B-Enhancement of HBV Vaccination in Persons Living With HIV (BEe-HIVe): Evaluation of HEPLISAV-B
Phase: PHASE3
Conditions: HIV Infection, Hepatitis B
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
A5379 
 
 
B-ENHANCEMENT OF HBV VACCINATION IN PERSONS LIVING WITH HIV (BEe-
HIVe): Evaluation of HEPLISAV-B 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
Dynavax Technologies Corporation 
 
 
IND # 019394 
 
 
 
The ACTG Hepatitis  
Transformative Science Group: 
Debika Bhattacharya, MD, Chair 
 
Protocol Co-Chairs: 
Kristen Marks, MD 
 
Kenneth E. Sherman, MD, PhD 
 
DAIDS Clinical Representative: 
Beverly Alston-Smith, MD 
 
Clinical Trials Specialist: 
Christina Vernon, MPH, PMP 
 
 
 
 
FINAL Version 3.0 
December 13, 2022 
 

 
 
A5379 
 
 
FINAL Version 3.0 
 
 
13Dec20222 
 
 
B-ENHANCEMENT OF HBV VACCINATION IN PERSONS LIVING WITH HIV (BEe-HIVe): 
Evaluation of HEPLISAV-B 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 

 
 
A5379 
 
 
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TABLE OF CONTENTS 
 
 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................. 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 12 
SCHEMA .................................................................................................................................. 13 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 15 
1.1 
Hypotheses ........................................................................................................ 15 
1.2 
Primary Objectives ............................................................................................. 15 
1.3 
Secondary Objectives ........................................................................................ 15 
1.4 
Exploratory Objectives ....................................................................................... 16 
1.5 
Exploratory Objectives for HIV Reservoir ........................................................... 17 
2.0 
INTRODUCTION ........................................................................................................... 17 
2.1 
Background ........................................................................................................ 17 
2.2 
Rationale ........................................................................................................... 20 
3.0 
STUDY DESIGN ........................................................................................................... 22 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 23 
4.1 
Inclusion Criteria, Groups A and B ..................................................................... 23 
4.2 
Inclusion Criteria, Group A only .......................................................................... 26 
4.3 
Inclusion Criterion, Group B only ........................................................................ 26 
4.4 
Exclusion Criteria, Groups A and B .................................................................... 26 
4.5 
Exclusion Criteria, Group A only ........................................................................ 28 
4.6 
Exclusion Criterion, Group B only ...................................................................... 28 
4.7 
Study Enrollment Procedures............................................................................. 28 
4.8 
Co-enrollment Guidelines ................................................................................... 29 
5.0 
STUDY TREATMENT ................................................................................................... 30 
5.1 
Study Product Formulations ............................................................................... 30 
5.2 
Regimens, Administration, and Duration ............................................................ 30 
5.3 
Study Product and Preparation for Administration .............................................. 31 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 32 
5.5 
Concomitant Medications ................................................................................... 33 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 35 
6.1 
Schedule of Evaluations..................................................................................... 35 
6.2 
Timing of Evaluations ......................................................................................... 40 
6.3 
Instructions for Evaluations ................................................................................ 42 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 48 
7.1 
Definition of Adverse Events .............................................................................. 49 
7.2 
Adverse Event Collection Requirements for This Protocol ................................. 49 

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CONTENTS (Cont’d) 
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Page 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 50 
7.4 
Study Monitoring ................................................................................................ 51 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 52 
8.1 
Toxicity .............................................................................................................. 52 
8.2 
Pregnancy.......................................................................................................... 52 
8.3  
Breastfeeding ..................................................................................................... 53 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 53 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 53 
9.2 
Premature Study Discontinuation ....................................................................... 53 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 54 
10.1 
General Design Issues ....................................................................................... 54 
10.2 
Outcome Measures ............................................................................................ 57 
10.3 
Randomization and Stratification ........................................................................ 60 
10.4 
Sample Size and Accrual ................................................................................... 60 
10.5 
Data and Safety Monitoring ................................................................................ 64 
10.6 
Analyses ............................................................................................................ 66 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 69 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 70 
12.1 
Records to Be Kept ............................................................................................ 70 
12.2 
Role of Data Management ................................................................................. 70 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 70 
12.4 
Reporting Protocol Deviations ........................................................................ 70 
13.0 
PARTICIPANTS ............................................................................................................ 71 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 71 
13.2 
Participant Confidentiality ................................................................................... 71 
13.3 
Study Discontinuation ........................................................................................ 71 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 71 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 71 
16.0 
REFERENCES .............................................................................................................. 73 
APPENDIX I: SAMPLE INFORMED CONSENT ....................................................................... 75 
ATTACHMENT A: STUDY VISITS AND PROCEDURES .......................................................... 88 
ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES ......................... 91 
APPENDIX II: SAMPLE INFORMED CONSENT FOR PARTICIPANTS WHO BECOME 
PREGNANT WHILE ON STUDY ................................................................................... 93 
 

 
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SITES PARTICIPATING IN THE STUDY 
 
A5379 is a multicenter study being conducted at US and non-US ACTG clinical research sites 
(CRSs). Non-US CRSs capable of receiving both ENGERIX-B and HEPLISAV-B can participate 
in Group A and Group B; however, the study is unable to import ENGERIX-B to CRSs in Kenya, 
Peru, Thailand, Uganda, and Zimbabwe. CRSs in these countries can participate in Group B 
and, if they are able to locally source ENGERIX-B and are team approved, can also participate 
in Group A.  
 

 
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PROTOCOL TEAM ROSTER 
 
Chair 
Kenneth E. Sherman, MD, PhD 
Cincinnati CRS 
Division of Digestive Diseases 
231 Albert Sabin Way 
Cincinnati, OH 45267 
Phone: 513-558-7200 
E-mail: kenneth.sherman@uc.edu 
 
Co-Chair 
Kristen Marks, MD 
Weill Cornell Chelsea CRS 
Division of Infectious Diseases 
525 East 68th Street, F2437 
New York, NY 10021 
Phone: 212-746-4177 
E-mail: markskr@med.cornell.edu 
 
DAIDS Clinical Representative  
Beverly L. Alston-Smith, MD  
DAIDS/NIAID/NIH/CCRB 
Complications and Co-Infections 
Research Branch 
5601 Fishers Lane 
Room 9F50 
Rockville, MD 20852 
Phone: 301-435-3773 
E-mail: balston@niaid.nih.gov 
 
Clinical Trials Specialist 
Christina Vernon, MPH, PMP 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3341 
E-mail: christina.vernon@dlhcorp.com
Statisticians 
Minhee Kang, PhD 
Statistical and Data Analysis Center 
Harvard T. H. Chan School of Public Health 
651 Huntington Avenue 
FXB Building, Room 503 
Boston, MA 02115 
Phone: 617-432-2819 
E-mail: mkang@sdac.harvard.edu 
 
Triin Umbleja, MSc 
Statistical and Data Analysis Center 
Harvard T. H. Chan School of Public Health 
651 Huntington Avenue 
FXB Building, Room 512A 
Boston, MA 02115 
Phone: 617-432-0118 
E-mail: tumbleja@sdac.harvard.edu 
 
Data Managers 
Stephanie Caruso, MBA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7322 
E-mail: scaruso@frontierscience.org 
 
Lillian Collins, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7308 
E-mail: collins@frontierscience.org 
 
DAIDS Pharmacists 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E18, MSC #9830 
Rockville, MD 20852 
Phone: 240-627-3593 
E-mail: oladapo.alli@nih.gov 

 
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DAIDS Pharmacists (Cont’d) 
Shawn Chiambah, PhD, RPh 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane 
Room 9A26, MSC #9829 
Rockville, MD 20852-9829 
Phone: 301-761-7336 
E-mail: shawn.chiambah@nih.gov 
 
Immunologist  
Andrea Cox, MD, PhD 
Johns Hopkins University CRS 
Division of Infectious Diseases 
551 Rangos Building 
855 N. Wolfe Street 
Baltimore, MD 21205 
Phone: 410-502-2715 
E-mail: acox@jhmi.edu 
 
Investigators 
Leolin Katsidzira 
Milton Park CRS 
Department of Medicine, College of Health 
Sciences 
University of Zimbabwe 
Parirenyatwa Hospital Complex 
Cnr Mazowe Street/Josiah Tongogara Street  
Harare 
Zimbabwe 
Phone: 263-772-377416 
E-mail: katsidzira.leo@gitclinic.co.zw 
 
Josphat Kosgei, MB, ChB, MSc  
Kenya Medical Research Institute/Walter 
Reed Project Clinical Research Center 
(KEMRI/WRP) CRS 
P.O. Box: 1357 
Hospital Road 
Kericho 20200 
Rift Valley 
Kenya 
Phone: 254-52-30686 
E-mail: josphat.kosgei@usamru-k.org 
 
Investigators (Cont’d) 
Hugo Perazzo, MD, PhD 
Instituto de Pesquisa Clinica Evandro 
Chagas CRS 
Av. Brasil, 4365 
LaPClin - INI/FIOCRUZ 
Rio de Janeiro 21040-360 
Brazil 
Phone: +55-21-38659129 
E-mail: perazzohugo@gmail.com 
 
Jennifer Price, MD, PhD 
University of California San Francisco 
HIV/AIDS CRS 
513 Parnassus Avenue, S-357 
San Francisco, CA 94143 
Phone: 415-502-1429 
E-mail: jennifer.price@ucsf.edu 
 
Patrice Severe, MD 
Les Centres Gheskio (Gheskio-INLR) CRS 
Cite de l’Exposition, Bicentenaire 
33 Boulevard Harry Truman 
Port au Prince HT-6110 
Haiti 
Phone: 509-29401431 
E-mail: patsevere@gheskio.org 
 
Field Representatives 
Kim Epperson, RN, BSN, CCRC 
Greensboro CRS 
301 East Wendover Avenue 
Suite 111 
Greensboro, NC 27401 
Phone: 336-832-3262 
Fax: 336-832-3230 
E-mail: kim.epperson@conehealth.com 
 
Laura Keck, RN 
Greensboro CRS 301 East Wendover Avenue 
Suite 111 
Greensboro, NC 27401 
Phone: 336-832-3263 
Fax: 336-832-3230 
E-mail: laura.keck@conehealth.com 
 

 
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Laboratory Technologist 
Michael Leonard, MLI, BS 
Vanderbilt Therapeutics (VT) CRS 
One Hundred Oaks 
719 Thompson Lane 
Suite 57180 
Nashville, TN 37204 
Phone: 615-875-1570 
E-mail: michael.leonard@vumc.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
Jan M. Kosmyna, MIS, RN, CCRP  
Case CRS 
10041 Brookside Circle 
North Royalton, OH 44133 
Phone: 419-344-4416 
E-mail: jankosmyna@gmail.com 
 
International Site Specialist 
Allegra Cermak, MFA 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3312 
E-mail: allegra.cermak@dlhcorp.com 
 
Industry Representative  
Kelvin McKoy, MD, MBA 
Dynavax 
2100 Powell Street, Suite 900 
Emeryville, CA 94608 
Phone: 202-271-0098 
E-mail: kmckoy@dynavax.com 
 
Laboratory Data Managers 
Kevin Knowles, MA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7238 
E-mail: knowles@fstrf.org 
 
 
Laboratory Data Managers (Cont’d) 
Philip Marzinek, BS 
Laboratory Data Manager 
Frontier Science Foundation 
Phone: 716-834-0900 Ext. 7399 
4033 Maple Road 
Amherst, NY 14226 
E-mail: marzinek@frontierscience.org 
 
Laboratory Specialists 
Ceora Beijer, BS 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
10990 Wilshire Boulevard, Suite #260 
Los Angeles, CA 90024 
Phone: 424-946-5709 
E-mail: cbeijer@milabcentral.org 
 
Sara Zabih, MS 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
10990 Wilshire Boulevard, Suite #260 
Los Angeles, CA 90024 
Phone: 424-946-5589 
Email: szabih@milabcentral.org 
 
 

 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5379@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5379@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5379 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Clinical Management Committee (CMC). 
• 
Send an e-mail message to actg.cmca5379@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic laboratory tests, contact the Protocol 
Immunologist.  
• 
Send an e-mail message to actg.teamA5379@fstrf.org (ATTENTION: Andrea Cox). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Stephanie 
Caruso and Lillian Collins directly.  
• 
For other questions, send an e-mail message to actg.teamA5379@fstrf.org (ATTENTION: 
Stephanie Caruso and Lillian Collins).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification number 
SID lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 

 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5379@fstrf.org (ATTENTION: Christina Vernon). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5379@fstrf.org (ATTENTION: Christina Vernon). 
 
For questions related to protocol activation at non-US sites, contact the ACTG Site Coordination 
Group.  
• 
Send an email message to actgsitecoordination@dlhcorp.com.  
 
