A Hepatitis B Vaccine Challenge Study to Demonstrate the Durability of Protection Against Hepatitis B Virus Infection in Healthy Children Vaccinated Approximately 9 Years Previously With a 2- or 3-Dose Infant Series and Toddler Dose of Vaxelis®
Phase: PHASE3
Conditions: Hepatitis B
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04490499 
Document Date: 
27-Apr-2020
A Hepatitis B Vaccine Challenge Study to Demonstrate the 
Durability of Protection Against Hepatitis B Virus Infection in 
Healthy Children Vaccinated Approximately 9 Years Previously 
With a 2- or 3-Dose Infant Series and Toddler Dose of Vaxelis®

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Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Hepatitis B Vaccine Challenge Study to Demonstrate the Durability of 
Protection Against Hepatitis B Virus Infection in Healthy Children Vaccinated 
Approximately 9 Years Previously With a 2- or 3-Dose Infant Series and Toddler Dose of 
Vaxelis®
Protocol Number: 013-00
Compound Number: V419
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
Not applicable
EudraCT
2020-000126-26
Approval Date: 27 April 2020
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Original Protocol
27-APR-2020
Not applicable
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................10
1.1
Synopsis.................................................................................................................10
1.2
Schema ..................................................................................................................13
1.3
Schedule of Activities...........................................................................................14
2
INTRODUCTION..........................................................................................................15
2.1
Study Rationale....................................................................................................15
2.2
Background ..........................................................................................................16
2.3
Benefit/Risk Assessment......................................................................................16
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................17
4
STUDY DESIGN............................................................................................................17
4.1
Overall Design......................................................................................................17
4.2
Scientific Rationale for Study Design.................................................................18
4.2.1
Rationale for Endpoints ...............................................................................18
4.2.1.1
Immunogenicity Endpoints................................................................18
4.3
Justification for Dose...........................................................................................19
4.4
Beginning and End of Study Definition .............................................................19
4.4.1
Clinical Criteria for Early Study Termination .............................................19
5
STUDY POPULATION ................................................................................................19
5.1
Inclusion Criteria.................................................................................................20
5.2
Exclusion Criteria................................................................................................20
5.3
Lifestyle Considerations......................................................................................22
5.4
Screen Failures.....................................................................................................22
5.5
Participant Replacement Strategy......................................................................22
6
STUDY INTERVENTION............................................................................................22
6.1
Study Intervention(s) Administered...................................................................22
6.2
Preparation/Handling/Storage/Accountability .................................................24
6.2.1
Dose Preparation..........................................................................................24
6.2.2
Handling, Storage, and Accountability........................................................24
6.3
Measures to Minimize Bias: Randomization and Blinding..............................25
6.3.1
Intervention Assignment..............................................................................25
6.3.2
Stratification.................................................................................................25
6.3.3
Blinding........................................................................................................25
6.4
Study Intervention Compliance..........................................................................25
6.5
Concomitant Therapy..........................................................................................25
 
 
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6.5.1
Rescue Medications and Supportive Care ...................................................25
6.6
Dose Modification (Escalation/Titration/Other)...............................................26
6.7
Intervention After the End of the Study............................................................26
6.8
Clinical Supplies Disclosure................................................................................26
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................26
7.1
Discontinuation of Study Intervention...............................................................26
7.2
Participant Withdrawal From the Study...........................................................26
7.3
Lost to Follow-up .................................................................................................26
8
STUDY ASSESSMENTS AND PROCEDURES........................................................27
8.1
Administrative and General Procedures ...........................................................28
8.1.1
Informed Consent/Assent.............................................................................28
8.1.1.1
General Informed Consent/Assent.....................................................28
8.1.2
Inclusion/Exclusion Criteria ........................................................................28
8.1.3
Participant Identification Card.....................................................................29
8.1.4
Medical History ...........................................................................................29
8.1.5
Prior and Concomitant Medications Review...............................................29
8.1.5.1
Prior Medications...............................................................................29
8.1.5.2
Concomitant Medications..................................................................29
8.1.6
Assignment of Screening Number...............................................................29
8.1.7
Assignment of Treatment/Allocation Number.............................................30
8.1.8
Study Intervention Administration ..............................................................30
8.1.8.1
Timing of Dose Administration.........................................................30
8.1.9
Discontinuation and Withdrawal .................................................................30
8.1.10
Participant Blinding/Unblinding..................................................................30
8.1.11
Calibration of Equipment.............................................................................31
8.2
Immunogenicity Assessments .............................................................................31
8.2.1
Hepatitis B ECi Assay .................................................................................31
8.3
Safety Assessments...............................................................................................31
8.3.1
Physical Examinations.................................................................................32
8.3.2
Body Temperature Measurement.................................................................32
8.3.3
Clinical Laboratory Assessments.................................................................32
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................32
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................33
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......34
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...34
 
 
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8.4.4
Regulatory Reporting Requirements for SAE .............................................35
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................35
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................35
8.4.7
Events of Clinical Interest............................................................................35
8.5
Treatment of Overdose........................................................................................35
8.6
Pharmacokinetics.................................................................................................36
8.7
Pharmacodynamics..............................................................................................36
8.8
Biomarkers ...........................................................................................................36
8.9
Planned Genetic Analysis Sample Collection....................................................36
8.10
Future Biomedical Research Sample Collection...............................................36
8.11
Medical Resource Utilization and Health Economics.......................................36
8.12
Visit Requirements...............................................................................................36
8.12.1
Screening......................................................................................................36
8.12.2
Treatment Period/Vaccination Visit ............................................................36
9
STATISTICAL ANALYSIS PLAN .............................................................................36
9.1
Statistical Analysis Plan Summary.....................................................................37
9.2
Responsibility for Analyses/In-house Blinding .................................................37
9.3
Hypotheses/Estimation ........................................................................................38
9.4
Analysis Endpoints...............................................................................................38
9.4.1
Immunogenicity Endpoints..........................................................................38
9.4.2
Safety Endpoints..........................................................................................38
9.5
Analysis Populations............................................................................................38
9.5.1
Immunogenicity Analysis Populations ........................................................38
9.5.2
Safety Analysis Populations ........................................................................39
9.6
Statistical Methods...............................................................................................39
9.6.1
Statistical Methods for Immunogenicity Analyses......................................39
9.6.2
Statistical Methods for Safety Analyses ......................................................39
9.7
Interim Analyses ..................................................................................................39
9.8
Multiplicity ...........................................................................................................39
9.9
Sample Size and Power Calculations .................................................................40
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................40
9.9.2
Sample Size and Power for Safety Analyses ...............................................40
9.10
Subgroup Analyses...............................................................................................41
9.11
Compliance (Medication Adherence).................................................................41
9.12
Extent of Exposure...............................................................................................41
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................42
 
