HepB-CpG Series for Healthcare Workers Who Are Hepatitis B Vaccine Nonresponders
Phase: PHASE4
Conditions: Healthcare Worker, Hepatitis B Vaccine, Nonresponder
Sponsor: University of Wisconsin, Madison

 
 
 
 NCT04456504 
HepB-CpG series for healthcare workers who are hepatitis B 
vaccine nonresponders 
6/11/2020 

~ i ~ 
 
 
 
 
 
 
 
 
HepB-CpG series for healthcare workers who are hepatitis B vaccine nonresponders 
 
 
 
Protocol Number: UW HSC-IRB #2020-0631 
Principal Investigator: Mary S. Hayney, PharmD, MPH 
 
 
 
 
 
Dynavax is supplying Heplisav-BTM for this study. 
 
 
[This document is confidential. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior 
authorization from the Sponsor or Principal Investigator.] 
 
 
 
Protocol Version History 
 
Protocol 
Version 
Version 
Date 
Summary of Revisions Made 
Rationale 
1.0 
05/28/2020 
Initial version 
 
2.0 
6/11/2020 
Edits regarding AE notification and added 
Data collection form 
Required elements  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

- i - 
 
REMINDER: update the Table of Contents before considering the document or draft final. To update the Table of 
Contents, right click anywhere below and then select “Update Field.”  
 
Table of Contents 
 
1.0 
STATEMENT OF COMPLIANCE .............................................................................................................. 1 
2.0 
LIST OF ABBREVIATIONS....................................................................................................................... 1 
3.0 
STUDY SUMMARY .................................................................................................................................. 3 
 
Synopsis ....................................................................................................................................... 1 
 
Schematic of Study Design ........................................................................................................... 3 
4.0 
KEY ROLES ............................................................................................................................................. 4 
5.0 
INTRODUCTION ...................................................................................................................................... 4 
 
Disease Background ..................................................................................................................... 4 
 
Current Standard of Care .............................................................................................................. 4 
 
Investigational Treatment .............................................................................................................. 4 
 
Rationale ....................................................................................................................................... 5 
6.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................ 5 
7.0 
STUDY DESIGN ....................................................................................................................................... 5 
 
General Design ............................................................................................................................. 5 
 
End of Study Definition .................................................................................................................. 6 
8.0 
SUBJECT SELECTION ............................................................................................................................ 6 
 
Inclusion & Exclusion Criteria ........................................................................................................ 6 
 
Subject Identification ..................................................................................................................... 6 
8 
Error! Bookmark not defined. 
8.4.1 
Electronic Medical Record (EMR) Query ............................................................................................................ 6 
 
Error! Bookmark not defined. 
 
Subject Recruitment ...................................................................................................................... 7 
8.5.1 
Recruitment through Employee Health ............................................................................................................... 7 
 
Error! Bookmark not defined. 
8.5.2 
Email ................................................................................................................................................................... 7 
8.5.3 
Telephone Recruitment ....................................................................................................................................... 7 
 
Remuneration and Retention Strategies ........................................................................................ 7 
 
Early Termination and Withdrawal ................................................................................................. 7 
9.0 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, ETC.) AND/OR PROCEDURAL 
INTERVENTION ....................................................................................................................................... 8 
 
Study Agent and Control Description ............................................................................................. 8 
9.1.1 
Source ................................................................................................................................................................ 8 
9.1.2 
Packaging and Labeling ...................................................................................................................................... 8 
9.1.3 
Preparation ......................................................................................................................................................... 8 
9.1.4 
Storage and Stability ........................................................................................................................................... 8 
9 
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9.1.5 
Dosing and Administration .................................................................................................................................. 8 
 
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10.0 STUDY VISITS AND PROCEDURES ....................................................................................................... 9 

- ii - 
 
Study Calendar ............................................................................................................................. 9 
 
Screening and Enrollment ............................................................................................................. 9 
10.2.1 
Pre-screening ...................................................................................................................................................... 9 
10.2.2 
Informed Consent ............................................................................................................................................... 9 
 
Error! Bookmark not defined. 
 
Error! Bookmark not defined. 
10.2.3 
Enrollment ......................................................................................................................................................... 10 
10.2.4 
Screen Failure and Re-enrollment .................................................................................................................... 10 
 
On-Study/Follow-up Visits ........................................................................................................... 10 
10.3.1 
Visit Number 1 .................................................................................................................................................. 10 
10.3.2 
Visit Number 2 .................................................................................................................................................. 10 
10.3.3 
Visit Number 3 .................................................................................................................................................. 10 
 
 
 
Error! Bookmark not defined. 
 
Unscheduled Visits ...................................................................................................................... 11 
 
Early Termination/Withdrawal Visit .............................................................................................. 11 
 
11.0 CORRELATIVE | SPECIAL STUDIES .................................................................................................... 11 
 
Biospecimen Collection Guidelines ............................................................................................. 11 
 
Assay Methodology ..................................................................................................................... 11 
12.0 DATA COLLECTION, HANDLING, SHARING, AND RECORD KEEPING .............................................. 11 
 
Data Collection ............................................................................................................................ 11 
12.1.1 
Data Collection Forms ...................................................................................................................................... 11 
 
Error! Bookmark not defined. 
 
Confidentiality and Privacy .......................................................................................................... 12 
 
Records Retention ...................................................................................................................... 12 
 
 ....................................................................................................... Error! Bookmark not defined. 
 
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e 
Error! Bookmark not defined. 
 
Protocol Deviations ..................................................................................................................... 13 
 
Publication and Data Sharing Policy ............................................................................................ 13 
 
 ...................................................... Error! Bookmark not defined.Error! Bookmark not defined. 
 