Study Products 
For questions or problems regarding study products, dose, supplies, records, and returns, e-
mail Oladapo Alli (oladapo.alli@nih.gov) and Shawn Chiambah (shawn.chiambah@nih.gov), 
Protocol Pharmacists. 
 
Study Vaccine Orders 
• 
For study products that will be centrally distributed by the Clinical Research Products 
Management Center (CRPMC), the site Pharmacist of Record must complete and return the 
Drug Supply Statement provided by the CRPMC after site protocol registration and place an 
order via the CRPMC’s internet ordering system (CIOS). Any questions regarding study 
product orders and distribution should be directed to the CRPMC via e-mail 
(bio.crpmc.ph@thermofisher.com).  
• 
For orders for ENGERIX-B at sites in Kenya, Peru, Thailand, Uganda, and Zimbabwe, 
country specific instructions can be found on the protocol-specific web page (PSWP).  
 
IND (Investigational New Drug) Number or Questions  
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  

 
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Telephone Calls 
Sites are responsible for documenting telephone calls made to A5379 team members.  
• 
Send an e-mail message to actg.teamA5379@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
BMI 
body mass index 
CAP 
College of American Pathologists 
CA-RNA 
cell associated HIV-1 RNA 
CDC 
Centers for Disease Control and Prevention 
CKD 
chronic kidney disease 
CLIA 
Clinical Laboratory Improvement Amendments 
CpG 
cytosine phosphoguanosine  
DNA 
deoxyribonucleic acid  
DVT 
deep venous thrombosis 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GMT 
geometric mean titers 
HBcAb 
hepatitis B virus core antibody 
HBsAb 
hepatitis B virus surface antibody 
HBsAg 
hepatitis B virus surface antigen  
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
IM 
intramuscular  
INR 
international normalized ratio  
IQA 
immunology quality assessment 
LRA 
latency reversal agent 
MAAE 
medically attended adverse event 
mcg 
microgram  
MIP1β 
macrophage inflammatory protein1β 
MOPS  
Manual of Procedures 
PCR 
polymerase chain reaction 
PE 
pulmonary embolism 
PIR 
post-injection reaction 
PLWH 
people living with HIV 
RNA-Seq 
RNA sequencing 
SNP  
single-nucleotide polymorphisms 
SPR 
seroprotection response(s) 
TLR9 
Toll-like receptor 9 
VQA 
 
Virology Quality Assurance

 
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SCHEMA 
 
A5379 
B-ENHANCEMENT OF HBV VACCINATION IN PERSONS LIVING WITH HIV (BEe-HIVe): 
Evaluation of HEPLISAV-B  
 
DESIGN 
A5379 is a phase III/IV, prospective, open-label, interventional, two group 
study being conducted at both US and non-US sites, with one group 
(Group A) consisting of a randomized, controlled trial with three study 
arms and the other group (Group B) consisting of a single arm. The study 
will involve adults living with HIV with a history of nonresponse to hepatitis 
B (HBV) vaccination (Group A HBV vaccine-experienced) and adults 
living with HIV with no known prior history of HBV vaccination (Group B 
HBV vaccine-naïve). Participants in Group A will be randomized 1:1:1 to 
receive HEPLISAV-B (Arm 1 [two doses] and Arm 2 [three doses]) or 
ENGERIX-B (Arm 3 [three doses]). Participants in Group B will receive 
three doses of HEPLISAV-B.  
 
In Group A, Arms 2 and 3, the first post-entry visit (≥16 to ≤28 hours post 
first vaccination) is scheduled only for sample collection, and is limited to 
US sites only. While attendance at this first post-entry visit is strongly 
encouraged, Group A, Arms 2 and 3, participants may opt out of it at 
screening. 
 
 
DURATION 
Participants will be on study for 72 weeks.  
 
 
SAMPLE SIZE 
634 participants: 561 in Group A (187 each in Arms 1, 2, and 3) and 73 in 
Group B. 
 
 
POPULATION  
Adults ≥18 and ≤70 years living with HIV with either prior history of HBV 
vaccination who failed to achieve protective levels of antibodies against 
HBV surface antigen (HBsAb <10 mlU/mL, negative, or indeterminate) 
(Group A) or those who were never vaccinated for HBV (Group B). 
Participants must be on antiretroviral therapy (ART) for >56 days 
immediately prior to study entry with an HIV-1 RNA <1000 copies/mL and 
a CD4+ T-cell count ≥100 cells/mm3 within 180 days prior to study entry. 
 
Enrollment of women is encouraged, and the study will aim to enroll a 
minimum of 30% of women in Group A and, separately, in Group B. In 
Group A, 168 slots will be reserved for women, and in Group B, 22 slots 
will be reserved for women. Enrollment will be monitored closely, and if 
determined necessary by the study team and approved by the AIDS 
Clinical Trials Group (ACTG) Scientific Agenda Steering Committee 
(SASC), the cap on male participant enrollment may be lifted. 

 
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Enrollment at non-US sites is also encouraged, and the study will initially 
reserve 30% in each group for participants from non-US sites: 168 slots 
for Group A and 22 slots for Group B. After 9 months from enrollment of 
the first participant, there will be flexibility for lifting these restrictions if 
required to ensure that enrollment completion is not delayed. 
 
 
STRATIFICATION 
Randomization in Group A will be stratified by sex assigned at birth (male 
versus female) and diabetes status (yes versus no). Diabetes is defined 
as an existing diagnosis of diabetes at screening, screening hemoglobin 
A1c ≥6.5%, or being treated with insulin or a hypoglycemic agent for a 
diagnosis of diabetes. 
 
 
REGIMEN  
Participants in Group A will be randomized to receive HEPLISAV-B two 
doses (Arm 1), HEPLISAV-B three doses (Arm 2), or ENGERIX-B three 
doses (Arm 3). Participants in Group B will receive HEPLISAV-B three 
doses. HEPLISAV-B will be administered intramuscularly as 0.5 mL dose 
(contains 20 micrograms [mcg] of HBsAg and 3000 mcg of cytosine 
phosphoguanosine [CpG] 1018) at weeks 0, 4, and 24 (except for 
participants in Group A, Arm 1 [weeks 0 and 4]). ENGERIX-B will be 
administered intramuscularly as 1 mL dose (contains 20 mcg HBsAg) at 
weeks 0, 4, and 24.  

 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 In participants living with HIV, HEPLISAV-B vaccination given as a two-dose 
series achieves noninferior seroprotection response (SPR) rate compared to 
standard dose ENGERIX-B. 
 
1.1.2 In participants living with HIV, HEPLISAV-B vaccination given as a three-dose 
series achieves superior SPR rate compared to standard dose ENGERIX-B. 
 
1.2 
Primary Objectives 
 
1.2.1 To compare the week 12 SPR of a two-dose regimen of HEPLISAV-B (Group A, 
Arm 1) versus the week 28 SPR of a standard three-dose regimen of ENGERIX-
B (Group A, Arm 3) in hepatitis B virus (HBV) vaccine-experienced participants 
living with HIV (Group A). 
 
1.2.2 To compare the week 28 SPR of a three-dose regimen of HEPLISAV-B (Group 
A, Arm 2) versus a standard three-dose regimen of ENGERIX-B (Group A, Arm 
3) in HBV vaccine-experienced participants living with HIV (Group A). 
 
1.2.3 To determine the week 28 SPR of a three-dose regimen of HEPLISAV-B in HBV 
vaccine-naïve participants living with HIV (Group B). 
 
1.2.4 To describe adverse events (AEs) reported in each study arm (Groups A and B, 
separately) over the duration of the study.  
 
1.3 
Secondary Objectives 
 
1.3.1 To compare the week 12 geometric mean titers (GMT) of a two-dose regimen of 
HEPLISAV-B (Group A, Arm 1) versus the week 28 GMT of a standard three-
dose regimen of ENGERIX-B (Group A, Arm 3) in HBV vaccine-experienced 
participants living with HIV (Group A). 
 
1.3.2 To compare the week 28 GMT of a three-dose regimen of HEPLISAV-B (Group 
A, Arm 2) versus a standard three-dose regimen of ENGERIX-B (Group A, Arm 
3) in HBV vaccine-experienced participants living with HIV (Group A). 
 
1.3.3 To compare the SPR and GMT 4, 8, 24, and 48 weeks after last vaccination of a 
two-dose regimen of HEPLISAV-B (Group A, Arm 1) versus a standard three- 
dose regimen of ENGERIX-B (Group A, Arm 3) in HBV vaccine-experienced 
participants living with HIV (Group A). 
 
1.3.4 To compare the SPR and GMT 8, 24, and 48 weeks after last vaccination of a 
three-dose regimen of HEPLISAV-B (Group A, Arm 2) versus a standard three- 

 
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dose regimen of ENGERIX-B (Group A, Arm 3) in HBV vaccine-experienced 
participants living with HIV (Group A). 
 
1.3.5 To compare the SPR and GMT 4, 8, 24 and 48 weeks after last vaccination of a 
two-dose regimen of HEPLISAV-B (Group A, Arm 1) versus a three-dose 
regimen of HEPLISAV-B (Group A, Arm 2) in HBV vaccine-experienced 
participants living with HIV (Group A). 
 
1.3.6 To assess SPR and GMT at weeks 4, 8, 12, and 24 between HEPLISAV-B 
(Group A, Arms 1 and 2 combined) and ENGERIX-B (Group A, Arm 3) in HBV 
vaccine-experienced participants living with HIV (Group A). 
 
1.3.7 To determine the week 28 GMT of a three-dose regimen of HEPLISAV-B in HBV 
vaccine-naïve participants living with HIV (Group B). 
 
1.3.8 To determine the weeks 32, 48, and 72 SPR and GMT of a three-dose regimen 
of HEPLISAV-B in HBV vaccine-naïve participants living with HIV (Group B). 
 
1.3.9 To determine the weeks 4, 8, 12, and 24 SPR and GMT with HEPLISAV-B in 
HBV vaccine-naïve participants living with HIV (Group B). 
 
1.3.10 To describe incidence of Grade ≥2 AEs within 4 weeks of each injection in each 
study arm (Groups A and B, separately). 
 
1.3.11 To assess host characteristics associated with vaccine response including 
factors such as age, sex, diabetes, body mass index (BMI), baseline CD4+ T-cell 
count, and smoking status (Groups A and B, separately). 
 
1.3.12 To compare SPR and GMT at week 72 between HEPLISAV-B two-dose (Group 
A, Arm 1) and three-dose arms (Group A, Arm 2). 
 
1.4 
Exploratory Objectives 
 
1.4.1 To compare SPR and GMT at weeks 4, 8, 12, 24, 28, 32, 48, and 72 with 
HEPLISAV-B in HBV vaccine-experienced participants (Group A, Arm 2) to HBV 
vaccine-naïve participants living with HIV (Group B). 
 
1.4.2 To compare HBV surface antigen-specific B and T-cell responses, including cell 
function and phenotype, at baseline and at weeks 12 and 28 with three doses of 
HEPLISAV-B (Group A, Arm 2) to a standard three-dose regimen of ENGERIX-B 
(Group A, Arm 3) in HBV vaccine-experienced participants living with HIV (Group 
A). 
 
1.4.3 To compare innate immune soluble factors at baseline and approximately 24 
hours after the first dose of HEPLISAV-B (Group A, Arm 2) and the first dose of 
ENGERIX-B (Group A, Arm 3) in HBV vaccine-experienced participants living 
with HIV (Group A). 

 
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1.4.4 To identify specific genes/gene sets via RNA sequencing (RNA-Seq) at 
approximately 24 hours after vaccination that differ from baseline and adaptive 
cell phenotypes at weeks 12 and 24 that are associated with SPR and GMT with 
HEPLISAV-B (Group A, Arm 2) compared to ENGERIX-B (Group A, Arm 3) in 
HBV vaccine-experienced participants living with HIV (Group A). 
 
1.4.5  To analyze single-nucleotide polymorphisms (SNPs) in TLR-9 and assess their 
associations with baseline and vaccine-induced responses (Group A, Arms 2 and 3). 
 
1.5 
Exploratory Objectives for HIV Reservoir 
 
1.5.1 To evaluate the level of HIV-1 gene expression at baseline and week 28 after 
injection with HEPLISAV-B (Group A, Arm 2) and ENGERIX-B (Group A, Arm 3) 
of cell-associated HIV-1 RNA (CA-RNA) in CD4+ T-cells from HBV vaccine-
experienced and vaccine-naïve participants living with HIV who have 
undetectable HIV RNA levels. 
 
1.5.2 To evaluate the impact of HEPLISAV-B (Group A, Arm 2) and ENGERIX-B 
(Group A, Arm 3) vaccination on intact provirus as measured by a digital droplet 
polymerase chain reaction (PCR) assay at baseline and week 28. 
 