 
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10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........42
10.1.1
Code of Conduct for Clinical Trials.............................................................42
10.1.2
Financial Disclosure.....................................................................................44
10.1.3
Data Protection.............................................................................................44
10.1.3.1
Confidentiality of Data ......................................................................45
10.1.3.2
Confidentiality of Participant Records...............................................45
10.1.3.3
Confidentiality of IRB/IEC Information............................................45
10.1.4
Committees Structure...................................................................................45
10.1.5
Publication Policy........................................................................................46
10.1.6
Compliance with Study Registration and Results Posting Requirements ...46
10.1.7
Compliance with Law, Audit, and Debarment ............................................46
10.1.8
Data Quality Assurance ...............................................................................47
10.1.9
Source Documents .......................................................................................48
10.1.10
Study and Site Closure.................................................................................48
10.2
Appendix 2: Clinical Laboratory Tests..............................................................49
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................50
10.3.1
Definition of AE ..........................................................................................50
10.3.2
Definition of SAE ........................................................................................51
10.3.3
Additional Events Reported.........................................................................52
10.3.4
Recording AE and SAE ...............................................................................52
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................56
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................58
10.5
Appendix 5: Contraceptive Guidance................................................................59
10.5.1
Definitions....................................................................................................59
10.5.2
Contraception Requirements........................................................................60
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................61
10.7
Appendix 7: Country-specific Requirements....................................................62
10.8
Appendix 8: Abbreviations .................................................................................63
11
REFERENCES...............................................................................................................64
 
 
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LIST OF TABLES
Table 1
Study Intervention............................................................................................23
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................33
Table 3
Estimates of the Half-width of the 95% Confidence Interval Under 
Different Assumptions.....................................................................................40
 
 
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LIST OF FIGURES
Figure 1
V419-013 Study Design.............................................................................13
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Hepatitis B Vaccine Challenge Study to Demonstrate the Durability of 
Protection Against Hepatitis B Virus Infection in Healthy Children Vaccinated 
Approximately 9 Years Previously With a 2- or 3-Dose Infant Series and Toddler Dose of 
Vaxelis®
Short Title: A Hepatitis B Vaccine Challenge Study After Previous Vaxelis® Vaccination.
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There is no formal hypothesis testing in this study.
Primary Objectives
Primary Endpoints
- Objective: To evaluate the proportion of 
participants with a protective anti-HBs level 
of ≥10 mIU/mL at 30 days post-challenge 
(Day 30) with HBVAXPRO™.
- Anti-HBs level
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate anti-HBs GMCs 
pre-challenge on Day 1 and 30 days post-
challenge with HBVAXPRO™.
- Anti-HBs level
 
 
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Long-term protection against HBV infection
Population
Healthy children 8 to 10 years of age who participated in 
Protocols V419-007 or V419-008 and received a 3 + 1 or 
a 2 + 1 (infant + toddler) Vaxelis® schedule, respectively
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
Not applicable
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 months from the time the first participant 
signs the informed consent/assent until the last 
participant’s last study-related telephone call or visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
Number of Participants:
Approximately 200 participants will be enrolled in the study.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen
Use
1
HBVAXPRO
™
Refer to 
product 
labeling
Single dose
IM
Single dose 
on Day 1
Challenge 
Agent
Abbreviations: admin. = administration; IM = intramuscular
Total 
Number of 
Intervention 
Groups
1 intervention group
Duration of 
Participation
Each participant will participate in the study for approximately 1 month from 
the time the participant or the participant’s legally acceptable representative 
signs the Informed Consent Form (ICF) through the final contact.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The key components of the study are depicted in Figure 1.
Figure 1
V419-013 Study Design
 
 
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1.3
Schedule of Activities
Study Period:
Intervention
Notes
Visit Number:
1
2
Scheduled Time:
Day 1
Day 30
Visit Window:
Not Applicable
Day 23 to Day 37
Administrative Procedures
Screening Procedures
Informed Consent/Assent
X
Consent/assent must be obtained before any study procedures.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Review of prior medications/vaccinations, a targeted physical 
examination, and temperature measurement are required at Visit 1 to 
determine eligibility.
Medical History
X
The participant’s medical history for the 5 years prior to Visit 1 (Day 
1) will be obtained.
Post-Enrollment Procedures
Assignment of Treatment/Allocation Number
X
Prior/Concomitant Medication and Non-
Study Vaccination Review
X
X
HBVAXPRO™Administration (Open-label)
X
Safety Procedures
Targeted Physical Examination
X
To be performed by the investigator or medically qualified designee.
Body Temperature Measurement
X
Each participant’s body temperature must be taken before 
vaccination. Participants who have febrile illness at or within 72 
hours of vaccination must be rescheduled.
Postvaccination Observation Period
X
Per current local standard of care
Collection of AEs Resulting in 
Discontinuation and SAE Monitoring
X
X
A scripted questionnaire can be found in the Investigator Trial File 
Binder (or equivalent) provided by the Sponsor.
Immunogenicity Procedures
Serum for Immunogenicity Assay 
X
X
Blood samples must be collected on Day 1 before vaccination. Sera 
from participants will be used to measure anti-HBs concentration.
AE = adverse event; anti-HBs = hepatitis B surface antibody; SAE = serious adverse event
 