 
 
 
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3.0STUDY ANALYSIS .................................................................................................................................... 13 
 
Statistical Hypotheses ................................................................................................................. 13 
 
Sample Size Justification ............................................................................................................ 13 
 
Subject Population(s) for Analysis ............................................................................................... 13 
 
Statistical Methods ...................................................................................................................... 14 
14.0 RISK/BENEFIT ASSESSMENT ............................................................................................................. 14 
 
Potential Benefits to the Subjects ................................................................................................ 14 
 
Known Potential Risks ................................................................................................................. 14 
14.2.1 
Known Procedural Risks ................................................................................................................................... 14 
14.2.2 
Known Interventional Risks ............................................................................................................................... 14 
15.0 DATA AND SAFETY MONITORING ...................................................................................................... 14 
 
Adverse Event (AE) Definition ..................................................................................................... 14 
 
Serious Adverse Event (SAE) Definition ...................................................................................... 14 

- iii - 
 
Classification of an Adverse Event .............................................................................................. 15 
15.3.1 
Severity of Event ............................................................................................................................................... 15 
15.3.2 
Relationship to Study, Study Procedure(s) and/or Study Intervention .............................................................. 15 
15.3.3 
Expectedness for Study, Study Procedure(s) and/or Study Intervention .......................................................... 16 
 
Time Period and Frequency for Event Assessment and Follow-Up ............................................. 16 
 
Reporting AEs and SAEs ............................................................................................................ 16 
16.5.1 
Reporting AEs ................................................................................................................................................... 16 
16.5.2 
Reporting SAEs ................................................................................................................................................ 16 
Unanticipated Problems ................................................................................................................... 17 
16.0 STUDY FEASIBILITY .................................................................... ERROR! BOOKMARK NOT DEFINED. 
 
Economic Burden to Subjects ..................................................................................................... 18 
 
Facilities and Locations ............................................................................................................... 18 
 
Feasibility of Recruiting the Required Number of Subjects .......................................................... 18 
 
Principal Investigator Considerations .......................................................................................... 18 
17.4.1 
Time Devoted to Conducting the Research ...................................................................................................... 18 
17.4.2 
Process for Informing Study Teams .................................................................................................................. 18 
 
Availability of Medical or Psychological Resources ..................................................................... 18 
17.0 REFERENCES ....................................................................................................................................... 18 
18.0 APPENDICES ........................................................................................................................................ 18 
 
Data collection form..................................................................................................................... 19 
 
 
 

Vaccination for healthcare worker hepatitis B 
vaccine nonresponders 
 
Hayney 
 
 
 
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1.0 
STATEMENT OF COMPLIANCE 
I confirm that I have read this protocol. I will comply with the IRB-approved protocol, and applicable 
regulations, guidelines, laws, and institutional policies.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitment.  
 
Name 
Signature 
Date 
 
Mary S. Hayney, PharmD, MPH 
__________________________________ 
_____________________________ 
___________________ 
Principal investigator 
 
 
 
 
 
 
 
 

Vaccination for healthcare worker hepatitis B 
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2.0 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
antiHBs 
Antibody to the hepatitis B surface antigen 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHHS 
Department of Health and Human Services 
DMC 
Data Monitoring Committee 
DSMB 
Data & Safety Monitoring Board  
DSMC 
Data & Safety Monitoring Committee 
DSMP 
Data & Safety Monitoring Plan 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HepB-CpG 
Hepatitis B vaccine with CpG adjuvant (Heplisav-BTM) 
HIPAA 
Health Insurance Portability and Accountability Act 
ICTR 
Institute for Clinical and Translational Research 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 
POC 
Point of Contact 
PRC 
Pharmaceutical Research Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sIRB 
single IRB 
SMART IRB 
Streamlined, Multisite, Accelerated Resources for Trials IRB 
SMC 
Safety Monitoring Committee 
SMP 
Study Monitoring Plan 
SMS 
Study Monitoring Service 
UP 
Unanticipated Problem 
 
 
 
 
 
 
 
 

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3.0 
STUDY SUMMARY 
 Synopsis 
 
Full Title 
HepB-CpG series for healthcare workers who are hepatitis B vaccine nonresponders 
Short Title 
Vaccination for healthcare worker hepatitis B vaccine nonresponders 
Protocol Number 
[HS IRB 2020-0631] 
ClinicalTrials.gov 
Identifier & 
Summary 
pending 
This study is being done to determine if healthcare workers who have previously failed to 
respond to hepatitis B vaccine series will respond to a hepatitis B with CpG adjuvant (hepB-
CpG) (Heplisav-B) 
Number of 
Site(s) 
The study will be conducted at UWHealth Employee Health Services 
Phase 
Phase 4 
Main Inclusion 
Criteria 
• 
Healthcare worker who has previously received at least 5 doses of hepatitis B vaccine 
with aluminum adjuvant (Recombivax B or Engerix B) and has an antibody to the 
hepatitis B surface antigen (antiHBs) that is less than 10 mIU/ml.   
• 
English-speaking (able to provide consent) 
Main Exclusion 
Criteria 
• 
Allergy to hepB-CpG or a component 
Objective(s) 
 Primary Objective  
• 
To measure the number of healthcare workers who failed to respond to 5 or more doses 
of hepatitis B vaccine with aluminum adjuvant who will respond to hepatitis B vaccine 
with CpG adjuvant series.  
Secondary Objectives  
• 
To measure the number of healthcare workers who respond to a single dose of hepB-
CpG 
• 
To determine risk factors associated with hepatitis B vaccine nonresponse, including age, 
smoking status, sex, diabetes, immunosuppression 
 
Endpoints 
Primary Endpoint 
• 
AntiHBs >10 mIU/ml following two doses of hepB-CpG 
Secondary Endpoint 
• 
AntiHBs >10 mIU/ml following a single dose of hepB-CpG  
 