1.5.3 To assess the impact of HEPLISAV-B (Group A, Arms 1 and 2) and ENGERIX-B 
(Group A, Arm 3) vaccination on markers of HIV-1 persistence, as measured by 
total deoxyribonucleic acid (DNA) levels at baseline and week 28. 
 
1.5.4 To measure levels of HIV-specific immunity and activation at baseline and week 28 
after HEPLISAV-B (Group A, Arm 2) and ENGERIX-B (Group A, Arm 3) 
vaccination, including: 
• 
HIV-1-specific immune responses 
• 
T-cell activation 
• 
Expression of exhaustion markers on T-cells 
 
1.5.5 To assess innate cellular markers and soluble factors in relationship to 
HEPLISAV- B (Group A, Arm 2) and ENGERIX-B (Group A, Arm 3) vaccination 
or virologic outcome measures. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
While vaccination is the cornerstone of prevention strategies for HBV, the response to 
current standard vaccination is suboptimal in those living with HIV. A host of studies 
document overall response rates, defined as achievement of ≥10 mIU/mL of hepatitis B 
surface antibody (HBsAb) to range from 30-70% following a standard three-dose series 
[1, 2]. Several studies have tried to improve these response rates with addition of 
adjuvants and increases in dose or dose frequency. Most strategies have proved to be 
ineffective or marginally effective. Some providers utilize an off-label strategy of double-

 
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dose vaccine (40 micrograms [mcg] recombinant HBV surface antigen [HBsAg]) given in 
four intramuscular (IM) doses. In a key study, this approach increased primary response 
rates to over 80% vs. 65% for controls receiving a standard three-dose vaccination 
series [3]. Geometric mean titers were higher using this regimen as well and this 
response persisted for up to 42 months of follow-up [4]. However, this approach still 
does not achieve the 95% response rates seen in individuals without HIV. Moreover, it is 
costly due to the double-dose requirement and often requires individuals to receive two 
injections at each visit using standard 20 mcg vaccine preparations.  
 
Efforts at repeat vaccination in those who failed a primary vaccination series are also 
variable. Irungu et al. reported achieving an overall 83% response with two courses of 
vaccination using 20 mcg dosing x three injections for each series [5]. Others reported 
lower rates of response following revaccination, even when 40 mcg doses were given for 
the repeat [6]. The French National Agency for Research on AIDS and Viral Hepatitis 
(ANRS) conducted a randomized controlled trial of comparing 20 mcg and 40 mcg in 
rigorously defined non-responders but did not find 40 mcg to achieve superior SPRs. 
Age, CD4+ count, sex, race, tobacco use/smoking status, BMI, and presence of liver 
disease are all associated with lack of vaccine efficacy [2, 6, 7]. 
 
Recently, a new vaccine for HBV prevention was approved by the United States (US) 
Food and Drug Administration (FDA). The HEPLISAV-B® vaccine (Dynavax 
Technologies Corporation) is a 0.5 mL aqueous mixture of the HBsAg (20 mcg) 
combined with 3 mg of CpG1018, an adjuvant Toll-like receptor 9 (TLR9) agonist. It is 
given as an IM injection at 0 and 1 months. In pivotal trials this regimen was superior to 
a three-dose vaccine series of ENGERIX-B, which has been licensed and used for many 
years in the US and worldwide. Table 2.1-1 below shows a comparison of SPR rates, 
including in diabetic participants who also have poor HBV vaccine responses. The 
responses were statistically higher than in control participants in difficult to vaccinate 
populations. Overall, the vaccine’s safety profile matched that of the ENGERIX-B 
product. A subsequent study involving participants with chronic kidney disease (CKD), 
another group with low vaccine response rates, compared a 0, 1, and 6 month schedule 
of HEPLISAV-B to a double-dose ENGERIX-B series of four doses (0, 1, 2, and 6 
months) in participants never exposed to HBV or HBV vaccination. For the primary 
endpoint, 89.5% achieved seroprotection at week 28 with HEPLISAV-B three doses 
compared to 81.3% with ENGERIX-B four double doses. In addition, superior peak 
immune responses, earlier seroprotection, and more persistent seroprotection were 
observed in the HEPLISAV-B arm. Of relevance to the A5379 study design, a third dose 
of HEPLISAV-B appeared to be important in this “difficult to vaccinate” population since 
SPR in the HEPLISAV-B group at week 12 (after two doses) was 64.3% compared to 
89.5% achieved after three doses [8]. Another randomized study compared a booster 
dose of HEPLISAV-B to ENGERIX-B and Fendrix (HBV vaccine indicated for individuals 
with renal insufficiency) in adults on hemodialysis with prior HBV vaccine but without 
current seroprotection (categorized as either prior non-responders or prior responders). 
At week 4, after dosing in prior non-responders, the SPR in the HEPLISAV-B group (16 
of 38 participants; 42.1%) was higher than the SPR in the ENGERIX-B group (7 of 37 
participants; 18.9%) and the Fendrix group (12 of 41 participants; 29.3%). At week 4, 
after dosing in prior responders, the SPR in the HEPLISAV-B group was 80.0% (12 of 15 

 
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participants), in the ENGERIX-B group was 90.9% (10 of 11 participants), and in the 
Fendrix group was 100% (10 of 10 participants) [Dynavax, Data on File]. 
 
Table 2.1-1: Comparison of SPR Rates 
 
 
In addition, a small prior pilot study conducted in people living with HIV (PLWH) (one-half 
of whom had experienced previous vaccination failure), utilizing a combination of 
ENGERIX-B with or without a different TLR-9 agonist, supports that TLR-9 agonist may 
also augment response in PLWH. In this study, which utilized a three-dose vaccine 
schedule of 0, 1, and 2 months, seroprotective titres were found in 19/19 (100%) of 
participants receiving CPG 7909 compared to 12/19 (63%) receiving ENGERIX-B (P = 
0.008) [9]. In follow up extending to 60 months, the participants who received the TLR-9 
agonist had statistically significantly higher seroprotection rates and GMTs as well [10]. 
The proposed study will compare the efficacy and safety of HEPLISAV-B and ENGERIX-
B in a population of HBV vaccine non-responders living with HIV. 
 
HEPLISAV-B is only approved for use in adults 18 years of age and older [HEPLISAV-
B® Package Insert, 2018]. Therefore, this study will not allow enrollment of participants 
under the age of 18 years. Participants, regardless of age, will receive ENGERIX-B 1 mL 
dose if they are randomized to the ENGERIX-B Arm 3 as done in prior HEPLISAV-B 
studies. 
 
Before it was approved by the FDA, HEPLISAV-B was tested in more than 9500 people. 
Overall, the side effects were similar to the side effects seen with other vaccines. In a 
single study (HBV-23), people who got HEPLISAV-B had myocardial infarctions more 
often than people who got ENGERIX-B (0.17% [n = 16] vs. 0.05% [n = 2]). In a further 
study, no causal relationship between HEPLISAV-B and myocardial infarction was found 
[11]. After FDA approval, Dynavax, the manufacturer of HEPLISAV-B, began conducting 
a large observational study of 30,000 people who received HEPLISAV-B and 30,000 
people who received ENGERIX-B to evaluate myocardial infarctions and the theoretical 
concern that vaccines can cause autoimmune disease. The study showed no 
relationship between HEPLISAV-B and myocardial infarctions. Of 31,183 recipients of 
HepB-CpG vaccine and 38,442 recipients of HepB-alum vaccine, rates of acute MI 
per 1000 person-years were 1.67 and 1.86, respectively [12]. One of the primary 
objectives of A5379 is to assess safety of the vaccine in PLWH.  

 
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There are no clinical studies of HEPLISAV-B in participants who are pregnant. 
Developmental toxicity studies done on female rats did not reveal any harm to the fetus 
due to this vaccine formulation. No AEs were observed on both pre and post-natal 
development up to the time of weaning. Current available human data on HEPLISAV-B 
administration in people who are pregnant are inadequate to inform vaccine-associated 
risks in pregnancy [HEPLISAV-B® Package Insert, 2018]. On account of lack of data on 
safety in pregnancy and the significantly low likelihood of obtaining evaluable data on 
pregnancy, this study will not enroll people who are pregnant. International Ethical 
Guidelines for Health-related Research Involving Humans (2016) require 
underrepresented groups, such as people who are pregnant, be provided access to 
research. Participants living with HIV are considered at risk for HBV, and pregnancy 
could further increase that risk on account of its impact on the immune system. Non-
responders to available HBV vaccines and who are living with HIV, currently have no 
good options for HBV vaccination. To ensure participants have the opportunity to 
achieve the best possible clinical outcomes, participants who become pregnant while 
on the study vaccine series will have the option to complete their scheduled vaccination 
series and continue on study. Both ENGERIX-B and HEPLISAV-B are FDA-approved 
marketed products. ENGERIX-B has been widely used in pregnancy, and registry 
information does not suggest any additional pregnancy-related risks [ENGERIX-B® 
Package Insert, 2018]. Participants who decide to continue on the study will be 
counseled on the potential unknown pregnancy-related risks of HEPLISAV-B due to the 
lack of adequate safety and efficacy data in humans. Such participants would need to 
complete a pregnancy-specific informed consent process. Participants who decide to 
stay on their vaccination series and participants who stop the series will continue 
evaluations on study per the schedule of evaluations (SOE). 
 
There are no data to inform on the excretion of HEPLISAV-B in human breast milk. It is 
not known what impact HEPLISAV-B could have on the breastfed infant or on milk 
production and excretion by the mother [HEPLISAV-B® Package Insert, 2018]. 
Therefore, people breastfeeding will not be enrolled. 
 
2.2 
Rationale 
 
Hepatitis B vaccination response to standard regimens is suboptimal in persons living 
with HIV. A variety of modalities to improve response (primary or secondary series) have 
been utilized but none have gained universal acceptance. Though many factors 
influence primary and secondary responses to vaccination (age, sex, CD4+ count, race, 
tobacco use, prior exposures, body weight, comorbidities such as diabetes and liver 
disease), the “real-world” presentation of PLWH without protective HBsAb titers (≥10 
mIU/mL) represents a decision point for clinicians. Key care outcomes include 
achievement of protective antibody levels with the minimum number of doses, the least 
number of total injections, and the best durability of response. To address these issues, 
the proposed trial will evaluate a two- and three-dose regimen of HEPLISAV-B, each 
compared to a standard three-dose regimen of ENGERIX-B in HBV vaccine-experienced 
participants with HBsAb <10 mIU/mL. The specific rationale for having a three-arm study 
is summarized below: 

 
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• 
The rate of response to either two or three doses of HEPLISAV-B in this population 
is difficult to estimate with precision. 
• 
Though arguments can be made for and against a strong response in the two-dose 
arm (e.g., most participants will have higher CD4+ levels), it is possible that the 
three-dose arm may be required to achieve acceptable rates of SPR. 
• 
If the two-dose arm is found to be non-inferior this would likely become a preferred 
regimen for PLWH. 
• 
Failure to achieve SPR in the two-dose arm does not predict response in the three-
dose arm, which was more effective in a dialysis population. 
 
We will stratify by sex assigned at birth (male versus female) and presence or absence of 
diabetes, and we will compare efficacy of two and three doses of HEPLISAV-B, each 
compared to ENGERIX-B in HBV vaccine-experienced participants (Group A). There is 
considerable variability in reports of SPR among those living with HIV. We have selected a 
70% response rate in the ENGERIX-B control. The response estimates come from prior 
studies documented above and accounts for the possibility that some persons may not 
have received full series or may be prior responders with waned immunity. (Thus higher 
response rates are expected in nonresponders than vaccine naïve participants in this 
study) [13]. The three-dose HEPLISAV-B arm will be compared to the ENGERIX-B control 
and assessed for superiority, at week 28, with an estimate of an 85% response rate 
selected for HEPLISAV-B based on the differential in SPR rates in the HEPLISAV-B 
studies described above. The two-dose HEPLISAV-B arm will be assessed for non-
inferiority to ENGERIX-B control using the same primary endpoints (week 12 SPR for 
HEPLISAV-B, week 28 SPR for ENGERIX-B) and noninferiority margin of 10% as used in 
Dynavax registrational trials of HEPLISAV-B (HBV-10, HBV-16). A non-inferiority 
comparison was chosen as most appropriate because of the advantages a two-dose 
schedule offers in terms of cost, convenience, and completion rates. For this study the 
HEPLISAV-B two-dose week 12 response was conservatively estimated at 75%. Week 12 
is used (rather than week 8) because prior studies demonstrated that HEPLISAV-B two-
dose SPR rises over time due to the TLR9 agonist effect (e.g., SPR 8 weeks after 
vaccination is greater than 4 weeks after vaccination). For three-dose arms, a consistent 
time point of week 28 was recommended by the US FDA for both HEPLISAV-B and 
ENGERIX-B; however, it is still anticipated that the SPR will increase over time in 
participants that receive HEPLISAV-B, so later endpoints will be examined in secondary 
analyses. Secondary analyses will focus on the SPR rates over time, HBV surface antibody 
(HBsAb) titers achieved, and other predictors of response in these participants including 
known variables that have been shown to affect vaccine response in other studies. 
 