 
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2
INTRODUCTION
2.1
Study Rationale
The purpose of this study is to demonstrate the durability of protection against HBV infection
approximately 9 years after vaccination with Vaxelis®. Vaxelis® (diphtheria, tetanus, 
pertussis [acellular, component], hepatitis B [rDNA], poliomyelitis [inactivated], and 
Haemophilus influenzae type b conjugate vaccine [adsorbed]) (DTaP5-HB-IPV-Hib) is a
hexavalent vaccine indicated for active immunization to prevent the diseases caused by these 
pathogens. Vaxelis® was approved in the EU in 2016 and in the US in 2018. The hepatitis B 
component of the vaccine contains 10 µg of HBsAg produced by recombinant DNA 
technology and adsorbed on aluminum. 
Hepatitis B vaccination results in increases in anti-HBs. Achievement of an anti-HBs 
concentration ≥10 mIU/mL 1 to 2 months after completion of a primary hepatitis B 
vaccination series is a globally accepted serologic correlate of protection against HBV 
infection [Plotkin, S. A. 2010] [World Health Organization 2017]. Anti-HBs levels wane 
over time and 15% to 50% of children who responded to the initial series will have low or 
undetectable levels 5 to 15 years later [Plotkin, S. A., et al 2008]. However, long-term 
protection is still expected due to the immune memory response [But, D. Y-K, et al 2008] 
[Bialek, S. R., et al 2008] [Roznovsky, L., et al 2010] [Su, F. H., et al 2007] [van der Sande, 
M. A. B., et al 2007] and additional doses of hepatitis B vaccine are not required or 
recommended [Schillie, S., et al 2018] [Leuridan, E. 2011] [FitzSimons, David, et al 2005] 
[European Consensus Group on Hepatitis B Immunity 2000].
Consistent with other marketed hexavalent vaccines which include a hepatitis B component, 
the EMA requested a post-licensure study to assess the long-term persistence of anti-HBs 3 
to 4 years after vaccination with Vaxelis® [European Medicines Agency 2013] [European 
Medicines Agency 2016]. The resultant study (V419-012) assessed children aged 4 to 5 years 
who received Vaxelis® or active comparator (Infanrix® hexa, GlaxoSmithKline Biologicals 
S.A, Rixensart, Belgium) in a 3 + 1 (Protocol V419-007: 3-dose primary series at 2, 3, and 4 
months of age and a toddler dose at 12 months of age) or a 2 + 1 (Protocol V419-008: 2-dose 
primary series at 2 and 4 months of age and a toddler dose at 11 to 12 months of age) 
schedule. All of the children who participated in Study V419-012 had achieved an anti-HBs 
level of ≥10 mIU/mL after their vaccination series in V419-007 and V419-008 and were 
considered protected against HBV infection. The proportion of participants who had 
anti-HBs levels of ≥10 mIU/mL 3 to 4 years after the 3 + 1 schedule was 70.2% (95% CI:
63.1% to 76.6%) and 82.0% (95% CI: 75.8% to 87.2%) in Vaxelis® and Infanrix® hexa 
recipients, respectively. The proportion of participants who had anti-HBs levels of 
≥10 mIU/mL 3 to 4 years after the 2+1 schedule was 65.8% (95% CI: 58.3% to 72.6%) and 
83.7% (95% CI: 77.7% to 88.6%) in Vaxelis® and Infanrix® hexa recipients, respectively
[CSR P012V419 2017].
Extended HBV protection after infant and toddler vaccinations has been documented with 
HBV-containing combination vaccines [Steiner, M., et al 2010] [Kosalaraksa, P., et al 2018] 
[Van Der Meeren, O., et al 2014] [Madhi, S. A., et al 2019]. Because the Phase 3 studies of 
 
 
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Vaxelis® (Protocols V419-007 and V419-008) were conducted approximately 9 years before 
the planned initiation of this protocol (V419-013), the Phase 3 cohort provides an excellent 
opportunity to assess long-term persistent protection against HBV infection specifically in
Vaxelis® recipients.
This clinical study is designed to evaluate the long-term durability of the immune protection
against HBV infection approximately 9 years after receipt of a 3 + 1 or 2 + 1 Vaxelis® series. 
Immune protection will be demonstrated by administering a hepatitis B vaccine
(HBVAXPRO™, MSD) challenge dose. Anti-HBs levels pre- and post-challenge will be 
measured. A post-challenge anti-HBs level of ≥10 mIU/mL is considered evidence of 
persistent protection against HBV infection consistent with the other approved hexavalent 
vaccines in the EU [Steiner, M., et al 2010] [Kosalaraksa, P., et al 2018] [Van Der Meeren, 
O., et al 2014] [Madhi, S. A., et al 2019].
2.2
Background
HBV infection is caused by a DNA virus that attacks the liver and can cause both acute and 
chronic disease. It is estimated that approximately 257 million people worldwide are living 
with HBV infection [World Health Organization 2017]. The severe complications of chronic 
HBV infection include liver cirrhosis, liver cancer, and death. Major progress towards 
diminishing HBV infection has been made through the introduction of routine hepatitis B 
vaccination in infancy. This has been facilitated by use of hepatitis B containing multi-valent 
vaccines. The active component of the hepatitis B vaccine is the viral surface protein 
(HBsAg). Response to this protein (anti-HBs) is an indicator of response to the vaccine. An 
anti-HBs level of ≥10 mIU/mL measured 1 to 2 months after administration of the last dose 
of the primary vaccination series is considered a reliable serological marker of protection 
against HBV infection [Plotkin, S. A. 2010] [World Health Organization 2017].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety, efficacy, and immunogenicity (as applicable) of a medicine or vaccine.
HBVAXPRO™has a well-defined safety profile. The benefit of a hepatitis B vaccine 
challenge dose has not been established. Additional doses of hepatitis B vaccine are often 
given to persons who are perceived to be at increased risk for exposure to the virus (for 
example health care workers or patients on dialysis) [Hess, L., et al 2020]. Review of 
post-marketing safety reports on patients who received 3 or more doses of hepatitis B vaccine 
[recombinant] did not identify any safety concerns.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the informed consent/assent documents.
 