• 
Measure effect of known hepatitis B vaccine nonresponse risk factors on response in this 
population 
Study Design 
Open label  
IND or IDE 
Number 
Not applicable 

Vaccination for healthcare worker hepatitis B 
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Hayney 
 
 
 
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Study 
Intervention 
Each individual who has completed at least 5 doses hepB vaccine with aluminum adjuvant series but 
is anti-HBs negative will be contacted by EHS staff and invited to receive the hepB-CpG two dose 
series on a 0 and 1 month schedule.  Antibody to the surface antigen will be measured after the first 
dose during the visit for the administration of the second dose. One month after completion of the 
series, each immunized individual will have another anti-HBs measured.   
Total Number of 
Subjects 
Up to 130 individuals will be recruited and enrolled.  
Study Population Healthcare workers who have received at least 5 doses of hepatitis B vaccine with aluminum 
adjuvant and have antiHBs < 10mIU/ml.  
Statistical 
Methodology 
We will count the number of individuals who seroconvert and have anti-HBs >10 mIU/ml and 
report a ratio with the total number immunized as the denominator.   We will develop a 
multivariate model to predict hepB-CpG response which will include age, sex, smoking 
status, diabetes, and immunosuppression as variables. 
Estimated 
Subject Duration 
The duration of the study for each subject is approximately 8 weeks. 
Estimated 
Enrollment 
Period & Study 
Duration 
Study enrollment and follow-up will occur over 12 months. 
 
 
 

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 Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Draw blood for antiHBs 
Dismiss from study 
Final Assessments 
EHS personnel will contact 
participant with antiHBs 
results 
Obtain written informed consent.  Perform baseline assessments and vaccine 
screening. 
Administer hepB-CpG by intramuscular injection  
Up to 130 healthcare workers who have received at least 5 doses of hepatitis B 
vaccine with aluminum adjuvant and antiHBs <10 MIU/ml 
Eligible individuals will be invited to participate by Employee Health Services 
(EHS) personnel.  
 
Draw blood for antiHBs 
Perform baseline assessments and vaccine screening. 
Administer hepB-CpG by intramuscular injection  
Prior to Enrollment 
Visit 1 
Time Point 
Visit 3 
Time Point
Visit 2 
Time Point 

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Hayney 
 
 
 
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4.0 
KEY ROLES 
  
The following is a list of all key personnel and roles: 
 
Principal Investigator 
Mary S. Hayney, PharmD, MPH 
Professor of Pharmacy  
University of Wisconsin School of Pharmacy 
777 Highland Avenue, Madison, WI 53705 
608-265-4666 
Participating Site(s) 
UWHealth Employee Health Services 
700 University Bay Drive 
Madison, WI 53705 
Local Laboratory Services 
UWHealth Clinical Laboratory 
601 Highland Avenue 
Madison, WI 53792  
Funding Sponsor (Supplying vaccine only) 
Dynavax 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
5.0 
INTRODUCTION 
 Disease Background 
Although the recombinant hepatitis B (hepB) vaccine with aluminum adjuvant as a three dose series 
induces seroprotection in about 95% of individuals, a small number of healthy individuals fail to mount an 
immune response.  Increasing age is an important risk factor for hepB vaccine response. 1  Healthcare 
personnel are among the individuals for whom protection from hepatitis B infection is very important.  
Employee Health Service (EHS) at the University of Wisconsin Hospital and Clinics screens employees 
with documented history of completion of the hepB vaccine 3-dose series for antibody to the hepatitis B 
surface antigen (anti-HBs) at time of hire.  Those who are found to have anti-HBs less than 10 mIU/ml 
receive a challenge dose. 2  If the anti-HBs remains less than 10 mIU/ml, two more doses of vaccine are 
administered.  Among the 15,000 employees, about 100 individuals have completed two hepB vaccine with 
aluminum adjuvant series but remain vaccine non-responders.  Heplisav-B (hepB-CpG) is a recently 
licensed hepB vaccine with a new adjuvant that is more immunogenic in the general adult population and 
patients with chronic kidney disease or diabetes.3-5  Given the superior immunogenicity of hepB-CpG in 
these individuals who were difficult to induce seroprotection, we hypothesize that 70% of the 101 non-
responders will mount an immune response to two doses of hepB-CpG.   
 Current Standard of Care 
With the recent licensure of hepatitis B vaccine with CpG antigen, the Advisory Committee on 
Immunization Practices (ACIP) has recommended this vaccine series as a vaccine that can be used for 
adults for whom hepatitis B immunization is recommended.  This vaccine series is more immunogenic in 
the general adult population and patients with chronic kidney disease or diabetes.  The ACIP has listed 
hepB-CpG as a vaccine that can be used for revaccination.   
 
 Investigational Treatment 
 

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     Although reimmunization is recommended for individuals at high risk of bloodborne pathogen exposure, 
including healthcare workers, we are prospectively using hepB-CpG series and measuring the vaccine 
response.  Each healthcare worker who wishes to receive the hepB-CpG series on a 0 and 1 month schedule 
will be asked for written informed consent and will have blood drawn for antiHBs one month after dose 1 and 
prior to administration of dose 2 and one month after the second dose.  
 Rationale 
The response rate to hepB-CpG series in healthcare workers who failed to respond to at least 5 doses of 
hepatitis B vaccine with aluminum adjuvant is not known.  If healthcare workers respond to this vaccine 
series, it may become the standard of care rather than an option among all hepatitis B vaccine 
preparations.  
6.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
To measure the number of healthcare 
workers who failed to respond to 5 or 
more doses of hepatitis B vaccine with 
aluminum adjuvant who will respond to 
hepatitis B vaccine with CpG adjuvant 
series 
antiHBs > 10mIU/ml after completion of the 
series 
Secondary 
To measure the number of healthcare 
workers who respond to a single dose of 
hepB-CpG 
 
antiHBs > 10mIU/ml after one dose of hepB-CpG 
To determine risk factors associated with 
hepatitis B vaccine nonresponse, 
including age, smoking status, sex, 
diabetes, immunosuppression 
 
Proportion of participants who are nonresponders 
with each risk factor and develop a multivariate 
model 
 
7.0 
STUDY DESIGN 
 General Design  
This Phase 4 single center, open label study will measure the response rate to hepB-CpG series in 
healthcare workers who have received at least 5 doses of hepatitis B vaccine with aluminum adjuvant and 
have antiHBs < 10mIU/ml.   
 