The rationale for testing a small group of HBV vaccine-naïve participants is also derived 
from US FDA guidance regarding the need for development of a point estimate for SPR 
in this group. In HBV vaccine-naïve participants living with HIV, we will evaluate the 
vaccine efficacy compared to historical response rates. These rates range from 35-70% 
in the literature, and we aim to show that response to HEPLISAV-B among HBV 
vaccine-naïve participants living with HIV will be greater than 55%. A prior ACTG study, 
A5220, provides rationale for choosing 55% as the response rate. A5220 was a two-arm, 
randomized ACTG study completed in 2008 to evaluate the efficacy and safety of 

 
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vaccinating participants living with HIV using HBV vaccine (40 mcg, Recombivax) at 
weeks 0, 4, and 12 with or without GM-CSF as an adjuvant. The study population 
consisted of participants naïve to HBV vaccination, ≥18 years of age, CD4+ cell count 
≥200 cells/mm3, and seronegative for HBV and HCV. The study enrolled 48 participants 
and concluded that GM-CSF did not have an effect: 65% without GM-CSF and 52% 
(with GM-CSF), 59% overall (95% CI, 43%, 73%).  
 
Exploratory Immunology Aims 
The BEe-HIVe trial hypothesis (refer to section 1.1.2) is that HEPLISAV-B vaccination 
(HBsAg with cytosine phosphoguanosine [CpG] 1018) in participants living with HIV 
achieves superior SPR rates compared to standard dose ENGERIX-B (HBsAg with 
alum). If correct, HEPLISAV-B vaccination will induce more robust immune responses 
than ENGERIX-B. Given that SPR is a measure of induction of antibodies against 
HBsAg, and that CD4+ T-cells are required to produce high affinity, robust antibody 
responses, CpG 1018 is therefore predicted to enhance HBV-specific CD4+ T function 
[14]. Antibodies are produced by B cells and plasma cells, which differentiate from B 
cells [14]. Thus, characterization of B cells specific for HBsAg is critical to understanding 
the generation of effective antibodies. Responses induced through HEPLISAV-B 
vaccination that differ from those induced by ENGERIX-B vaccination have high 
potential to identify 1) pathways critical to induction of robust antibody responses to 
inform rational vaccine design and 2) pathways impaired in HIV infection, activation of 
which requires more robust stimulation (CpG versus alum) to overcome HIV-specific 
impairment. 
 
HIV cure/eradication strategies have included a variety of latency reversal strategies, 
including TLR9 agonist treatment. The adjuvant in HEPLISAV-B, CpG 1018 is a TLR9 
agonist and its mechanism of action has been shown to require TLR9 activation [15]. 
Previous studies, including a study of a different CpG TLR9 agonist administered as part 
of a pneumococcal vaccine regimen, have shown that TLR9 activation in HIV infection 
increases HIV-1 transcription and reduces proviral DNA, key outcomes in HIV-1 
eradication therapy. These changes in the HIV reservoir occurred in association with 
enhanced cellular immunity [16, 17]. Thus, a thorough assessment of the HIV reservoir 
and immune responses before and after vaccination with HEPLISAV-B could determine 
whether CpG 1018 might serve as a latency reversal agent (LRA), and, if so, its 
mechanism of action as an LRA. This has the potential to highlight pathways of immune 
activation critical to latency reversal. 
 
3.0 
STUDY DESIGN 
 
A5379 is a phase III/IV, prospective, open-label, interventional, two-group study, 
enrolling concurrently, with one group (Group A) consisting of a randomized, controlled 
trial with three study arms and the other group (Group B) consisting of a single study 
arm. The study will be conducted at both US and non-US sites. The study will involve 
adults living with HIV with prior history of HBV vaccination who do not have antibodies 
against HBsAg at protective levels (HBsAb <10 mlU/mL, negative, or indeterminate) 
(Group A non-responders) and adults living with HIV with no known prior history of HBV 
vaccination (Group B HBV vaccine-naïve). Participants in Group A will be randomized 

 
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1:1:1 to receive HEPLISAV-B (Arms 1 and 2) or ENGERIX-B (Arm 3). Arm 3 (ENGERIX-
B) will serve as the control arm for both Arms 1 and 2. Participants in Group B will 
receive HEPLISAV-B. The target sample size is 634 participants: 561 in Group A (187 
each in Arms 1, 2, and 3) and 73 in Group B. The participant enrollment target for 
women is at least 30% in each study group. Enrollment at non-US sites is encouraged 
(refer to Schema for further details about the non-US and women participant enrollment 
plan). Participants will be on study for 72 weeks. Randomization in Group A will be 
stratified by sex assigned at birth and diabetes (refer to Schema for the definition). 
 
HEPLISAV-B will be administered intramuscularly as 0.5 mL dose (contains 20 mcg of 
HBsAg and 3000 mcg of CpG 1018) at: 
• 
Weeks 0 and 4 for all participants in Group A, Arm 1; 
• 
Weeks 0, 4, and 24 for all participants in Group A, Arm 2; and 
• 
Weeks 0, 4, and 24 for all participants in Group B. 
  
ENGERIX-B will be administered intramuscularly as 1 mL dose (contains 20 mcg 
HBsAg) at weeks 0, 4, and 24 for all participants in Group A, Arm 3.  
 
Group A  
Group A (non-responders) will include participants living with HIV with a history of HBV 
vaccination who do not have HBsAb at protective levels (HBsAb <10 mIU/mL, negative, 
or indeterminate). Participants in Group A will be randomized 1:1:1 to receive 
HEPLISAV-B two doses (Arm 1), HEPLISAV-B three doses (Arm 2), or ENGERIX-B 
three doses (Arm 3). The primary outcome for Group A will be percent of participants 
with ≥10 mIU/mL HBsAb measured at week 12 for Arm 1 and week 28 for Arms 2 and 3. 
Refer to the SOE for seroprotection rate assessment time points. 
 
Group B  
Group B (HBV vaccine-naïve) will include participants living with HIV who have no prior 
known history of receiving HBV vaccination. The primary outcome for Group B will be 
SPR 4 weeks after the vaccination series (week 28), and we will examine if SPR 
proportion is greater than 55%. Refer to the SOE for seroprotection rate assessment 
time points. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria, Groups A and B  
 
NOTE: See sections 4.2 and 4.3 for inclusion criteria specific to Group A and Group B, 
respectively. 
 
4.1.1 HIV-1 infection, documented by:  
 
• 
Any licensed rapid HIV test or HIV enzyme or chemiluminescence 
immunoassay (E/CIA) test kit at any time prior to study entry  
AND 

 
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• 
Confirmed by one of the following:  
o A licensed Western blot 
o A second antibody test by a method other than the initial rapid HIV and/or 
E/CIA 
o HIV-1 antigen, or 
o Plasma HIV-1 RNA viral load 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies, or for sites located in countries other than the US, a kit that has 
been certified or licensed by an oversight body within that country and validated 
internally. Non-US sites are encouraged to use US FDA-approved methods for 
IND studies. 
 
The Council for International Organizations of Medical Sciences/World 
Health Organization [18] and Centers for Disease Control and Prevention (CDC) 
guidelines mandate that confirmation of the initial test result must use a test that 
is different from the one used for the initial assessment. A reactive initial rapid 
test should be confirmed by either another type of rapid assay or an E/CIA that is 
based on a different antigen preparation and/or different test principle (e.g., 
indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.2 On HIV-1 antiretroviral therapy (ART) for >56 days immediately prior to study 
entry. 
 
NOTE: Changes to ART due to ART toxicity in the 28 days prior to study 
entry are not allowed. For questions related to ART toxicity, sites should 
contact the team per the Study Management section. 
 
4.1.3 CD4+ T-cell count ≥100 cells/mm3 obtained within 180 days prior to study entry 
at any US laboratory that has a Clinical Laboratory Improvement Amendments 
(CLIA) certification or its equivalent, or at any network-approved non-US 
laboratory that is DAIDS Immunology Quality Assessment (IQA) certified. 
 
NOTE: If multiple results are available within 180 days prior to study entry, use 
most recent result. 
 
4.1.4 HIV-1 RNA <1000 copies/mL obtained within 180 days prior to study entry by any 
US laboratory that has a CLIA certification or its equivalent, or at any network-
approved non-US laboratory that is Virology Quality Assurance (VQA) certified. 
 
NOTE: If multiple results are available within 180 days prior to study entry, use 
most recent result. 
 
4.1.5 The following laboratory values obtained within 45 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. 

 
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• 
Hemoglobin ≥9 g/dL for men and ≥8 g/dL for women.  
o NOTE: Men and women are defined by sex assigned at birth for this 
study. 
• 
International normalized ratio (INR) ≤1.5 x ULN, except for individuals with 
known hemophilia or a stable anticoagulant regimen affecting INR. 
• 
Albumin ≥3 g/dL  
• 
Aspartate aminotransferase (AST) (SGOT) ≤2.5  ULN  
• 
Alanine aminotransferase (ALT) (SGPT) ≤2.5  ULN 
• 
Hemoglobin A1c <9.0% 
 
4.1.6 For individuals of reproductive potential who can become pregnant, a negative 
serum or urine pregnancy test (urine test must have a sensitivity of <25 mIU/mL) 
within 2 days prior to study entry by any US clinic or laboratory that has a CLIA 
certification or its equivalent, or is using a point of care (POC)/CLIA-waived test, 
or at any network-approved non-US laboratory or clinic that operates in 
accordance with GCLP and participates in appropriate external quality assurance 
programs. 
 
NOTE A: Individuals of reproductive potential are defined as those who have 
reached menarche and who have not been post-menopausal for at 
least 24 consecutive months (i.e., have had menses within the 
preceding 24 months), and have not undergone surgical sterilization 
such as hysterectomy, bilateral oophorectomy, tubal ligation, or 
salpingectomy. 
 
NOTE B: Individual report is considered acceptable documentation of 
reproductive status. 
 
4.1.7 If participating in sexual activity that could lead to pregnancy, individuals of 
reproductive potential who can become pregnant must agree to use 
contraception throughout the study. At least one of the following must be used 
throughout the study: 
• 
Condom (male or female) with or without spermicide 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
 
4.1.8 Adequate venous access for the purpose of phlebotomy. 
 
4.1.9 Age ≥18 and ≤70 years. 
 
4.1.10 Ability and willingness of individual or, if the individual lacks decision-making 
capacity, their legal guardian/representative to provide informed consent. 
 
4.1.11 Willingness to be contacted by telephone, text message, or e-mail by study staff 
throughout the study. 

 
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4.2 
Inclusion Criteria, Group A only 
 
4.2.1 Serum Hepatitis B antibody <10 mlU/mL, non-reactive (negative), or 
indeterminate as determined by a CLIA- or College of American Pathologists 
(CAP)-certified or equivalent laboratory within 45 days prior to study entry. 
 
NOTE A:  If a mlU/mL value is given, the decision should be made on the value. 
For example, if a value of ≥10 mlU/mL is given and also reported as 
indeterminate, the individual would be considered ineligible based on 
the numeric report.  
 
NOTE B: Refer to table on the protocol-specific web page (PSWP) for further 
details.  
 
4.2.2 Documentation of HBV vaccination >168 days prior to study entry. 
 
NOTE A: Completion of the vaccination series is not required. 
 
NOTE B: Multiple past vaccination series are permitted. 
 
NOTE C: Documentation of combination HBV vaccinations (e.g., Twinrix) are 
acceptable.  
 
4.3 
Inclusion Criterion, Group B only 
 
4.3.1 Serum Hepatitis B antibody non-reactive (negative) as determined by a CLIA- or 
CAP-certified or equivalent laboratory within 45 days prior to study entry. 
 
4.4 
Exclusion Criteria, Groups A and B  
 
NOTE: See sections 4.5 and 4.6 for exclusion criteria specific to Group A and Group B, 
respectively. 
 
4.4.1 Infection or prior exposure to HBV defined as HBsAg positive or HBV core 
antibody (HBcAb) positive any time prior to or at screening. 
 
NOTE A: Individuals with any documented history of HBcAb positive or HBsAg 
positive should not undergo testing at screening because even if 
results at screening are negative, they are ineligible. 
 
NOTE B: Individuals without documented history or with history of HBcAb 
negative or HBsAg negative results will have HBcAb and HBsAg 
testing performed at screening to determine eligibility. 
 