 
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no formal hypothesis testing in this study.
Objectives
Endpoints
Primary
•
Objective: To evaluate the proportion of 
participants with a protective anti-HBs 
level of ≥10 mIU/mL at 30 days 
post-challenge (Day 30) with 
HBVAXPRO™.
•
Anti-HBs level
Secondary
•
Objective: To evaluate anti-HBs GMCs 
pre-challenge on Day 1 and 30 days post-
challenge with HBVAXPRO™.
•
Anti-HBs level
4
STUDY DESIGN
4.1
Overall Design
This is a single group, open-label, single-dose, and multi-site study conducted in Finland in 
healthy participants 8 to 10 years of age who participated in Protocols V419-007 or 
V419-008 and received a 3 + 1 or a 2 + 1 (infant + toddler) Vaxelis® schedule, respectively. 
Study participants are challenged with HBVAXPRO™vaccine in this study.
Blood samples for immunogenicity assays will be drawn immediately before vaccination at 
Visit 1 (Day 1) and at 30 days post-challenge at Visit 2 (Day 30).
Information for SAEs, regardless of whether the events are considered vaccine-related by the 
investigator, will be collected from the time consent is signed through completion of 
participation in the study. AEs resulting in discontinuation from study will also be collected.
This information will be collected using the scripted questionnaire found in the Investigator 
Trial File Binder (or equivalent) provided by the Sponsor.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
 
 
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4.2
Scientific Rationale for Study Design
The purpose of this study is to demonstrate durable protection against HBV infection 
approximately 9 years after vaccination with Vaxelis®. This will be done by using a hepatitis 
B “challenge” in the form of a HBV vaccine (HBVAXPRO™). Antibody responses to 
hepatitis B vaccination wane over time and continued protection against HBV infection is 
expected through immune memory. Long-term protection against HBV infection, which is 
indicative of immune memory from prior vaccination, can be demonstrated in different ways. 
It is most commonly demonstrated by measuring anti-HBs levels before and after a challenge 
dose of HBV surface antigen, ie, a HBV vaccine [Leuridan, E. 2011] [Brunskole Hummel, I., 
et al 2016] [Van Damme, P., et al 2019].
The risks for acquiring HBV infection vary throughout life. It is highest in infancy and 
during the first 5 years of life and then is affected later in life by behavioral factors and health 
status. The timing of the prior Vaxelis® Phase 3 studies (V419-007 and V419-008) and the 
age of the participants, which is prior to onset of increased risk activities, make this an 
excellent opportunity to evaluate ongoing protection by demonstrating responses before and 
after a HBV vaccine challenge. This has been demonstrated for other hepatitis B-containing 
multi-valent vaccines through similar HBV vaccine challenge studies [Steiner, M., et al
2010] [Kosalaraksa, P., et al 2018] [Van Der Meeren, O., et al 2014].
This study design facilitates the demonstration of the persistence of the protective immune 
response against HBV infection using a hepatitis B vaccine challenge. Measurement and 
evaluation of pre- and post-challenge anti-HBs levels will enable demonstration of protective 
immunity against HBV.
Rapid increases in antibody levels within a short period after antigen challenge (ie, an 
anamnestic response) are an indication of the presence of immune memory. HBV infection,
however, has a long incubation period (from 30 to 180 days with an average of 75 days) and 
the anamnestic response may take longer to peak [World Health Organization 2017]. Studies 
assessing early responses at 7 or 14 days post-challenge have shown response rates of 20% or 
50% respectively, but reaching up to 100% by 30 days [FitzSimons, David, et al 2005] 
[Sharma, R., et al 2015] [Leuridan, E. 2011] [Van Damme, P., et al 2019] [Hammitt, L. L., et 
al 2007] [Jan, C. F., et al 2010]. In order to capture full response to the challenge dose, this 
study will measure anti-HBs responses at 30 days post-challenge. Given the long incubation 
period of the HBV infection, an immune response measured at 30 days post-challenge (ie, 
exposure) is an adequate time point to measure early enough response to protect against 
infection.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The primary immunogenicity endpoint for the study is the proportion of participants with a 
protective anti-HBs level of ≥10 mIU/mL at 30 days post-challenge with HBVAXPRO™. 
The anti-HBs concentration of ≥10 mIU/mL is a serologic correlate of protection that is 
widely accepted as the threshold for protection against HBV infection [Plotkin, S. A. 2010] 
 
 
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[World Health Organization 2017]. Attaining the ≥10 mIU/mL threshold after a single 
challenge dose of HBV vaccine (in the setting of completion of a prior hepatitis B 
vaccination series) is a commonly used and accepted method to demonstrate the persistence 
of protection against HBV infection [Schillie, S., et al 2018]. Response to a single primary 
dose of HBV vaccine in an individual who is vaccine-naïve, is generally not sufficient to 
achieve this protective concentration. It is for this reason that a 2- or 3- dose primary series is 
required for protection in HBV vaccine-naïve individuals [Cassidy, W. M., et al 2001] 
[Schillie, S., et al 2018]. Furthermore, the response to a challenge dose (ie, after a prior 
vaccination series) can be differentiated from that of a response to a single vaccine in a HBV 
vaccine-naïve participant, by the significantly higher GMC achieved in the setting of a 
challenge and a higher proportion achieving anti-HBs ≥10 mIU/mL [Cassidy, W. M., et al 
2001] [Hammitt, L. L., et al 2007].
4.3
Justification for Dose
HBVAXPRO™is a well-established hepatitis B vaccine that has been used worldwide since 
its initial licensure in 1986. The dose of 5 µg (0.5 mL) is approved for persons from birth 
through 15 years of age.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
 