The study population will consist of 130 healthcare workers who have received at least 5 doses of hepatitis 
B vaccine with aluminum adjuvant and have antiHBs < 10mIU/ml.   
 
All study visits will be done at Employee Health Services.  During visit 1, written informed consent for 
participation will be obtained.  Each participant will be screened for vaccine contraindications.  Participants 

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will be briefly interviewed for known hepatitis B vaccine nonresponse risk factors—age, sex, smoking 
status, diabetes, and immunosuppression. 
 
Each participant will receive hepB-CpG intramuscularly at visit 1 and at visit 2 will have a blood draw for 
antiHBs and receive hepB-CpG dose 2 intramuscularly.  A blood draw for antiHBs will be done at visit 3 
one month following dose 2.  The vaccine administration will be documented in the Wisconsin 
Immunization Registry (the WIR) and the antiHBs results will be retained in the Employee Health electronic 
medical record (Agility).   
 
Subject accrual will occur over 6 months at UWHealth Employee Health Services.  Subjects will complete 3 
study visits over the course of approximately 8 weeks. Each subject will contribute 2.  
 End of Study Definition 
A subject is considered to have completed the study if they receive both doses of hepB-CpG and the blood 
draw one month after the second dose.   
8.0 
SUBJECT SELECTION 
 Inclusion & Exclusion Criteria   
 Eligibility will be determined by inclusion and exclusion criteria below. 
 
Inclusion Criteria  
1. Willing to provide informed consent. 
2. Willing to comply with all study procedures and be available for the duration of the study. 
3. healthcare workers who have received at least 5 doses of hepatitis B vaccine with aluminum 
adjuvant and have antiHBs < 10mIU/ml 
4. Individuals at least 18 years of age. 
5. Females of childbearing potential will be asked about the possibility of pregnancy as is the 
standard of care for immunization services.  If a female indicates that she may be pregnant, 
study participation will be postponed until pregnancy is completed or the female reports that 
she is not pregnant. 
 
Exclusion Criteria 
1. Women who are pregnant or planning on becoming pregnant during the study.   
2. Allergy to the vaccine or a component of the vaccine 
3. Not suitable for study participation due to other reasons, such as inability or unwillingness to 
comply with the study procedures, at the discretion of the investigators. 
 Subject Identification 
8.2.1 Electronic Medical Record (EMR) Query  
Potential subjects will be identified via Agility (the EMR used by EHS) query.  Eligible individuals are 
flagged in the system as they require special prophylaxis following bloodborne pathogen exposures.  
The research team will conduct further prescreening of individual records to further refine the list of 
potential subjects.   

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 Subject Recruitment 
Up to 130 subjects will be recruited from UWHealth. Specific recruitment strategies are as follows (non-
comprehensive list): 
8.3.1 Recruitment through Employee Health Practice 
If the potential subject is agreeable, they will be provided contact information for the study team or the 
research team will initiate contact. 
8.3.2 Email 
An email invitation from EHS staff describing the study will be sent to eligible individuals.   
8.3.3 Telephone Recruitment 
When potential subjects contact the study team, a brief description of the study’s purpose and 
participation requirements will be reviewed. This must also include a statement that participation is 
voluntary. The screener will ask the caller if s/he has any questions and about interest in participating. 
After all questions have been answered, the study team member will ask if the potential subject is 
interested in proceeding to the next step in recruitment for the study (e.g., scheduling a visit to learn 
more and go through the consent process, or answering some screening questions).] 
 Retention Strategies 
Strategies for retention include:  
• 
Appointment for the next visit will be set at the end of each visit 
• 
Email visit reminder 3 days prior to visit and day prior if appointment is before 10am or day of visit if 
visit is at 10am or later. 
• 
Recall reminders for missed appointment.  Each participant will be contacted three times by email and 
then with two phone calls at least 2 days apart.  
• 
Flexible study visit windows and be used with the following limits to accommodate subject schedules.   
Time between visits 1 and 2 
Not less than 28 days and not more than 60 days 
Time between visits 2 and 3  
Not less than 28 days and not more than 60 days 
 
 Early Termination and Withdrawal 
  
Subjects are free to withdraw from participation in the study at any time upon request. 
 
The Principal Investigator (PI) may discontinue or withdraw a subject from the study for the following 
reasons at her discretion: 
• 
Pregnancy 
• 
Subject non-compliance with study requirements (e.g., study intervention non-compliance)  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the subject 
• 
If the subject is no longer an appropriate candidate for participation   
 
The following actions must be taken if a subject withdraws, or fails to return for a required study visit: 
• 
The site will attempt to contact the subject and reschedule the missed visit by email and phone as in 
8.4 above and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain if the subject wishes to and/or should continue in the study. 

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• 
Before a subject is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the subject as described in 8.4 above. These contact attempts shall be documented 
the study file.  
• 
If the subject continues to be unreachable, s/he will be considered to have withdrawn from the study 
with a primary reason of lost to follow-up. The withdrawn date is the last day of attempted contact. 
 