4.4.2 Serum HBsAb level ≥10 mlU/mL or positive at screening or any other time prior 
to screening. 

 
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4.4.3 Presence of any active or acute AIDS-defining opportunistic infections within 45 
days prior to study entry.  
 
  
NOTE: A list of AIDS-defining opportunistic infections is located on the PSWP. 
 
4.4.4 History of solid organ transplantation. 
 
4.4.5 Current or prior history of clinical hepatic decompensation (e.g., ascites, 
encephalopathy, or variceal hemorrhage). 
 
4.4.6 Diagnosis of chronic kidney disease (CKD) stage G4 (estimated glomerular 
filtration rate [eGFR] of 15-29 mL/min) or CKD stage G5 also referred to as End-
Stage Renal Disease (eGFR of <15 mL/min). 
 
NOTE: The Cockcroft-Gault formula located on the A5379 PSWP can be used to 
calculate creatinine clearance as an estimate of eGFR. 
 
4.4.7 Cancer diagnosis within 5 years prior to study entry, other than squamous or 
basal cell carcinoma of the skin and/or resolved or inactive cutaneous Kaposi 
sarcoma. 
 
4.4.8 Currently receiving chemotherapy. 
 
4.4.9 Chronic use and/or receipt of the following within 45 days prior to study entry: 
systemically administered immunosuppressive agents (e.g., prednisone 
equivalent >10 mg/day, systemic corticosteroids [more than 3 consecutive days]) 
or other immunomodulators, with the exception of inhaled steroids. 
 
4.4.10 Currently breastfeeding.  
 
4.4.11 Individuals who plan to become pregnant during the study. 
 
4.4.12 Plan to discontinue ART during the study. 
 
4.4.13 Known allergy/sensitivity or any hypersensitivity to any HBV vaccine or yeast.  
 
4.4.14 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.4.15 Active, serious infection (other than HIV-1 or hepatitis C virus [HCV]) requiring 
parenteral antibiotics, antivirals, or antifungals within 45 days prior to study entry. 
 
4.4.16 Receipt of any inactivated virus vaccine, non-replicating vaccine (including 
live), or mRNA vaccine, within 14 days prior to study entry. 
 
 
NOTE: Receipt of flu vaccine within 14 days prior to study entry is allowed. 

 
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4.4.17 Receipt of any of the following within 45 days prior to study entry: 
 
• 
Live, replicating virus vaccine 
• 
Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage 
colony-stimulating factor (GM-CSF) 
• 
Any other investigational medicinal agent 
 
4.4.18 Receipt of immunoglobulin or blood products within 90 days prior to study entry. 
 
4.4.19 Receipt of an injection of DNA plasmids or oligonucleotides within 60 days prior 
to study entry. 
 
4.5 
Exclusion Criteria, Group A only 
 
4.5.1 Hepatitis B virus vaccination ≤168 days prior to study entry. 
 
4.5.2 Receipt of HEPLISAV-B vaccine at any time prior to study entry. 
 
4.6 
Exclusion Criterion, Group B only 
 
4.6.1 Known HBV vaccination prior to study entry. 
 
4.7 
Study Enrollment Procedures 
 
4.7.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by the institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE) responsible for 
oversight of the study. Upon receiving final approval, sites will submit all required 
protocol registration documents to the DAIDS Protocol Registration Office 
(DAIDS PRO) at the Regulatory Support Center (RSC). The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all of the required 
documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s) 

 
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WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the legal 
representative if the participant is under guardianship) will be asked to read and 
sign the approved protocol consent form.  
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they qualify. An ACTG Screening Checklist must be 
entered through the DMC Study Enrollment System.  
 
4.7.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.7.3  Randomization/Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be keyed into the database.  
 
Participants who meet the enrollment criteria will be registered or randomized to 
the study according to standard ACTG DMC procedures.  
 
4.8 
Co-enrollment Guidelines  
 
United States sites are encouraged to co-enroll participants in A5128, “Plan for 
Obtaining Informed Consent to Use Stored Human Biological Materials (HBM) for 
Currently Unspecified Analyses.” Co-enrollment in A5128 does not require permission 
from the A5379 protocol chairs.  
 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-US Clinical Research Sites for Currently Unspecified 
Genetic Analyses.” Co-enrollment in A5243 does not require permission from the A5379 
protocol chairs.  
 
Individuals who consent to these additional studies would have additional blood drawn 
for these studies. Participants must be made aware that they can schedule this 
additional blood draw if they feel the need to do that. 

 
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For specific questions and approval for co-enrollment in other studies, sites should first 
check the PSWP or contact the protocol team via e-mail as described in the Study 
Management section. 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as study-provided HEPLISAV-B or ENGERIX-B. 
 
5.1 
Study Product Formulations 
 
5.1.1 HEPLISAV-B  
 
Hepatitis B Vaccine (Recombinant) adjuvanted, 0.5 mL dose contains 20 mcg of 
HBsAg and 3000 mcg of CpG 1018. HEPLISAV-B is a clear to slightly 
opalescent, colorless to slightly yellow solution available in vials and prefilled 
syringes as a sterile solution for intramuscular injection. It should be stored in a 
refrigerator at 2°C to 8°C (35°F to 46°F) and should not be frozen. Do not 
administer if product has been frozen.  
 
5.1.2 ENGERIX-B  
 
Hepatitis B Vaccine (Recombinant), 1 mL dose contains 20 mcg HBsAg. 
ENGERIX-B is a sterile, homogeneous, turbid, white suspension available in two 
presentations, as single-dose vials and prefilled syringes for intramuscular 
injection. ENGERIX-B is stored refrigerated between 2° and 8°C (35° and 46°F) 
and should not be frozen. Do not administer if product has been frozen. 
 
5.2 
Regimens, Administration, and Duration 
 
At entry, Group A participants will be randomized 1:1:1 to Arms 1, 2, and 3 as follows: 
 
Arm 1: HEPLISAV-B, 0.5 mL dose administered intramuscularly at weeks 0 and 4. 
 
Arm 2: HEPLISAV-B, 0.5 mL dose administered intramuscularly at weeks 0, 4, and 24. 
 
Arm 3: ENGERIX-B, 1 mL dose administered intramuscularly at weeks 0, 4, and 24. 
 
Group B participants will receive HEPLISAV-B intramuscularly as 0.5 mL dose at weeks 
0, 4, and 24. 
 
Participants should remain on their non-study-provided ART throughout the study (72 
weeks). 
 

 
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Table 5.2-1: Dosing 
Group A 
Week 0 
Week 4 
Week 24 
Arm 1 
HEPLISAV-B 0.5 
mL dose IM 
HEPLISAV-B 0.5 
mL dose IM 
- 
Arm 2 
HEPLISAV-B 0.5 
mL dose IM 
HEPLISAV-B 0.5 
mL dose IM 
HEPLISAV-B 0.5 
mL dose IM 
Arm 3 
ENGERIX-B 1 mL 
dose IM 
ENGERIX-B 1 mL 
dose IM 
ENGERIX-B 1 mL 
dose IM 
Group B 
Week 0 
Week 4 
Week 24 
All Participants 
HEPLISAV-B 0.5 
mL dose IM 
HEPLISAV-B 
0.5mL dose IM 
HEPLISAV-B 0.5 
mL dose IM 
5.3  
Study Product and Preparation for Administration 
 
5.3.1 HEPLISAV-B  
 
1. HEPLISAV-B should be inspected visually for particulate matter and 
discoloration prior to administration. If either of these conditions exists, the 
vaccine should not be administered.  
2. The injection site on the arm to be used for immunization will be gently 
rubbed with an alcohol pad to disinfect the site.  
3. The center seals of the vials will be removed, and the vial stoppers wiped 
with an alcohol wipe prior to insertion of a sterile needle attached to a sterile 
syringe. The study staff will determine the needle size depending upon the 
participant’s deltoid muscle size. 
4. Use a sterile needle and sterile syringe to withdraw the vaccine dose from the 
vial prior to intramuscular injection. Administer within 4 hours of drawing up 
dose in a syringe. HEPLISAV-B can be kept at room temperature (20°C - 
25°C) for up to 8 hours but exposure time to room temperature should be 
minimized. Changing needles between drawing vaccine from a vial and 
injecting it into a recipient is not necessary unless the needle has been 
damaged or contaminated. 
5. For the prefilled syringes, attach a sterile needle and administer 
intramuscularly. The study staff will determine the needle size depending 
upon the participant’s deltoid muscle size. HEPLISAV-B should be 
administered as soon as possible. HEPLISAV-B can be kept at room 
temperature (20°C-25°C) for up to 8 hours but exposure time to room 
temperature should be minimized. 
6. Administer HEPLISAV-B by intramuscular injection in the deltoid region. 
 

 
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5.3.2 ENGERIX-B  
 
1. Shake well before use and inspect visually for particulate matter and 
discoloration prior to administration. If either of these conditions exists, the 
vaccine should not be administered.  
2. The injection site on the arm to be used for immunization will be gently 
rubbed with an alcohol pad to disinfect the site.  
3. For the vials, remove the center seals of the vials and wipe the vial stoppers 
with an alcohol wipe prior to insertion of a sterile needle attached to a sterile 
syringe. The study staff will determine the needle size depending upon the 
participant’s deltoid muscle size. 
4. Use a sterile needle and sterile syringe to withdraw the vaccine dose from the 
vial prior to intramuscular injection. Administer within 4 hours of drawing up 
dose in a syringe. ENGERIX-B can be kept at room temperature (20°C- 
25°C) for up to 72 hours but exposure time to room temperature should be 
minimized. Changing needles between drawing vaccine from a vial and 
injecting it into a recipient is not necessary unless the needle has been 
damaged or contaminated. 
5. For the prefilled syringes, attach a sterile needle and administer 
intramuscularly. The study staff will determine the needle size depending 
upon the participant’s deltoid muscle size. ENGERIX-B should be 
administered as soon as possible. ENGERIX-B can be kept at room 
temperature (20°C-25°C) for up to 72 hours but exposure time to room 
temperature should be minimized. 
6. Administer ENGERIX-B by intramuscular injection in the deltoid region. 
 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.4.1 Study Product Acquisition/Distribution 
 
HEPLISAV-B® (Dynavax Technologies Corporation) will be available through the 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Research 
Products Management Center (CRPMC). The site pharmacist should obtain the 
study product(s) for this protocol by following the instructions in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
For sites that ENGERIX-B® will be centrally distributed to from the CRPMC, the 
site pharmacist should obtain the study product(s) for this protocol by following 
the instructions in the manual Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks.  
 
ENGERIX-B® (GlaxoSmithKline Biologicals) will be available through the National 
Institute of Allergy and Infectious Diseases (NIAID) Clinical Research Products 
Management Center (CRPMC) to all US sites, as well as non-US sites that the 
vaccine can be distributed to by the CRPMC.  
 

 
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For non-US sites that are unable to receive ENGERIX-B® from the CRPMC due 
to importation documentation limitation, the vaccine will be locally sourced.  
Any study product not provided by the study must comply with the NIAID 
(DAIDS) policy that outlines the process for authorizing the use of study products 
not marketed in the US in NIAID (DAIDS)-supported and/or -sponsored clinical 
trials. This policy is available on the NIAID (DAIDS) website at 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 
5.4.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. At US clinical 
research sites (CRSs), all unused study products must be returned to the NIAID 
CRPMC (or as otherwise directed by the sponsor) after the study is completed or 
terminated. The procedures to be followed are provided in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. At non-US CRSs, 
the site pharmacist must follow the instructions in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks for the destruction of unused 
study products. 
 
5.5 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.5.1 Required Medications 
 
All participants should continue their current ART regimen for the duration of the 
study. Changes in ART are discouraged during the study, but are allowed if 
clinical need arises as determined by sites and the participant’s treating provider. 
Sites must report all ART changes on the eCRF on the next study visit following 
the change in therapy. Antiretroviral therapy will not be provided by the study. 
 
5.5.2 Prohibited Medications 
 
HBV vaccine preparations other than study vaccines HEPLISAV-B and 
ENGERIX-B are prohibited. Standard-of-care (SOC) vaccines, including 
COVID-19 vaccines, will be permitted during the conduct of this study. If 
administration of a COVID-19 vaccine occurs after study entry and near the 
second or third study vaccine dose, adjust the second or third dose of the 
study vaccine to avoid immediate overlap reactogenicity; however, it is not 
prohibited to give them together, and this is at the discretion of the site 

 
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investigator. If an SOC vaccine and/or COVID-19 vaccine is administered on 
the same day as the study-provided vaccine, use different arms. Refer to the 
A5379 PSWP for further details about COVID-19 vaccines and this study. 
 
