® will be presented separately to allow 
for comparisons.  All safety analyses will be presented 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 Sci-B-Vac™ lot, Sci-B-Vac™ treatment group and Engerix-B® 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 2. 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).  
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 

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summaries will be presented overall by time point (i.e., after each vaccination). 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 
- 
AEs that are very likely, probably or possibly related to vaccine 
- 
AEs of special interest 
- 
AEs leading to vaccine/study withdrawal 
9.8.3 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. 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 2 for vital signs and Appendix 3 for laboratory 
parameters.  
9.9 Planned Interim Report 
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 
principal investigator. During the study, the investigator must maintain complete and accurate 
documentation for the study. 

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10.2 Data capture methods 
Clinical data (including AEs, concomitant medications, and reactogenicity 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. 
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 site, as 
dictated by ICH GCP, any institutional requirements, applicable laws or regulations, including national laws 
governing the archiving of medical files of subjects; otherwise, the minimum retention period will default 
to 25 years after the end of the clinical trial. 
The investigator/institution must notify the Sponsor of any changes in the archival arrangements, 
including, but not limited to, archival at an off-study site facility, transfer of ownership of the records in 
the event the investigator leaves the study site. 
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 
5.1.1 Quality Assurance and Quality Control, Section 5.20 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. 

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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 relevant 
ethical body to institution policies. The site PRINCIPAL INVESTIGATOR /study staff is responsible for 
knowing and adhering to their institution policies. 
11 QUALITY CONTROL AND QUALITY MANAGEMENT 
Standard Operating Procedures (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, beginning with the data entry system and generate data quality control checks that 
will be run on the database. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
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 ClinicalTrials.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 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).  

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An Independent Ethics committee 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 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 Principal 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 Principal 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 Principal 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 Principal 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.  

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Records of all study review and approval documents must be kept on file by the Principal 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 
Principal 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. 
 
 

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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. 

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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. 
Canadian Immunization Guide: Part 4 - Active Vaccines-Hepatitis B Vaccine 
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.) 
18. 
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. 
19. 
Stephanne J. Development and production aspects of a recombinant yeast-derived hepatitis B 
vaccine. Vaccine 1990;8 Suppl:S69-73; discussion S9-80. 
20. 
Neurath AR, Kent SB, Strick N, Taylor P, Stevens CE. Hepatitis B virus contains pre-S gene-encoded 
domains. Nature 1985;315:154-6. 
21. 
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. 
22. 
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. 
23. 
Coppola N, Onorato L, Minichini C, et al. Clinical significance of hepatitis B surface antigen 
mutants. World J Hepatol 2015;7:2729-39. 
24. 
National 
Kidney 
Foundation. 
CKD-EPI 
Creatinine 
Equation. 
 
[available 
at: 
https://www.kidney/org/content/ckd-epi-creatinine-equation-2009, accessed on March 16, 2017]  
 
 
 
 

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15 APPENDICES 

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15.1 Appendix 1: Schedule of Events 
 
Screening 
Visit 
V1  
Safety 
Follow-up 
Phone Call  
V2 
Safety 
Follow-up 
Phone Call  
Safety 
Follow--up  
Phone Call  
V3 
Safety 
Follow-up  
Phone Call  
V4 ( I ) 
V5 
End of 
Study Visit 
Timelines (days) 
-28 
0 
 
28 
 
 
168 
 
196 
336(a) 
Range (days) 
-28 
to 0 
 
V1 
+ 5-9 
-3/+7 
V2 
+ 5-9 
V2 
+21-35 
+/-7 
V3 
+ 5-9 
+/-7 
+/-14 
Screening 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Exam (b) 
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 
 
 
 
Serum chemistry, 
hematology, HbA1C 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Inclusion & Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Confirmation of 
enrollment 
X 
X 
 
 
 
 
 
 
 
 
Vaccination 
 
X 
 
X 
 
 
X 
 
 
 
Immunogenicity 
 
X (c) 
 
 
 
 
X (c) 
 
X 
X 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X (d) 
 
X (d) 
 
 
X (d) 
 
X 
 
Subject instructed to 
complete diary 
 
X 
X 
X 
X 
 
X 
X 
 
 
Local & Systemic 
Reactions 
 
X 
X(e) 
X 
X(e) 
X(e) 
X 
X(e) 
 
 
Unsolicited Non Serious 
AEs 
 
X 
X(g) 
X(g) 
X(g) 
X(g) 
X(f) 
X(g) 
X(g) 
X(f) 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events, 
Medically significant 
event and NOCI (h) 
Continuous 
Sub-Study (select sites) 
 
 
A1* 
 
A2* 
 
 
A3* 
 
 
Serum chemistry, 
hematology 
 
X (c)  
X(j) 
 
X(j) 
 
 
X(j) 
 
 
 
(a) Or earlier in case of withdrawal (reason for withdrawal to be documented in eCRF) 
(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 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 7 days 
(+/-2 days) after each vaccination, and 28 days (+/- 7 days) after the second vaccination to inquire about 
AEs. 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.  

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(f) 
Only AEs requiring medical attention 
(g) All AEs 
(h) NOCI = new onset of chronic illness 
(i) 
Visit 4 should be scheduled at least 3 weeks after Visit 3 
(j) 
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.  

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15.2 Appendix 2: FDA guidelines for grading vaccine reactions  
Table 2: Injection site reactions grading  
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pain (pain without 
touching) 
Does not 
interfere with 
activity 
Repeated use 
of non- 
narcotic pain 
reliever 
> 24 hours or 
interferes 
with activity 
Any use of 
narcotic pain 
reliever or 
prevents 
daily activity 
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 
Pruritus associated 
with injection 
See also Skin: 
Pruritus (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 requiring 
ш 48 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. 
 
 
 
 

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Table 3: 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 
39.0 – 40 
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. 
 
 
 
 
 
 
 
 
 
 

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Table 4: 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 
> 800g/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 
 
 
 

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15.3 Appendix 3: 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 to the clinical sites. 
 
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 

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Serum *  
Mild (Grade 
1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 4)** 
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 
-- 
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.  
  
 
 

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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 

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Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening (Grade 4) 
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 
-- 
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.  
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.