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Is healthy (based on a review of medical history and targeted physical examination) 
based on the clinical judgment of the investigator.
2. Has participated in Protocol V419-007 and received a 3 + 1 Vaxelis® schedule or 
participated in Protocol V419-008 and received a 2 + 1 Vaxelis® schedule.
Demographics
3. Is male or female, 8 years to 10 years of age, at the time of signing the informed 
consent/assent.
Informed Consent/Assent
4. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of diagnosis (clinical, serological, or microbiological) of HBV infection.
2. Has a known or suspected impairment of immunological function (eg, HIV, 
splenectomy).
3. Has a known hypersensitivity to any component of the study vaccine.
4. Has a known or suspected blood dyscrasias, leukemia, lymphomas of any type or other 
malignant neoplasms affecting the haematopoietic and lymphatic system.
5. Has a bleeding disorder contraindicating intramuscular vaccinations.
6. *Had a recent febrile illness (defined as oral temperature ≥38.1°C [≥100.5°F]; axillary 
temperature ≥37.8°C [≥100.0°F]) occurring within 72 hours prior to receipt of study 
vaccine.
Prior/Concomitant Therapy
7. Has received any hepatitis B vaccine after participation in Protocol V419-007 or 
V419-008.
 
 
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8. *Is receiving immunosuppressive therapy, including chemotherapeutic agents used to 
treat cancer or other conditions, and interventions associated with organ or bone marrow 
transplantation, or autoimmune disease.
9. *Meets one or more of the following systemic steroid exclusion criteria:
a.
Has received any dose of systemic steroids within 7 days prior to entering study.
b. Is expected to require systemic steroids ≥20 mg/day for ≥5 consecutive days through 
the course of the participant’s participation in the study.
Note: Topical, ophthalmic, intra-articular or soft-tissue (eg, bursa, tendon steroid 
injections), and inhaled/nebulized steroids are permitted.
10. *Has received any licensed, non-live vaccine within the 14 days before receipt of study 
vaccine or is scheduled to receive any licensed, non-live vaccine within 30 days 
following receipt of any study vaccine. Exception: Inactivated influenza vaccine may be 
administered but must be given at least 7 days before receipt of any study vaccine or at 
least 15 days after receipt of any study vaccine.
11. *Has received any licensed live vaccine within 30 days before receipt of study vaccine or 
is scheduled to receive any live vaccine within 30 days following receipt of any study 
vaccine.
12. *Has received a blood transfusion or blood products, including immunoglobulins within 
the 6 months before receipt of study vaccine or is scheduled to receive a blood 
transfusion or blood product within 30 days of receipt of study vaccine. Autologous 
blood transfusions are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
13. *Has participated in another clinical study of an investigational product within 2 months 
before study vaccination at Visit 1 (Day 1) or plans to participate anytime during the 
duration of the current clinical study. Participants enrolled in observational studies may 
be included; these will be reviewed on a case-by-case basis for approval by the Sponsor.
Diagnostic Assessments
Not applicable
Other Exclusions
14
Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study. 
For items with an asterisk (*), if the participant meets these exclusion criteria, the Day 1 Visit 
may be rescheduled for a time when these criteria are not met.
 
 
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5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (HBVAXPRO™) will be packaged to support enrollment. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 1.
 
 
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Table 1
Study Intervention
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit 
Dose 
Strength
Dosage 
Level
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
1
Experimental
HBVAXPRO™
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
Product 
labeling
0.5 mL
IM
Single dose 
on Day 1
Challenge 
Agent
NIMP
Central
admin. = administration; IMP = investigational medicinal product; NIMP = non-investigational medicinal product
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the European Economic Area (EEA).
Country differences with respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided inSection 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the vaccine administered.
6.4
Study Intervention Compliance
Participants will receive single-dose of HBVAXPRO™administered at the study site. The 
date and time of administration will be recorded in the source document and in the eCRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study (see Section 5.2 for details). Systemic steroids ≥20 mg/day for 
≥5 consecutive days are prohibited through the course of the study.
If there is a clinical indication for any medications or vaccinations specifically prohibited, the 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant in the 
study requires the mutual agreement of the investigator, the Sponsor, and the participant or 
the participant’s legally acceptable representative.
If a medical condition requires the use of a prohibited steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate eCRF.
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
 
 
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6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
 
 
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•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 7 mL (3.5 mL at each of Visits 1 and 2).
 
 
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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical study. If 
there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form, and any written information provided to the participant must receive the 
IRB/IEC’s approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable, will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study. The investigator should 
consult with the Sponsor’s Clinical Director for any questions about participant eligibility.
 