5.5.3 Precautionary Medications 
 
There are no precautionary medications.

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Group A (Arm 1 only)  
Evaluations 
Screening 
Entry (Day 
0) 
Post-Entry Evaluations 
(Weeks) 
Premature 
Study 
Discontinuation 
Evaluations 
(*refer to section 
6.2.4) 
 
4 
8 
12 
24 
28 
52 
72 
Visit Windows 
Within 45 
days 
≥24 hours 
after 
screening 
-4/+7 
days 
±7 days 
±14 days 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Examination  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Respiration Rate 
X 
X 
X 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
Tobacco Use 
 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
Modifications 
 
X 
X 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
 
 
X 
 
 
X* 
Liver Function Tests 
X 
X 
X 
X 
 
 
X 
 
 
X* 
INR 
X 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
 
 
 
 
X 
 
 
X* 
Hemoglobin A1c  
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testing (within 2 
days prior to the participant 
receiving HEPLISAV-B) 
 
X 
X 
 
 
 
 
 
X 
X 
CD4+/CD8+ 
X 
X 
 
 
 
 
X 
 
 
X* 
HBsAg Qualitative and HBcAb 
Total 
X 
 
 
 
 
 
 
 
 
 
Serum for HBsAb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA 
X 
 
 
 
 
 
X 
 
 
X* 
Vaccine Administration 
HEPLISAV-B 
 
X 
X 
 
 
 
 
 
 
 
Post-vaccination Assessment 
 
X 
X 
 
 
 
 
 
 
 
Diary Card 
(D= distributed; C= collected)  
 
XD 
XD,C 
XC 
 
 
 
 
 
 
Remote Contact (refer to section 
6.3.12 for contact window) 
 
X 
X 
X 
 
 
 
 
 
 
 
 

 
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Table 6.1-2: Group A (Arms 2 and 3 only)  
Evaluations 
Screening 
Entry 
(Day 0) 
Post-Entry 
Evaluation 
Post-Entry Evaluations 
(Weeks) 
Premature 
Study 
Discontinuation 
Evaluations 
(*refer to 
section 6.2.4) 
4 
8 12 24 28 32 48 72 
Visit Windows 
Within 45 
days 
≥24 hours 
after 
screening 
≥16 to ≤28 
hours post 
1st 
vaccination; 
at US sites 
only and is 
optional 
-4/+7 
days 
±7 days 
±14 
days 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Examination 
 
X 
 
X 
X X 
X 
X 
X X 
X 
X 
Respiration Rate 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
Tobacco Use 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
 
X 
X X 
X 
X 
X X 
X 
X 
Study Treatment Modifications 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Hematology 
X 
X 
 
X 
X 
 
 
X 
 
 
 
X* 
Liver Function Tests 
X 
X 
 
X 
X 
 
 
X 
 
 
 
X* 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
 
 
 
 
 
X 
 
 
 
X* 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing (within 2 
days prior to the participant 
receiving HEPLISAV-B or 
ENGERIX-B) 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
CD4+/CD8+ 
X 
X 
 
 
 
 
 
X 
 
 
 
X* 
HBsAg Qualitative and HBcAb 
Total 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum for HBsAb 
X 
X 
 
X 
X X 
X 
X 
X X 
X 
X 
Plasma HIV-1 RNA 
X 
X 
 
 
 
 
 
X 
 
 
 
X* 
Stored Plasma and PBMC for 
Immunologic & Latency 
Testing 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X* 
Stored PBMC for Genetic 
Testing 
 
 
 
 
 
X 
 
 
 
 
 
 
Vaccine Administration 
 
X 
 
X 
 
 
X 
 
 
 
 
 

 
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HEPLISAV-B 
(Group A Arm 2) 
Vaccine Administration 
ENGERIX-B (Group A Arm 3) 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Post-vaccination Assessment 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Diary Card 
(D= distributed; C= collected)  
 
XD 
 
XD,C XC  
XD XC 
 
 
 
 
Remote Contact (refer to 
section 6.3.12 for contact 
window) 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 

 
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Table 6.1-3: Group B Only 
Evaluations 
Screening 
Entry 
(Day 0) 
Post-Entry Evaluations 
(Weeks) 
Premature Study 
Discontinuation 
Evaluations 
(*refer to section 
6.2.4) 
4 
8 12 24 28 32 48 
72 
Visit Windows 
Within 45 
days 
≥24 
hours 
after 
screening 
-4/+7 
days 
±7 days 
±14 days 
Documentation of HIV-1 
X 
 
 
 
 
 
  
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Examination  
 
X 
X 
X X 
X X X 
X 
X 
X 
Respiration Rate 
X 
X 
X 
 
 
X 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
Tobacco Use 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
X 
X X 
X X X 
X 
X 
X 
Study Treatment 
Modifications 
 
X 
X 
 
 
X 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
 
 
X 
 
 
 
X* 
Liver Function Tests 
X 
X 
X 
X 
 
 
X 
 
 
 
X* 
INR 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
 
 
 
 
X 
 
 
 
X* 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
(within 2 days prior to 
the participant 
receiving HEPLISAV-B) 
 
X 
X 
 
 
X 
 
 
 
X 
X 
CD4+/CD8+ 
X 
X 
 
 
 
 
X 
 
 
 
X* 
HBsAg Qualitative and 
HBcAb Total 
X 
 
 
 
 
 
 
 
 
 
 
Serum for HBsAb 
X 
X 
X 
X X 
X X X 
X 
X 
X 
Plasma HIV-1 RNA 
X 
 
 
 
 
 
X 
 
 
 
X* 
Vaccine Administration 
HEPLISAV-B 
 
X 
X 
 
 
X 
 
 
 
 
 
Post-vaccination 
Assessment 
 
X 
X 
 
 
X 
 
 
 
 
 
Diary Card 
(D= distributed; 
C= collected) 
 
XD 
XD,C XC 
 
XD XC  
 
 
 

 
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Remote Contact (refer to 
section 6.3.12 for contact 
window) 
 
X 
X 
X 
 
X X 
 
 
 
 

 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant starting any study 
treatments. 
 
Screening 
Screening evaluations to determine eligibility must be completed within 45 days 
prior to study entry unless otherwise specified. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after screening evaluations unless 
otherwise specified. Participants must begin the study vaccine series within 72 
hours after registration/randomization. 
 
6.2.3 Post-Entry Evaluations 
 
At US sites, participants in Arms 2 and 3 in Group A are strongly encouraged to 
return to the clinic for a blood collection between 16 and 28 hours after the first 
vaccine administration. This visit should occur in the morning to account for 
peripheral blood mononuclear cell (PBMC) processing. Note that this visit is 
encouraged; however, participants may opt out at screening. This visit will not be 
conducted at non-US sites. 
 
Group A, Arm 1, evaluations at week 4 must occur -4/+7 days of the visit, weeks 
8 through 28 must occur ±7 days of the visit, and after 28 weeks must occur ±14 
days of the visit as shown in Table 6.1-1. Group A (Arms 2 and 3) and Group B 
evaluations at week 4 must occur -4/+7 days of the visit, weeks 8 through 32 
must occur ±7 days of the visit, and after week 32 must occur ±14 days of the 
visit as shown in Tables 6.1-2 and 6.1-3. 
 
Missed Vaccination Visits 
If any participant misses the week 4 visit (visit window -4/+7 days), reschedule as 
soon as possible and no later than week 8 (visit window ±7 days). Similarly, if 
any participant in Group A, Arms 2 and 3, or Group B misses the week 24 visit 
(visit window ±7 days), reschedule as soon as possible and no later than week 
28 (visit window ±7 days). If the participant cannot come in until their next 
scheduled study visit, combine the two visits. 
 
When the last vaccination in the dose series is delayed as described above, 
schedule a visit at 8 weeks after the second vaccination for the two-dose 

 
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series, or at 4 weeks after the third vaccination for the three-dose series, 
for HBsAb sample collection to determine SPR. For the three-dose series, 
this delay may lead to an SPR visit at study week 32. For the two-dose 
series, there is no corresponding week in the visit schedule that can be 
applicable when the vaccination delay occurs, and an unscheduled visit is 
warranted. 
 
For participants who have incomplete vaccine series, participants will be 
followed on study. Missing dose 2 in a two-dose series results in premature 
treatment discontinuation; however, if a participant misses the second dose 
in a three-dose series, this does not lead to premature treatment 
discontinuation. Dose 3 is allowed to be given if dose 2 is missed. 
 
Remote Data Collection 
Study visits may be conducted remotely (e.g., telephone, telehealth) in the 
following situations: 
• 
A participant is unable to attend a visit because of illness, lockdown status, 
or quarantine; the site must inform the CMC (actg.cmca5379@fstrf.org) 
• 
The site is temporarily unable to conduct non-essential visits in the 
clinic; the site must inform the CMC (actg.cmca5379@fstrf.org) 
 
Remote visits should be conducted during the visit window according to 
the SOE. Regardless of the situation, sites should document which visits 
were conducted remotely. For visits that are conducted remotely, the site 
should attempt to obtain as much of the visit-specific required information 
based on the SOE as possible and record it on the relevant eCRF. 
 
In addition to the remote visit, the participant should be scheduled for an 
in-person visit for all evaluations that were not conducted at the remote 
visit. If the in-person visit evaluations are outside of the visit window, have 
the participant in as soon as possible for safety-related evaluations as an 
unscheduled visit. If within a week of the next scheduled visit window, then 
wait for the next scheduled visit and add any safety lab evaluations not 
already being performed. If the participant is unable or prefers not to come 
to the site for a visit, priority safety labs are permitted to be done at a local 
lab or as part of the standard of care. Record these on an eCRF. The 
priority safety labs include: chemistry, hematology, and liver function tests. 
 
We ask the sites to prioritize sample collection for HBsAb testing for SPR 
determination. Primary SPR determination occurs at week 12 for Arm 1 in 
Group A, and week 28 for Arms 2 and 3 in Group A and for Group B when 
vaccines are administered as prescribed. If there is a need to limit in-person 
interactions at the site, the in-person component can be restricted to the 
blood draw, and the remaining visit evaluations can be completed remotely. 
 
Study Completion Evaluations 
Week 72 will be the participant’s final scheduled visit on-study. 

 
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6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized or Registered Participants Who Do Not Start Study 
Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. No 
other evaluations are needed. 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely permanently discontinue study vaccination series 
will not have the discontinuation evaluations performed. Participants should 
continue to attend all study visits and receive study evaluations per section 6.1. 
They will be followed on study/off study treatment through completion of the study.  
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study before week 28 will 
have the discontinuation evaluations performed per the SOE prior to being taken 
off the study. 
  
Group A, Arm 1, and Group B participants who prematurely discontinue from the 
study after week 28 will only have a clinical assessment, pregnancy test, and 
serum for HBsAb performed prior to being taken off the study.  
 
Group A, Arms 2 or 3 participants who prematurely discontinue from the study 
after week 28 will only have a clinical assessment, pregnancy test, and serum for 
HBsAb performed prior to being taken off the study; however, if they discontinue 
after week 28 but before the week 48 visit, they will also have plasma and PBMC 
stored for immunologic and latency testing. Plasma and PBMC for immunologic 
and latency testing will not be stored at the discontinuation visit if the participant 
discontinues after week 48. 
 
6.3 
Instructions for Evaluations 
 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/score-source-documentation-
requirements.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), and AE reporting 
requirements. 
 
The protocol team and/or study monitoring entity (e.g., DSMB) may determine that 
additional source data associated with procedures or evaluations performed per 

 
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protocol should be entered into eCRFs so that the data can be used for analysis 
or to otherwise assist with interpretation of study findings. In such cases, sites 
will be officially instructed to enter the additional data into eCRFs from available 
source documentation.  
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded on the eCRF regardless of when the diagnosis 
was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary artery disease 
• 
Cerebrovascular disease (history of stroke) 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic HCV (active or inactive) 
• 
Chronic kidney disease 
• 
Hypertension 
• 
Hypercholesterolemia 
 
Any allergies to any medications and their formulations must also be documented.  
 
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  
 
Table 6.3.3-1: Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy 
Within 60 days prior to entry 
HBV vaccination1 
Complete history 
Immune-based therapy 
Within 1 years prior to entry 
Blinded study treatment 
Within 1 years prior to entry 
HIV-1-related vaccines 
Within 1 years prior to entry 
COVID-19 vaccines 
Complete History 

 
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Medication Category 
Complete History or Timeframe 
Prescription drugs for treatment of 
opportunistic infections 
Within 60 days prior to entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
Within 60 days prior to entry 
Prescription drugs (other) 
Within 45 days prior to entry 
Herbal/dietary supplements 
Within 45 days prior to entry 
Sex-hormone medications or sex-
hormone analogues or antagonists2 
Within 1 year except as noted below 
 
1 If available, record dates, dose, and specific vaccine name (e.g., Hepatavax, 
ENGERIX-B, Twinrix) on the eCRF at screening. 
2 Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); oral, 
injectable, implanted, or patch contraceptives; vaginal ring, creams, or inserts; 
estrogen, progesterone, or testosterone therapy; leuprolide or other synthetic 
gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase inhibitors or 
any other androgen, estrogen, or progesterone analogue or antagonist therapy.  
 