9.0 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, ETC.) AND/OR PROCEDURAL 
INTERVENTION  
 Study Agent and Control Description 
Study Product 
 Recombinant hepatitis B vaccine with CpG adjuvant (Heplisav-B, Dynavax) 
9.1.1 Source 
 All study drug will be provided free of charge by Dynavax, Emeryville, CA during the treatment phase.   
 
Dynavax, Emeryville, CA will distribute hepB-CpG to UWHealth PRC. Each shipment will include a 
temperature-monitoring device to verify maintenance of the cold chain during transit, as well as a 
packing slip. On delivery of the product to the site, the person in charge of product receipt will use 
departmental procedures for unpacking and storing the vaccine, including checking that the cold chain 
was maintained during shipment (i.e., verification of the temperature indicator). The contents of the 
shipment will then be reviewed and verified against the packing slip, and will be documented as 
instructed at the initiation visit.  
 
If the temperature-monitoring indicator reflects that the cold chain has been broken, the entire shipment 
must be immediately quarantined.  The principal investigator will contact Dynavax for instructions.  
9.1.2 Packaging and Labeling 
• 
The vaccine will be supplied as the commercial product and labeled as such.   
 
9.1.3 Preparation 
The vaccine will be supplied as a single-dose prefilled syringe.   
 
9.1.4 Storage and Stability 
Storage Conditions 
Store in a refrigerator at 2°C to 8°C (36°F to 46°F). 
Do not freeze; discard if the vaccine has been frozen. 
9.1.5 Dosing and Administration 
HepB-CpG will be supplied as 0.5 mL single-dose, pre-filled syringes. No preparation is required. 
Administer as follows: 
 
• 
Visually inspect the syringe for particulate matter and/or discoloration prior to administration. If 
either of these conditions exist, do not administer 
• 
Gently shake the prefilled syringe 
• 
Identify the deltoid muscle (upper arm) and cleanse the injection site with alcohol 
• 
Insert needle (22 to 25 -gauge 1-inch needle recommended; 1 ½ inch needle recommended for 
those with BMI ≥ 30) at a 90 degree angle to the skin and inject entire contents of the syringe 

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intramuscularly. Do not inject the vaccine subcutaneously or intravenously. Care should be taken to 
avoid administering the injection into or near blood vessels and nerves. 
• 
Monitor the subject for at least 15 minutes post administration] 
10.0 
STUDY VISITS AND PROCEDURES 
 
Study Calendar 
The procedures performed at each study visit are listed in the table below. 
 
Procedure 
Visit 1 
Visit 2 
Visit 3 
End of 
study/early 
withdrawal 
Visit Window 
Day 0 
Day 28- 42 
Day 28-42 
following 
visit 2  
Informed Consent 
X 
 
 
Review Eligibility Criteria 
X 
 
 
Demographics1 
X 
 
 
Obtain Medical History2 
X 
 
 
Vital Signs3 
X 
X 
X 
Vaccine screening 
X 
X 
 
Vaccine administration 
X 
X 
  
Blood draw  
 
X 
X 
Adverse Events 
Review/Assessment 
  
X 
X 
1 Age, sex, dates of previous hepatitis B vaccine doses and antiHBs 
2 Self-reported smoking history, diabetes, immunosuppression 
3 vitals as standard of practice at EHS for immunization visit 
 
Screening and Enrollment 
The Screening and Enrollment visits and procedures are described in detail below. 
10.2.1 Pre-screening 
Potential participants will be identified and invited to participate by EHS staff.  Potential participant are 
UWHealth healthcare workers who have received at least 5 doses of hepatitis B vaccine with aluminum 
adjuvant and have antiHBs < 10mIU/ml  
10.2.2 Informed Consent 
Preliminarily eligible subjects will be invited to EHS for informed consent and formal screening. The 
informed consent process will be conducted following all federal and institutional regulations relating to 
informed consent. Informed consent will be obtained prior to conducting any study-related activities. 
 
The informed consent process will be performed as follows: 
• 
The principal investigator or a co-investigator will review the informed consent form and discuss the 
study in detail with the potential research subject. 

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• 
The principal investigator or a co-investigator will explain the study, its risks and benefits, what 
would be required of the research subject, and alternatives to participation. 
• 
The research subject will be given the opportunity to take the informed consent form home so that 
s/he may discuss it with family members, friends, clergy or others when possible.   
• 
The subject will have the opportunity to ask questions and have all questions answered by the 
principal investigator or a co-investigator. 
• 
The informed consent document must be signed and dated by the research subject. 
• 
The principal investigator or a co-investigator will review the informed consent document to ensure 
that all fields that require a response are complete (i.e., checkbox marked yes or no, etc.) as 
applicable. 
• 
The research subject will be given a copy of the signed and dated informed consent form. The 
original signed informed consent form is kept the study binder. 
10.2.3 Enrollment 
A research subject will be defined as “enrolled” in the study when they meet the following criteria: 
• 
The subject has been consented by study staff.  
• 
The subject and study staff have completed all screening documentation. 
• 
The study staff has verified that the subject meets all of the inclusion criteria. 
• 
The study staff has verified that subject meets none of the exclusion criteria. 
• 
The subject has been assigned to the protocol by study staff.  
• 
The subject has scheduled a study visit which can follow the informed consent process described 
above. 
10.2.4 Screen Failure and Re-enrollment 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
possible pregnancy may be rescreened. Rescreened subjects should be assigned a new subject ID 
number when they are re-screened. 
 