 
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent/assent. At the time of intervention
allocation, site personnel will add the treatment/allocation number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
The participant’s medical history for the 5 years prior to Visit 1 (Day 1) will be obtained by 
the investigator or qualified designee at Visit 1 (Day 1) before vaccination.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The collection of previous medications and vaccinations (within the 30 days prior to 
Visit 1/Day 1) will be limited to the not allowed medications and vaccinations that should 
have led to the participant’s ineligibility (see Section 5.2); these medications and 
vaccinations, if any, should be recorded in the eCRF.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication and non-study vaccination on 
the appropriate eCRF, if any, taken by the participant during the study per data entry 
guidelines.
If a medical condition requires the use of a prohibited steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
 
 
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Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
8.1.7
Assignment of Treatment/Allocation Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation.  Once a treatment/allocation number is 
assigned to a participant, it can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Study intervention is given on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
8.1.8.1
Timing of Dose Administration
Study vaccine will be administered as indicated in Section 1.3. All participants will be 
monitored for any immediate reactions as per local standard of care.
Participants must be afebrile for at least 72 hours prior to vaccination (Section 1.3).
Blood samples must be collected before study vaccination on Day 1.
8.1.9
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention 
(see Section 7.1).
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit (Visit 2) at the time of withdrawal. Any AEs that 
are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
 
 
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8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure anti-HBs concentration using the hepatitis B 
ECi assay.
Blood collection, storage and shipment instructions for serum samples will be provided in the 
operations/laboratory manual.
8.2.1
Hepatitis B ECi Assay
The purpose of the hepatitis B ECi assay is to detect total antibody to human plasma-derived 
HBsAg subtypes ad and ay before and after vaccination with HBsAg containing vaccine(s). 
This is the primary assay used to evaluate the serological response to the vaccine(s). The 
assay is a solid phase sandwich enzyme-labeled immunoassay. Results for the assay are 
reported in mIU/mL.
This assay involves the reaction of anti-HBs in a test sample with HBsAg (ad and ay 
subtypes) coated onto the wells. An HRP-labeled HBsAg conjugate (ad and ay subtypes) 
then formed a complex with the bound anti-HBs, forming an “antigen sandwich”. Unbound 
materials were removed by washing. A reagent that contained luminogenic substrates (a 
luminol derivative and a peracid salt) and an electron transfer agent was added to the wells. 
The HRP in the bound conjugate catalyzed the oxidation of the luminol derivative, producing 
light. The electron transfer agent increased the level and duration of the light produced. The 
amount of HRP conjugate bound and subsequent light produced was indicative of the 
concentration of anti-HBs present in the sample.
Three internally prepared control serum pools, consisting of a high-positive, low-positive, 
and negative control, were used to monitor the performance of the assay. These pools were 
each prepared from 4 individual human immune sera obtained from an external vendor. 
Additionally, there were anti-HBs positive and negative manufacturer-supplied controls, 
which were prepared from freeze-dried recalcified human plasma. The hepatitis B WHO 
International reference standard at 10 mIU/mL was also run as a control in every assay. The 
LLOQ of the assay is 5 mIU/mL.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in this section.
 
 
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Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A targeted physical examination will be performed as indicated in Section 1.3. Any clinically 
significant abnormality will be recorded on the appropriate eCRF. The targeted physical 
examination procedure includes obtaining vital signs (heart rate, respiratory rate, and body
temperature), auscultation of the heart and lung, and examination of the abdomen, further 
assessment if deemed necessary by the investigator or medically qualified designee.
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Body Temperature Measurement
Pre-vaccination body temperature will be taken by study staff as indicated in Section 1.3. 
Participants who have febrile illness (defined as oral temperature ≥38.1°C [≥100.5°F] or 
axillary ≥37.8°C [≥100.0°F]) within 72 hours of vaccination must be rescheduled.
Oral is the preferred method of obtaining participant’s temperature. If an axillary temperature 
is reported to be ≥37.8°C (≥100.0°F), an oral temperature must be taken. Temperature 
readings should be taken at approximately the same time each day. Use of temporal or 
tympanic thermometers to collect temperature for this study is prohibited.
8.3.3
Clinical Laboratory Assessments
There are no laboratory safety evaluations required by the protocol.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of a NSAE that leads to exclusion from study or results in 
discontinuation from study or SAE as well as other reportable safety events. Investigators 
remain responsible for following up NSAEs that lead to exclusion from study or result in 
discontinuation from study, SAEs, and other reportable safety events for outcome according 
to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of a 
NSAE that leads to exclusion from study or results in discontinuation from study or SAE as 
well as other reportable safety events with respect to seriousness, intensity and causality.
 
 
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before allocation must be reported by the investigator if they cause the participant to be 
excluded from the study, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo, or a procedure.
NSAEs that lead to exclusion from study or result in discontinuation from study, SAEs 
including death, and other reportable safety events must be reported by the investigator 
throughout the duration of the individual’s participation in the study, regardless of whether or 
not related to the Sponsor's product.
Investigators are not obligated to actively seek NSAEs or SAEs or other reportable safety 
events in former study participants. However, if the investigator learns of any SAE, including 
a death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up NSAEs that lead to exclusion from study or result in discontinuation 
from study, SAEs, and other reportable safety events will be recorded and reported to the 
Sponsor or designee within the time frames as indicated Table 2.
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report if: 
- led to 
discontinuation 
from study
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion 
of study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
 
 
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
ECI (require 
regulatory 
reporting)
There are no events of clinical interest for this study.
ECI (do not 
require 
regulatory 
reporting)
There are no events of clinical interest for this study.
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting NSAEs that lead to exclusion from 
study or result in discontinuation from study and/or SAEs and other reportable safety events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial NSAE that lead to exclusion from study or result in discontinuation from 
study /SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, and other reportable safety events, including pregnancy 
and exposure during breastfeeding, cancer, and overdose will be followed until resolution, 
stabilization, until the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). In addition, the investigator will make every attempt to follow all 
NSAEs that lead to exclusion from study or result in discontinuation from study that occur in
 
 
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allocated participants for outcome. Further information on follow-up procedures is given in
Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable
8.4.7
Events of Clinical Interest
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of study vaccine.
No specific information is available on the treatment of overdose.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
 