6.3.4 Clinical Assessments 
 
Complete Physical Examination 
A complete physical examination will be performed at screening and is to include 
at a minimum an examination of the skin, head, mouth, and neck; auscultation of 
the chest; cardiac examination; abdominal examination; and examination of the 
lower extremities for edema. The complete physical examination will also include 
vital signs (temperature, pulse, respiration rate, and blood pressure). 
 
Targeted Physical Examination 
Post-screening, per the SOE, a targeted physical examination is to include vital 
signs (temperature, pulse, and blood pressure), and is to be driven by any 
previously identified or new signs or symptoms including diagnoses that the 
participant has experienced since the last visit. 
 
Respiration Rate 
Respiration rate is required to be recorded on the eCRF at screening, entry, and 
week 4 for Group A (Arm 1) and at screening, entry, and weeks 4 and 24 for 
Group A (Arms 2 and 3) and Group B. 
 
Height 
Height is required to be recorded on the eCRF at study entry only. 
 
Weight 
Weight is required to be recorded on the eCRF at study entry only. 
 

 
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Tobacco Use 
History of smoking tobacco, including the number of cigarettes smoked per day 
and the number of years the participant smoked, is required to be recorded on 
the eCRF at study entry only. 
 
Pregnancy 
Post-entry, see section 8.2 for collection requirements for pregnancy.  
 
Refer to section 7.2 for AE collection requirements and section 7.3.2 for events 
that meet EAE reporting requirements. 
 
Concomitant Medications 
Post-entry, the following ongoing, new, and discontinued concomitant 
medications must be recorded on the eCRFs: 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
section 6.3.3 for examples). 
• 
Corticosteroids  
• 
Intravenous immunoglobulins 
• 
Inactivated or live virus vaccine 
• 
Vaccines (experimental or standard of care, including COVID-19 
vaccines and COVID-19 booster vaccines) 
• 
Intravenous immunoglobulin therapy  
• 
All immunotherapeutic, immunomodulators, steroids, and other 
immunosuppressives 
• 
Antiretrovirals 
• 
Any concomitant medication associated with an SAE or medically attended 
adverse event (MAAE) 
• 
Any concomitant medication associated with a Grade ≥2 AE 
• 
Any concomitant medication associated with Grade ≥1 local and systemic 
injection reactions within 7 days after any study vaccine injection. 
 
Study Treatment Modifications 
All modifications to study vaccine including initial doses, missed doses, and 
permanent discontinuation of treatment will be recorded on the eCRFs. 
 
6.3.5 Laboratory Evaluations 
 
At screening and entry all laboratory values must be recorded on the eCRF. For 
post-entry assessments, record on the eCRF all laboratory values for 
hemoglobin, creatinine, AST, ALT, and platelet counts regardless of grade; 
record abnormal laboratory findings as per section 7.2.  
 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), 
white blood cell count (WBC), differential WBC, absolute neutrophil count (ANC), 
platelets. 

 
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Liver Function Tests 
Total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, indirect 
bilirubin. 
 
INR 
To be performed at a local laboratory. 
 
Chemistry 
Glucose, creatine kinase, electrolytes (e.g., sodium, potassium, chloride, phosphate, 
bicarbonate), calcium, creatinine, blood urea nitrogen (BUN), total protein, albumin, 
globulin (globulin is calculated: total protein minus total albumin). 
 
Hemoglobin A1c  
Record HbA1c per the SOE.  
 
Pregnancy Testing 
Participants of reproductive potential who can become pregnant: Serum or urine 
-HCG (urine test must have a sensitivity of <25 mIU/mL). Pregnancy testing 
results must be negative within 2 days prior to the participant receiving 
HEPLISAV-B or ENGERIX-B. Post-entry, note that a subsequent pregnancy test 
is not required for pregnant participants who consented to continue with the 
study. Record pregnancy and pregnancy outcome per section 8.2. 
 
6.3.6 Immunologic Studies 
 
CD4+/CD8+ 
Screening absolute CD4+/CD8+ count and percentages must be performed 
within 180 days prior to study entry at a laboratory that possesses a CLIA 
certification or equivalent (US sites) or IQA certification (non-US sites). 
 
For entry and post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent (US sites) or IQA certification (non-US sites). 
 
HBsAg Qualitative and HBcAb Total 
Qualitative HBsAg and HBcAb total will be performed by the site’s local 
laboratory per the SOE for individuals without documented history of HBsAg and 
HBcAb or with history of HBsAg positive or HBcAb positive results. Results will 
not be collected on an eCRF. 
 
Serum for HBsAb 
Serum HBsAb will be collected, tested, and stored per the SOE. Refer to the 
A5379 Laboratory Processing Chart (LPC) for detail. 
 

 
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6.3.7 Virologic Studies 
 
The A5379 LPC provides instructions for processing, storing, and shipping the 
samples described below. 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 180 days prior to study entry at a 
laboratory that possesses a CLIA certification or equivalent (US sites) or VQA 
certification (non-US sites). Eligibility will be determined based on the screening value.  
 
For entry (Group A, Arms 2 and 3 only) and post-entry (both Groups), HIV-1 RNA 
testing must be performed at the protocol-designated laboratory. 
 
6.3.8 Stored Plasma and PBMC 
 
Only sites certified by the IQA Cryopreservation PT Program at the Duke 
Human Vaccine Institute are required to collect PBMCs. 
 
Stored Plasma and PBMC for Immunologic and Latency Testing 
For Group A, Arms 2 and 3 only, plasma and PBMC will be stored for 
immunologic and latency studies per the SOE.  
 
Analyses on Stored Specimens  
For Group A, Arms 2 and 3 only, PBMC will be stored for genetic testing per the SOE. 
 
Plasma for cytokines and chemokines will be measured with the assay per the 
manufacturer’s recommendations.  
 
RNA-Seq  
Participants will undergo isolation of specific cell types and the cell subsets will 
be analyzed via RNA-Seq. 
 
Analysis of HBV- and HIV-specific T Cell Responses  
Samples for assessment of T cell responses will be collected at the indicated 
time points. Depending on availability of PBMCs, assays will be performed on 
selected samples to further characterize cross-reactivity, function, and phenotype 
of the induced response.  
 
Analysis of the HIV Reservoir  
CD4+ T-cells will be isolated from PBMC at time points indicated in the SOE. The 
following will be measured at baseline and at week 28 after first injection with 
HEPLISAV-B (Group A, Arms 2 and 3): 1) HIV reservoir size; 2) cell associated 
HIV-1 RNA; and 3) total DNA levels.  
 
6.3.9 Vaccine Administration (HEPLISAV-B and ENGERIX-B) 
 
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Participants will be counseled on the importance of receiving all vaccine doses 
given the probability of a suboptimal response for participants that do not receive 
all doses. 
 
Vaccine should be deferred for fever on the day of vaccination defined as oral 
temperature >38°C, until the participant is afebrile for 24 hours. If participant 
remains febrile and cannot be rescheduled within the visit window, reschedule 
according to section 6.2.3. It is acceptable to defer the injection for either time 
point. Refer to section 6.2.3 about missed vaccination visits. 
 
6.3.10 Post-vaccination Assessment 
 
Participants should remain in clinic for 30 minutes after injection. Record oral 
temperature 30 minutes after injection in source documents. At the end of this 
observation period, assess for any post-injection reactions (PIRs) and AEs, and 
record any reportable events on the eCRF, as described in section 7.0. 
 
6.3.11 Diary Card 
 
A diary card along with a standard measuring device and thermometer will be 
distributed to each participant per the SOE. The diary card collects temperature 
and reactions to the vaccine (i.e., pain, redness, and swelling at or near the 
injection site, malaise, headache, myalgia, and fatigue) that the participant 
records for 7 days post vaccine administration.  
 
The completed diary card will be collected at the next study visit following the 
vaccine administration. Entries will be reviewed. AEs identified will be recorded 
on the eCRF according to section 7.2. Any information that meets the study 
eCRF data entry requirements should be entered on the associated eCRF(s).  
 
The diary card is posted on the PSWP. 
 
6.3.12 Remote Contact 
 
Participants will be contacted via e-mail, text message, or telephone by study 
staff 3-5 business days after vaccination study visits (at weeks 0, 4, and 24 for 
Group A, Arm 2 and 3, and Group B and at weeks 0 and 4 for Group A, Arm 
1) to remind them to complete the diary card (i.e., document any injection site 
reactions). Three to five business days prior to study visits at weeks 4, 8, and 28 
(contact for the week 28 study visit is not applicable for Group A, Arm 1), 
participants will be contacted via e-mail, text message, or telephone by study 
staff to remind them to bring the diary card at the next study visit. Contact will be 
recorded in the source documents and will not be recorded on the eCRF. Refer 
to the Manual of Procedures (MOPS) for remote contact guidance.  
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 

 
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7.1 
Definition of Adverse Events 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or diagnosis that occurs in a study participant during the conduct of 
the study REGARDLESS of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition.  
 
7.2 
Adverse Event Collection Requirements for This Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
• 
All Grade ≥2 AEs. 
• 
All AEs that led to a change in study treatment regardless of grade. 
• 
All AEs meeting SAE definition or EAE reporting requirement. 
• 
All Grade ≥1 local and systemic injection reactions within 7 days of any study 
vaccine injection. 
• 
All MAAEs, defined as AEs with medically attended visits that were not routine visits for 
physical examination or vaccination, such as visits for hospitalization, an emergency 
room visit, or an otherwise unscheduled visit to or from a medical personnel for any 
reason. 
• 
All potential immune-mediated AEs regardless of grade. A list of potential immune-
mediated AEs is posted on the A5379 PSWP. 
 
Sites will assess AE relationship to investigational product based on the stated criteria 
written in the DAIDS EAE Manual Version 2.0 for all AEs, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-
adverse-events-daids. 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based 
reporting system.  
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the DAIDS AE Grading Table corrected Version 2.1, July 2017, which can be found on 
the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-
event-grading-tables.  
 
Targeted Local and Systemic Adverse Reactions 
Participants will self-monitor for local and systemic adverse reactions using diary cards 
for a 7-day period starting on the day of vaccination. The completed diaries will be used 
by site staff to record any AEs. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  

 
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• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above). 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are:  
o Hepatitis B Vaccine (Recombinant) Adjuvanted (HEPLISAV-B) 
o Hepatitis B Vaccine (Recombinant) (ENGERIX-B) 
• 
In addition to the EAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are:  
o All myocardial infarctions 
o Strokes 
o New onset of diabetes  
o Herpes zoster 
o Autoimmune diseases 
o Any potential immune-mediated AEs  
o Thromboembolic diseases  
o Deep venous thrombosis (DVT) 

 
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o Pulmonary embolism (PE) 
o Any abnormal pregnancy outcomes 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table corrected Version 2.1, July 2017, must be used 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables. 
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is the study duration (i.e., 
through week 72). 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
7.4 
Study Monitoring 
 
The protocol core team (which includes the chairs and medical officer) will monitor the 
conduct and safety of the study via regular summaries of accrual, study discontinuation, 
data completeness, and AEs, as appropriate.  
 
The DAIDS clinical representative will review and assess select EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs as applicable. Additionally, the DAIDS clinical 
representative will review aggregated AE summaries pooled across treatment arms 
prepared by the SDAC following the schedule for Data and Safety Monitoring Board 
(DSMB)-monitored studies. 
 
The study will undergo interim review at least annually by a NIAID-appointed DSMB. The 
first interim review will occur no more than 1 year after the enrollment of the first study 
participant. An interim review may also be convened if a concern is identified by the 
DAIDS clinical representative, the study chairs, or study statistician in consultation with 
the team. See sections 10.1 and 10.5 for statistical and other considerations related to 
interim monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study, Progress, Data and Safety 
Monitoring Plan developed by the Statistical and Data Management Center (SDMC) 
before clinical trial initiation. See section 10.5 for further information on the Data and 
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8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
All vaccines in this study are expected to be well tolerated. Injection-site reactions are 
expected to spontaneously subside. Local pruritus and pain can be treated with oral 
medications. If significant symptoms of pain and induration persist for more than 12 
hours, an ice pack may be applied locally for 30 minutes every 2 hours, as needed. Use 
of an ice pack within 12 hours post-vaccination and after the onset of symptoms is 
discouraged as it may interfere with the action of the vaccine. 
 