On-Study/Follow-up Visits 
After subjects have been enrolled, the On-Study/Follow-up visit and the procedures performed at each visit 
are described in detail below. 
10.3.1 Visit Number 1  
The following activities will be done during visit 1 which can directly follow the informed consent and 
enrollment phases. 
• 
Limited interview for medical history to collect age, sex, race, ethnicity, and self-reported 
smoking history, diabetes and immunosuppression.  Hepatitis B vaccine history and antiHBs 
dates, UWHealth department and location will be collected from Agility, the EHS EMR.  
(research) 
• 
Vitals (per EHS routine) 
• 
Vaccine screening (research) 
• 
Vaccine administration and aftercare (research) 
Visit 1 is expected to take about 45 minutes.  
10.3.2 Visit Number 2 
The following activities will be done during visit 2 which is done 28-42 days after visit 1. 
• 
Vitals (per EHS routine) 
• 
Ask about adverse events following hepB-CpG.  Report to VAERS if appropriate (routine) 
• 
Blood draw for antiHBs (research) 
• 
Vaccine screening (research) 
• 
Vaccine administration and aftercare (research) 

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Visit 2 is expected to take about 30 minutes.  
 
10.3.3 Visit Number 3  
The following activities will be done during visit 3 which is done 28-42 days after visit 3. 
• 
Vitals (per EHS routine) 
• 
Ask about adverse events following hepB-CpG.  Report to VAERS if appropriate (routine) 
• 
Blood draw for antiHBs (research) 
• 
Dismiss from study participation with information that EHS employee will contact with antiHBs 
results (research) 
Visit 3 is expected to take about 15 minutes.  
 
 
Unscheduled Visits 
Unscheduled visits will not occur for this study. 
 
Early Termination/Withdrawal Visit 
Subjects who are either withdrawn or terminated early from the study will have one final visit to to follow up 
regarding adverse events. 
11.0 
CORRELATIVE | SPECIAL STUDIES 
 
Biospecimen Collection Guidelines 
Standard phlebotomy procedures to collect 3ml in red top with yellow ring and sent to the UWHealth 
Clinical Lab for antiHBs.   
 
Assay Methodology 
  
The UWHealth Clinical Laboratory uses a chemiluminescent immunoassay to measure antiHBs.  
12.0 
DATA COLLECTION, HANDLING, SHARING, AND RECORD KEEPING 
 
Data Collection  
 
12.1.1 Data Collection Forms 
Standardized data collection forms (e.g., source documents, case report forms, standardized 
assessment forms, etc.) are used to ensure data collected are consistent and compliant with the 
protocol and IRB application.  
 
Data collection is the responsibility of study team members under the supervision of the Principal 
Investigator (PI). The PI is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the recorded and reported data. Data will be collected from the participant and the EHS 
EMR as described in Section 10.  
 

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All data collection forms must be completed in a legible manner; any missing data will be explained. 
Data entry errors will be corrected with a single line through the incorrect entry and the correct data is 
entered above/near the correction. All changes will be initialed and dated. 
 
Data collection forms are maintained in the subject files and retained as described in Section 12.3: 
Records Retention. 
 
Confidentiality and Privacy 
Subject confidentiality and privacy is strictly held in trust by the participating investigators and their staff.  
The sponsor will have no access to the study data.  This confidentiality is extended to cover testing of 
biological samples and to the clinical information relating to subjects. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence.  
 
All research activities will be conducted in as private a setting as possible. 
 
All study staff engaged in the conduct of this project have completed training on the protection of human 
subjects and the Health Insurance Portability and Accountability (HIPAA) Privacy Rule. In addition, all key 
personnel (i.e.., Principal Investigator, individuals involved in identifying/recruiting subjects, obtaining 
informed consent, or interacting and intervening with subjects) have undergone Good Clinical Practice 
(GCP) training. 
 
Information about study subjects will be kept confidential and managed according to HIPAA requirements. 
All subjects will a combined informed consent and HIPAA authorization form that includes specific privacy 
and confidentiality rights. Study data will be maintained per federal, state, and institutional data policies. 
 
The investigator(s) will ensure that the identities of subjects are protected by using coded subject 
information. The log of subject identifying information that links subjects to their study-specific identification 
number will be maintained by the investigator. The log and all study records will be maintained in locked 
rooms and access will be limited to essential study personnel. Electronic study records/files will be stored 
on a School of Pharmacy server and accessed via networked computers that are password-protected with 
access provided only to authorized study personnel.  
 
Authorized representatives of the following groups may need to review this research as part of their 
responsibilities to protect research subjects: representatives of the IRB and federal oversight agencies, 
such as the Food and Drug Administration (FDA). The clinical study site will permit access to such records. 
 
Study staff may use e-mail to communicate with research subjects, if the subject has agreed to using email 
in the Informed Consent form. The information contained in emails will be limited to study visit time and 
date information and general questions. All emails to subjects will be sent from UW/wisc.edu or uwhealth 
accounts; personal, home or Gmail email accounts will not be used. 
 
 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for a minimum period of 7 years 
following completion of the study per UW-Madison institutional policy, or at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product, whichever comes last. 

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Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or investigational plan 
requirements. The noncompliance may be either on the part of the subject, the investigator, or the study 
site staff. As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly.  
 
It is the responsibility of the Principal Investigator and study staff to use continuous vigilance to identify and 
report deviations. The Principal Investigator is responsible for assessing whether the deviation constitutes 
noncompliance as defined by the reviewing IRB and will report the deviation within the timeframes posted 
on the HS IRB website of the discovery.  
 
Publication and Data Sharing Policy 
The Principal Investigators will work with the co-investigators to draft a manuscript for publication regarding 
the findings of this study.  All precautions will be taken to avoid identification of an research participant in 
the publication.   
13.0 
STUDY ANALYSIS 
 
Statistical Hypotheses 
• 
Primary Efficacy Endpoint(s):  
AntiHBs >10 mIU/ml following two doses of hepB-CpG 
Descriptive statistics will be used to report the result, including number of responders and ratio of 
responders.   
 