 
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the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Future Biomedical Research Sample Collection
Not applicable
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening procedures/eligibility criteria will be conducted at Visit 1 as outlined in 
Section 1.3. Screening procedures may be repeated after consultation with the Sponsor.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in an sSAP and 
referenced in the CSR for the study. Post-hoc exploratory analyses will be clearly identified 
in the CSR.
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
A Hepatitis B Vaccine Challenge Study to Demonstrate the Durability of 
Protection Against Hepatitis B Virus Infection in Healthy Children 
Vaccinated Approximately 9 Years Previously With a 2- or 3-Dose 
Infant Series and Toddler Dose of Vaxelis®
Treatment Assignment
This is a single group, open-label, non-randomized study. Participants 
will receive a single-dose of HBVAXPRO™.
Analysis Populations
Immunogenicity: Per-Protocol (PP);
Safety: All Participants as Treated (APaT)
Primary Endpoint
Immunogenicity: proportion of participants with a protective anti-HBs
level of ≥10 mIU/mL at 30 days post-challenge with HBVAXPRO™
Key Secondary Endpoint
Immunogenicity: anti-HBs GMCs pre-challenge on Day 1 and 30 days
post-challenge with HBVAXPRO™
Statistical Methods for Key 
Immunogenicity Analyses
No statistical hypothesis testing will be performed for immunogenicity 
analyses in this study. For the immunogenicity endpoint, the point 
estimates and corresponding 95% CIs will be provided.
Statistical Methods for Key 
Safety Analyses
Any AEs resulting in discontinuation from study and SAEs will be 
reported and summarized descriptively.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
No statistical hypothesis testing will be performed for immunogenicity 
analyses in this study. Therefore, no adjustments for multiplicity are 
needed in this study.
Sample Size and Power 
This is an estimation study. This study will enroll approximately 200 
participants and will allow estimation of the primary immunogenicity 
endpoint with a 95% CI.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a non-randomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant vaccination assignments 
after each participant is enrolled and vaccination is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.
 
 
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9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study, and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
Immunogenicity and safety endpoints that will be evaluated are listed below.
9.4.1
Immunogenicity Endpoints
The primary immunogenicity endpoint is the proportion of participants with a protective 
anti-HBs level of ≥10 mIU/mL at 30 days post-challenge with HBVAXPRO™, described in 
Section 3 and Section 4.2.1.1.
The secondary immunogenicity endpoint is the anti-HBs GMCs pre-challenge on Day 1 and 
30 days post-challenge with HBVAXPRO™.
The exploratory immunogenicity endpoint includes the proportion of participants with a 
≥4-fold rise in anti-HBs level from pre-challenge on Day 1 to 30 days post-challenge with 
HBVAXPRO™.
9.4.2
Safety Endpoints
This study will monitor safety through the collection of AEs resulting in discontinuation 
from study and SAEs at Visit 1 and Visit 2 (Day 30).
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this study. The PP population consists of all enrolled participants without deviations 
from the protocol that may substantially affect the results of the immunogenicity endpoint.
Potential deviations that may result in the exclusion of a participant from the PP population 
for all immunogenicity analyses include:

Failure to receive study vaccine at Visit 1 (Day 1)

Receipt of a prohibited medication or prohibited vaccine prior to study vaccination

Receipt of a prohibited medication or prohibited vaccine prior to blood sample 
collection at Visit 2 (Day 30)

Collection of a blood sample at Visit 2 outside of the pre-specified analysis window 
(Day 23 to Day 44)
 
 
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9.5.2
Safety Analysis Populations
Safety summaries will be conducted in the APaT population, which consists of all 
participants who received study vaccine and had safety follow-up data after the vaccination.
9.6
Statistical Methods
Statistical methods relating to immunogenicity analyses are described in Section 9.6.1.
Statistical methods relating to safety analyses are described in Section 9.6.2.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the immunogenicity objectives. No 
statistical hypothesis testing will be performed for immunogenicity analyses in this study.
Point estimates and 95% CIs will be provided for both the primary and secondary 
immunogenicity objectives.
The point estimate for the primary immunogenicity objective will be calculated as the 
proportion of participants with a protective anti-HBs level of ≥10 mIU/mL at 30 days 
post-challenge with HBVAXPRO™. The CIs will be calculated based on the exact method 
proposed by Clopper and Pearson [Collett, D. 1999].
The point estimates for the secondary immunogenicity objective will be calculated by 
exponentiating the estimates of the mean of the natural log values. The 95% CIs will be 
derived by exponentiating the bounds of the CIs of the mean of the natural log values based 
on the t-distribution.
9.6.2
Statistical Methods for Safety Analyses
The proportion of participants with AEs resulting in discontinuation from study and any 
SAEs will be reported and summarized descriptively. The point estimates and the 95% CIs 
will be calculated using the Clopper Pearson method [Collett, D. 1999].
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
No statistical hypothesis testing will be performed for immunogenicity analyses in this study. 
Therefore, no multiplicity adjustment is required in this study.
 
 
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9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
Since this is an estimation study, no formal power calculation for immunogenicity was 
performed. This study will enroll approximately 200 participants and will allow estimation of 
the primary immunogenicity endpoint with a 95% CI with a half-width of 4.0 percentage 
points. This is based on the following assumptions: 1) approximately 200 participants
enrolled, 2) an underlying response rate of 95%. The calculation is based on the exact 
binomial method proposed by Clopper and Pearson [Collett, D. 1999]. In order to evaluate 
the potential impact of limited enrollment and attenuated response rate, the half-width of the 
95% CI is evaluated under different sample size and response rate assumptions. Table 3
summarizes estimates of the half-width of the CI under various sample size and response 
rate.
Table 3
Estimates of the Half-width of the 95% Confidence Interval Under Different 
Assumptions
Evaluable Sample 
Size
Assumed Response Rate
85%
90%
95%
125
7.5%
6.6%
5.4%
150
6.7%
6.0%
4.7%
175
6.1%
5.4%
4.4%
200
5.7%
5.0%
4.0%
225
5.4%
4.7%
3.7%
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying percentage of participants with an SAE in the 
study population. If the underlying incidence of an SAE is 0.80% (1 of every 124 participants 
receiving the vaccine), there is an 80% chance of observing at least 1 SAE among 200 
participants. If the underlying incidence of an SAE is 0.35% (1 of every 289 participants 
receiving the vaccine), there is an 50% chance of observing at least 1 SAE among 200 
participants. If no SAEs are observed among the 200 participants, this study will provide 
95% confidence that the underlying percentage of participants with SAE is <1.49% (one in 
every 67 participants).
 