• 
Secondary Efficacy Endpoint(s): 
AntiHBs >10 mIU/ml following two doses of hepB-CpG 
Descriptive statistics will be used to report the result, including number of responders and ratio of 
responders.   
 
Proportion of participants who are nonresponders with each risk factor and develop a multivariate 
model 
Descriptive statistics will be used to report the result for each risk factor, including number of 
responders and ratio of responders.  Multivariate analysis will be used to develop a model.  
 
 
 
Sample Size Justification 
In an effort to be fair to all potentially eligible UWHC healthcare workers, we want to offer the hepB-CpG 
vaccine series to all known eligible individuals (those who have failed to respond to at least 5 doses of 
hepatitis B vaccine with aluminum adjuvant).   
 
 
Subject Population(s) for Analysis 
Analyses will include all individuals who received at least one dose of hepB-CpG.  We will also do a per-
protocol analysis for hepB-CpG one dose and two doses.   

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Statistical Methods 
.  
Descriptive statistics will be used to report the number and ratio of vaccine responders to both doses and 
one dose and with regard to known risk factors for hepatitis B vaccine nonresponse.  A multivariate model 
with the risk factors will be developed.  
   
14.0 
RISK/BENEFIT ASSESSMENT 
 
Potential Benefits to the Subjects 
The potential benefits to research subjects associated with this study include participants’ safety as 
healthcare providers should they be converted to hepatitis B vaccine responders.   
 
If hepB-CpG has a high response rate, this vaccine could become the preferred vaccine series for 
nonresponders.   
 
 
Known Potential Risks 
14.2.1 Known Procedural Risks 
Procedure: Risk description(s) 
 
• 
Blood Draw: The risks of drawing blood from a vein include discomfort at the site of puncture; 
possible bruising and swelling around the puncture site; rarely an infection; and, uncommonly, 
faintness from the procedure. 
14.2.2 Known Interventional Risks 
. 
• 
HepB-CpG:  Risks of hepatitis B immunization include soreness at the injection site, fever, or 
fainting.  Anaphylaxis occurs very rarely.  No information regarding hepB-CpG during pregnancy is 
available.   
Hepatitis B immunization is recommended for all healthcare workers at risk for bloodborne pathogens 
exposure.  Repeated series, including the use of hepB-CpG series, is one strategy to convert 
nonresponders to responders so participation in this study conforms with current immunization 
recommendations for healthcare providers.  (Heplisav-B package insert, Vaccine Information Statement 
published by the CDC) 
15.0 
DATA AND SAFETY MONITORING  
 
Adverse Event (AE) Definition 
Adverse event (AE) means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related.  
 
Serious Adverse Event (SAE) Definition 
An adverse event is considered "serious" if, in the view of either the investigator or sponsor, it meets any of 
the following criteria: 
• 
Results in death 

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• 
Is life-threatening  
• 
Requires an inpatient hospitalization or prolongation of an existing hospitalization  
• 
Results in persistent or significant disability or incapacity.  
• 
Results in a congenital anomaly/birth defect. 
• 
A medical event, based on appropriate medical judgment, that is believed to jeopardize the subject 
and/or requires medical or surgical intervention to prevent one of the outcomes defining a SAE. For 
example: allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
convulsions that may not result in hospitalization 
 
Classification of an Adverse Event 
15.3.1 Severity of Event 
All AEs will be assessed by the clinician using  the Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0, each event searchable using the Safety Profiler website (https://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx). For AEs not included in the protocol-defined grading system, the 
following guidelines will be used to describe severity.  
 
Mild 
(Grade 1) 
Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
Moderate 
(Grade 2) 
Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference 
with functioning. 
Severe 
(Grade 3) 
Events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
potentially life-threatening or incapacitating. 
Life Threatening 
(Grade 4) 
The subject was at risk of death at the time of the event. 
Fatal 
(Grade 5) 
The event caused death. 
 
15.3.2 Relationship to Study, Study Procedure(s) and/or Study Intervention(s) 
 For all collected AEs, the clinician who examines and evaluates the subject will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
 
Definitely Related 
Clearly related to the study procedures/intervention and other 
possible contributing factors can be ruled out. 
Probably Related 
Likely related to the study procedures/intervention and the influence 
of other factors is unlikely. 
Possibly Related 
Possibly related to the study procedures/intervention and there are 
other factors that could be equally likely. 
Unlikely to be related Doubtfully related to the study procedures/intervention and there is 
another likely cause. 
Unrelated 
Clearly not related to the study procedures/intervention and/or 
evidence exists that the event is definitely related to another cause. 
 

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15.3.3 Expectedness for Study, Study Procedure(s) and/or Study Intervention(s) 
The PI will be responsible for determining whether an AE is expected or unexpected in relation to the 
study procedures and intervention(s) (as applicable).  
 
 
For studies not evaluating an investigational drug: An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously described in the 
clinical protocol, the IRB application, or the informed consent document. The expectedness could be 
based on study procedures or the characteristics of the patient population.  
 
Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate 
CRF. Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. AEs 
will be reported to the Vaccine Adverse Event Reporting System (VAERS) as this is the standard of 
practice. 
 
Any medical condition that is present at the time that the subject is screened will be considered as baseline 
and not reported as an AE. However, if the study subject’s condition deteriorates at any time during the 
study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as intermittent require documentation of onset 
and duration of each episode.  
 
The PI will record all reportable events with start dates occurring any time after the administration of the 
study drug and for up to 30 days after the date of the last dose of study drug or at Visit 3. At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution, stabilization, or completion of study participation. 
 
Reporting AEs and SAEs  
15.5.1 Reporting AEs 
The Principal Investigator will be notified regarding any AE reported by a participant.  AEs will be reported 
to the Vaccine Adverse Event Reporting System (VAERS) as this is the standard of practice. 
15.5.2 Reporting SAEs 
The investigator will i report to the IRB any SAE, whether or not considered study intervention-related, 
including those listed in the protocol and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. The report will be made within the timeframes 
posted on the HS IRB website.  
 