 
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9.10
Subgroup Analyses
For both primary and secondary immunogenicity endpoints, the point estimates will be 
calculated by subgroup of prior Vaxelis® schedule, respectively (ie, 3 + 1 schedule in 
Protocol V419-007, 2 + 1 schedule in Protocol V419-008). The point estimates and 
corresponding 95% CIs will be reported for each subgroup.
9.11
Compliance (Medication Adherence)
Given that participants will receive just a single dose of HBVAXPRO™, compliance will not 
be calculated.
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of subjects 
vaccinated with HBVAXPRO™.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations, (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
 
 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
 
 
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
 
 
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Not applicable
 
 
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10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
 
 
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
 
 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
There are no laboratory safety evaluations required by the protocol.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
·
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
 
 
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•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

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.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE that leads to exclusion from study or results in discontinuation from study and SAE 
recording

When a NSAE leads to exclusion from study or results in discontinuation from 
study/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory, and diagnostics reports) related to the event.

The investigator will record all relevant NSAE that leads to exclusion or results in 
discontinuation from study /SAE information on the AE CRFs/worksheets at each 
examination.
 
 
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
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the NSAE that lead to exclusion or 
results in discontinuation from study/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each NSAE that led to 
exclusion from study or resulted in discontinuation from study and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the NSAE resulting in discontinuation from study or 
SAE?
•
The determination of the likelihood that the Sponsor’s product caused the NSAE 
resulting in discontinuation from study or SAE will be provided by an investigator who is 
a qualified physician. The investigator’s signed/dated initials on the source document or 
worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialled document must be retained for 
the required regulatory time frame. The criteria below are intended as reference 
 
 
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guidelines to assist the investigator in assessing the likelihood of a relationship between 
the test product and the NSAE resulting in discontinuation from study or SAE based upon 
the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the NSAE resulting in discontinuation from study or SAE;
the greater the correlation with the components and their respective elements (in number 
and/or intensity), the more likely the Sponsor’s product caused the NSAE resulting in 
discontinuation from study or SAE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the NSAE resulting in discontinuation from study or SAE
follow in a reasonable temporal sequence from administration of the Sponsor’s 
product? Is the time of onset of the NSAE resulting in discontinuation from study or 
SAE compatible with a vaccine-induced effect?
-
Likely Cause: Is the NSAE resulting in discontinuation from study or SAE not 
reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
◦
If yes, did the NSAE resulting in discontinuation from study or SAE recur or 
worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial NSAE resulting in discontinuation 
from study or SAE resulted in death or permanent disability, or (2) the study is a single-dose 
vaccine study; or (3) Sponsor’s product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the NSAE resulting in discontinuation from study or SAE consistent with previous 
knowledge regarding the Sponsor’s product or drug class pharmacology or toxicology?
 
 
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•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the NSAE resulting in discontinuation from study or SAE onset relative to 
the administration of the Sponsor’s product is reasonable. The NSAE resulting 
in discontinuation from study or SAE is more likely explained by the Sponsor’s 
product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
NSAE resulting in discontinuation from study or SAE onset relative to 
administration of the Sponsor’s product is not reasonable OR the NSAE 
resulting in discontinuation from study or SAE is more likely explained by 
another cause than the Sponsor’s product. (Also entered for a participant with 
overdose without an associated NSAE resulting in discontinuation from study or 
SAE.)
•
For each NSAE resulting in discontinuation from study /SAE, the investigator must 
document in the medical notes that he/she has reviewed the NSAE resulting in 
discontinuation from study /SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of NSAE Resulting in Discontinuation From Study and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the NSAE resulted in discontinuation from study
or SAE as fully as possible. This may include additional laboratory tests or 
 
 
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investigations, histopathological examinations, or consultation with other health care 
professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
NSAEs that led to exclusion from study or result in discontinuation from study, SAE, 
and other reportable safety event reporting to Sponsor via electronic data collection 
tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
 
 
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SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
 
 
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
HBVAXPRO™ has a well-defined safety profile. There is no contraindication in pregnancy.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
anti-HBs
hepatitis B surface antibody
APaT
All Participants as Treated
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
DNA
deoxyribonucleic acid 
ECi
enhanced chemiluminescence
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
EMA
European Medicines Agency
EU
European Union
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice 
GMC
geometric mean concentration
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HIV
human immunodeficiency virus
HRP
horseradish peroxidase
HRT
hormone replacement therapy
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LLOQ
lower limit of quantification
NSAE
nonserious adverse event
PK
pharmacokinetic
PP
per-protocol
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
US
United States
WHO
World Health Organization
WOCBP
women of childbearing potential
 
 
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11
REFERENCES
[Bialek, S. R., et al 2008]
Bialek SR, Bower WA, Novak R, 
Helgenberger L, Auerbach SB, Williams IT, et 
al. Persistence of protection against hepatitis B 
virus infection among adolescents vaccinated 
with recombinant hepatitis B vaccine 
beginning at birth: a 15-year follow-up study. 
Pediatr Infect Dis J. 2008 Oct;27(10):881-5.
04R0CY
[Brunskole Hummel, I., et al 
2016]
Brunskole Hummel I, Zitzmann A, Erl M, 
Wenzel JJ, Jilg W. Characteristics of immune 
memory 10-15 years after primary hepatitis B 
vaccination. Vaccine. 2016;34:636-42.
05FSX7
[But, D. Y-K, et al 2008]
But DY-K, Lai C-L, Lim W-L, Fung J, Wong 
DK-H, Yuen M-F. Twenty-two years follow-
up of a prospective randomized trial of 
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