All SAEs will be followed until satisfactory resolution or until the principal investigator deems the event 
to be chronic or the subject is stable.  
 

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The investigator will be responsible for notifying the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible and within the timeframes posted on the HS IRB 
website after the investigator's initial receipt of the information. 
 
 
Unanticipated Problems 
An unanticipated problem (UP), as defined by the DHHS Office for Human Research Protection (OHRP), is 
any incident, experience, or outcome that meets all of the following criteria:  
• 
The incidence, experience, or outcome is unexpected given the research procedures described in 
protocol-related documents (e.g., the study protocol, the informed consent documents) and the 
characteristics of the subject population being studied. An event may be considered unexpected if it 
exceeds the nature, severity, or frequency described in the study-related documents, product labeling, 
or package insert. 
• 
The incidence, experience, or outcome is related or probably related to participation in the research 
study. “Probably related” means the incidence, experience, or outcome is more likely than not to be 
caused by the research study procedures. 
• 
The occurrence of the incidence, experience, or outcome suggests that the research places subjects or 
others at a greater risk of harm (physical, psychological, economic, or social) than was previously 
known or recognized.  
 
The investigator will report UPs to the reviewing IRB within the timeframe posted on the HS IRB website. 
The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP;  
• 
A description of any changes to the protocol, informed consent documents, or other corrective actions 
that have been taken or are proposed in response to the UP. 
 
 
 
Protocol Deviations 
Refer to section 12.4. 
 
Data Safety Monitoring Plan 
The study involves a small number of participants, is conducted at only one site, and/or the range of 
possible study events having an important impact on risks and benefits to participants is narrow, the 
principal investigator (PI) will perform the monitoring functions.  
 
    The type of data or events to be captured under the monitoring plan:  Reported adverse events by 
participants at visits 2 and 3. Study accruals, protocol deviations, protocol violations, and unanticipated 
problems will also be monitored. 
    The name(s) of the person(s) who will be responsible for monitoring the data collected (i.e. study 
accruals, protocol deviations, protocol violations, unanticipated problems, adverse events) and their 
respective roles (e.g. investigators, research sponsor):  Mary Hayney, Principal Investigator, is responsible.  
    The frequency of assessments/analysis of data or events captured by the monitoring plan (e.g. a 
periodic time interval or after a specific number of participants are enrolled):  Monitoring will be done 
monthly.   

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    The time frame for reporting unanticipated problems, adverse events, protocol deviations, and protocol 
violations.  These will be reported by study personnel to the PI as they are discovered.  The PI will report 
them to the IRB as within the timeframes posted on the HS IRB website. Reports to VAERS or FDA will be 
done at the same time. 
     Plans to monitor adherence to the IRB-approved protocol and assure the validity and integrity of data:  
The data collection forms and adverse event descriptions will be reviewed by the PI monthly.   
16.0 Economic Burden to Subjects 
Subjects will not have to pay for study procedures. The subject will not be billed by the healthcare system or 
their health insurance company for any costs related to a study procedure.  
 
16.1Facilities and Locations 
Study visits will take place at Employee Health Services.   
16.2 Feasibility of Recruiting the Required Number of Subjects 
 
 Employee Health Services has responsibility for the occupational health and safety of the over 15,000 
UWHealth employees.  The staff estimates that about 100 individuals will qualify for this study.   
16.3  Principal Investigator Considerations 
15.8.1 Time Devoted to Conducting the Research 
. 
The Principal Investigator is a professor in the School of Pharmacy.  She has dedicated time for 
research and is committed to completing this research study. 
16.4 Process for Informing Study Teams 
The study team has completed three research studies already.  They have a history of efficient conduct 
of research studies.  The Principal Investigator will provide the protocol and in-person training or 
training via video conference on the protocol and the consent process.  A review of all study procedures 
will be included in the training.   
16.5Availability of Medical or Psychological Resources 
Not applicable 
17.0 REFERENCES 
 
1. Jackson S, Lentino J, Kopp J, et al. Immunogenicity of a two-dose investigational hepatitis B 
vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed 
hepatitis B vaccine in adults. Vaccine. 2018;36(5):668-674. 
2. Hyer RN, Janssen RS. Immunogenicity and safety of a 2-dose hepatitis B vaccine, HBsAg/CpG 
1018, in persons with diabetes mellitus aged 60–70 years. Vaccine. 2019;37(39):5854-5861. 
3. Janssen RS, Mangoo-Karim R, Pergola PE, et al. Immunogenicity and safety of an investigational 
hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a 

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licensed hepatitis B vaccine in patients with chronic kidney disease. Vaccine. 2013;31(46):5306-
5313 
4. Schillie S, Vellozzi C, Reingold A, et al. Prevention of Hepatitis B Virus Infection in the United 
States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb 
Mortal Wkly Rep. 2018;67(RR No.-1):1-31. 
 
16.0 
18.0  APPENDICES 
18.1 Data collection form (appendix A) 
 
Data Collection Form 
Subject ID 
Date of birth 
UWH Dept 
UWH location 
Sex 
Race 
Ethnicity 
Diabetes yes/no 
Smoking yes/no/past 
Immunosuppression 
yes/no 
HepB dose 1 
HepB dose 2 
HepB dose 3 
antiHBs date 
antiHBs result 
HepB dose 4 
antiHBs date 
antiHBs result 
HepB dose 5  
HepB dose 6 
antiHBs date 
antiHBs result 
HepB-CpG dose 1 
antiHBs date 
antiHBs result 
HepB-CpG dose 2 
antiHBs date 
antiHBs result