Results related to participant safety and significant clinical findings requiring medical 
attention and follow up will be provided to the participant and their treating medical provider. 
 
Vaccine-related Hypersensitivity 
A participant who develops study vaccine-related hypersensitivity reactions believed to 
be secondary to any of the constituents of HEPLISAV-B or ENGERIX-B will not receive 
any further dosing of study vaccines. These reactions may manifest with signs and 
symptoms that may include, but are not limited to fever, chills, headache, rash, pruritus, 
hypo- or hypertension, bronchospasm, or other symptoms. Appropriate medical therapy 
including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen should be available for use in the treatment of such reactions. Participants 
should be carefully observed until the complete resolution of all signs and symptoms. In 
each case of vaccine related hypersensitivity, the site investigator should institute 
treatment measures according to the best available medical practice. The CMC must be 
notified within 24 hours by e-mail at actg.cmcA5379@fstrf.org.  
 
8.2 
Pregnancy  
 
Pregnancy and pregnancy outcome will be recorded on the eCRFs. The CMC 
(actg.cmca5379@fstrf.org) must be notified of all on study pregnancies. 
 
US sites must inform participants of the voluntary HEPLISAV-B pregnancy registry if a 
pregnancy occurs within 90 days after HEPLISAV-B administration and provide the 
registry telephone number: 1-844-443-7732. US sites should encourage the participant 
to call; however, the registry is voluntary and the participant may choose to enroll or not. 
The HEPLISAV-B pregnancy registry is restricted to US sites only. 
 
Pregnancies that occur on study should also be reported prospectively to The 
Antiretroviral Pregnancy Registry. More information is available at www.apregistry.com. 
Telephone: 800-258-4263; Fax: 800-800-1052. (For studies conducted at sites outside 
the United States, report to The Antiretroviral Pregnancy Registry—Telephone: 910-679-
1598; Fax: 44-1628-789-666 or 910-256-0637.) 
 
Pregnancy Outcomes and Reporting 
Because the study vaccines hold the prospect of direct benefit for the pregnant 
participant, participants who have received any dose of study vaccine and become 

 
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pregnant on study will be offered the option to stay on study with study vaccine or stop 
study vaccine. Individuals on HEPLISAV-B who choose to stay on the study vaccine will 
be counseled on the lack of adequate safety, efficacy, and fetal toxicity data of the 
vaccine in pregnant individuals. All pregnant participants will need to complete a 
pregnancy-specific consent process. Study follow up will continue according to section 
6.0 for the duration of the study. In case of termination of pregnancy, the participant will 
continue with the evaluations and vaccination schedule per the SOE. The investigator 
and study team will have no part in any decision related to terminating the pregnancy.  
 
If a participant has completed the study or chooses to discontinue from the study before 
the end of the pregnancy, then site staff should request permission to contact her 
regarding pregnancy outcomes at the end of pregnancy. If the information is obtained, 
pregnancy outcomes will be submitted on an eCRF at the end of the pregnancy.  
 
8.3  
Breastfeeding 
 
There are no data to inform on the excretion of HEPLISAV-B in human breast milk. It is 
not known what impact HEPLISAV-B could have on the breastfed infant or on milk 
production and excretion by the mother.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
• 
Vaccine-related toxicity/hypersensitivity reaction or other severe reaction to the study 
vaccine (see section 8.1 Toxicity). 
• 
An SAE that is assessed as related to study vaccination. 
• 
A new onset or worsened potentially immune-mediated AE, regardless of 
assessment of relationship to study vaccination. 
• 
Requirement for prohibited concomitant medications (see section 5.5). 
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
• 
Missed 2nd dose in the allowed timeframe (see section 6.2.3) for a two-dose 
series. 
• 
Missed 3rd dose in the allowed timeframe (see section 6.2.3) for a three-dose 
series. 
 
9.2 
Premature Study Discontinuation 
• 
Request by the participant to withdraw. 
• 
Failure to start study treatment. 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter.  
 

 
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10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues  
 
A5379 is a prospective, open-label study to evaluate immunogenicity of the HBV vaccine 
HEPLISAV-B in two study populations living with HIV: prior HBV vaccine recipients who 
are deemed non-responders (Group A) and individuals who are naïve to HBV 
vaccination (Group B). The study is designed separately for the two study populations 
and will be conducted as separate evaluations for all primary and key secondary 
analyses. Because the study populations for Groups A and B are different, no 
adjustment of type I error is planned for conducting two population studies under the 
same protocol mainly for administrative efficiency.  
 
For the study arms with three-dose vaccine administrations (at weeks 0, 4, and 24), 
seroprotection response (SPR, HBsAb ≥10 mIU/mL) at 4 weeks after the vaccination 
series (at week 28) will be assessed for the primary analysis. For the HEPLISAV-B arm 
with a two-dose vaccine administration (at weeks 0 and 4), SPR at 8 weeks after the 
vaccination series (at week 12) will be assessed for the primary analysis. Section 2.2 
provides the rationale behind the choice of outcome measure for the primary analysis. 
 
10.1.1 Group A (Non-responders) 
 
The study in Group A is designed to address two primary objectives: 
 
1. To determine if the HEPLISAV-B vaccine administered as a two-dose 
vaccination series at weeks 0 and 4 (Arm 1) is non-inferior to the standard 
ENGERIX-B vaccine administered as a three-dose vaccination series at 
weeks 0, 4, and 24 (Arm 3). 
 
2. To determine if the HEPLISAV-B vaccine administered as a three-dose 
vaccination series at weeks 0, 4, and 24 (Arm 2) is superior to the standard 
ENGERIX-B vaccine administered as a three-dose vaccination series at 
weeks 0, 4, and 24 (Arm 3). 
 
The study is designed as an open-label three-arm study, where participants are 
randomized to the following study arms: 
 
Arm 1: Two doses of HEPLISAV-B at weeks 0 and 4 
Arm 2: Three doses of HEPLISAV-B at weeks 0, 4, and 24 
Arm 3: Three doses of ENGERIX-B at weeks 0, 4, and 24 
 
Arm 3 serves as the control arm for both comparisons in Group A. The first 
primary objective in Group A will be addressed by comparing Arm 1 to Arm 3, 
and the second primary objective in Group A will be addressed by comparing 
Arm 2 to Arm 3. Arm 1 allows the assessment of long-term antibody responses at 
48 weeks after the two-dose vaccination series. It is necessary to support the 
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responses 48 weeks later. The latter antibody response is proposed as a key 
secondary outcome, to be evaluated as an important supporting analysis. 
 
In Group A, a two-sided type I error rate is targeted at the pre-specified overall 
alpha level of 5% for the two primary analysis comparisons. To preserve the 
overall type I error rate in Group A and to allow flexible interim monitoring, a 
Bonferroni correction is applied, and a two-sided type I error rate of 2.5% each 
for the comparison between Arm 1 and Arm 3 and for the comparison between 
Arm 2 and Arm 3 is allocated. Interim monitoring is considered independently for 
the two primary objectives as follows. 
 
1. For the primary objective on the comparison between Arm 1 and Arm 3, interim 
monitoring will not include early formal non-inferiority analyses using the 
accumulating data on the primary outcome for early study conclusion on non-
inferiority. This is because the long-term antibody data in the study provide 
important supporting information on how the primary results in these study arms 
should be interpreted for future guidance. As such, the sample size for Arm 1 is not 
adjusted for interim looks. Interim monitoring on SPR will focus on assessments 
related to potential harm, where Arm 1 may be closed early if there is sufficiently 
compelling evidence in the interim data that suggest poor response to the two-dose 
vaccination series that may be deemed harmful. 
 
2. For the primary objective on the comparison between Arm 2 and Arm 3, 
interim monitoring will include efficacy analyses, if the enrollment rate allows 
such early looks to be meaningful in assessing future conduct of the study. 
The sample sizes for Arms 2 and 3 are adjusted for the potential interim 
efficacy looks. Interim monitoring considerations will also include assessment 
for compelling evidence of lack of benefit and possibly potential harm in 
continuing Arm 2. Interim looks strictly based on “futility" which (in statistical 
usage) are based on the potential failure to reject the specified null 
hypothesis are not planned in this study. (See Freidlin et al. [19] regarding 
interim looks related to futility versus inefficacy.) 
 
The sample size of 187 in each arm was determined by the larger of the 
sample sizes needed for the two primary analysis comparisons. The sample 
size of 187 each in Arms 1 and 3 was determined to show non-inferiority of 
two-dose administration of HEPLISAV-B (Arm 1) compared to the standard 
three-dose ENGERIX-B vaccination (Arm 3, control). The team anticipates 
that two doses of HEPLISAV-B (Arm 1) will result in a higher SPR proportion 
than the control arm (Arm 3), but the objective is to show non-inferiority with a 
margin of 10%. That is, the study seeks to show that the amount by which the 
two-dose HEPLISAV-B series (Arm 1) is inferior to the control (Arm 3) is less 
than a 10% difference in the SPR proportions. Therefore, the study is 
powered for a non-inferiority design but under the assumption that the SPR 
proportion is somewhat higher with two-dose administration of HEPLISAV-B. 
The non-inferiority margin of 10% was chosen in accordance with a previous 
FDA study on HEPLISAV-B. (See section 2.2, Rationale.) And the sample 

 
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size of 187 in Arm 2 provides good power to show superiority of three-dose 
administration of HEPLISAV-B (Arm 2) compared to the standard three-dose 
ENGERIX-B vaccination (Arm 3, control).  
 
These sample sizes provide at least 80% power to conclude in two statistical 
tests that 1) Arm 1 is non-inferior to Arm 3, and 2) Arm 2 is superior to Arm 3, 
each with a well-controlled two-sided type I error of 2.5% with Bonferroni 
correction for the two primary objectives. The assumption of 70% SPR 
proportion at 4 weeks after the vaccination series for the control arm (Arm 3) 
is based on the literature review of a limited number of studies on repeat  
vaccination in those who failed a primary vaccination series (See section 2.1, 
Background.) The assumption of 75% SPR proportion in HEPLISAV-B Arm 1 
and 85% SPR proportion in Arm 2 are based on the results of prior 
HEPLISAV-B studies. (See section 2.1.) 
 
10.1.2 Group B (HBV Vaccine-naïve) 
 
Group B consists of individuals who have no known prior history of HBV 
vaccination. The study in Group B will be conducted as a prospective, single-arm 
study of the three-dose vaccination series with HEPLISAV-B in HBV vaccine-
naïve participants. The primary study objective is to evaluate seroprotective 
response (SPR) at 4 weeks after the vaccination series. 
 
Group B study is designed to conclude that the true SPR proportion is greater 
than 55% with good precision. This will be assessed by examining if a two-sided 
95% confidence interval (CI) for the sample proportion is entirely above 55%. 
This is equivalent to showing that the SPR proportion is higher than 55% in a 
one-sided test with a type I error of 2.5%, where the aim is to rule out SPR 
proportions below or equal to 55%. The threshold of 55% was chosen based on 
the completed A5220 study. (See section 2.2.) 
 
Group B sample size of 73 participants was chosen to show with 90% power that 
the SPR proportion is greater than 55% in this study population and to account for 
a potential missed visit or loss to follow-up prior to the primary outcome visit at 
week 28. Assuming the underlying SPR proportion is 75% with a three-dose 
vaccine series with HEPLISAV-B and assuming no more than 10% loss to follow-
up prior to week 28, this sample size would provide the targeted analysis sample 
size of 65. The team considers an SPR proportion of 75% to be plausible based on 
the results of HEPLISAV-B studies in individuals with diabetes and in individuals 
with kidney disease, which are deemed to be populations challenged with low 
vaccine responses (refer to section 2.1) The targeted sample size will provide good 
precision around the estimated SPR proportion to give guidance on the use of 
HEPLISAV-B vaccine in HIV-1 positive persons without prior HBV vaccination. 
 

 
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No formal interim efficacy analysis is planned because the aim of Group B is to 
provide an SPR estimate with good precision for persons living with HIV. Interim 
monitoring will consist of data reviews to ensure that there is no harm and the 
study is conducted appropriately. 
 
10.1.3 Groups A and B 
 
In both Groups A and B, the primary outcome of achieving SPR after the 
vaccination series (at week 28 with a three-dose series and at week 12 with a 
two-dose series) may be evaluated prior to the completion of study follow-up at 
week 72. The primary analysis timeline will be driven by the last participant’s 
completion of the primary outcome visit, rather than the study completion date. 
As such, the primary analysis timelines will be derived separately for Groups A 
and B. Results from the SPR analysis may be presented publicly, for example at 
a conference, upon completion of relevant data prior to the study database 
finalization.  
 
The final analysis for the two study groups may occur separately after 
complete follow-up and data finalization. 
 
The primary analysis on SPR will be conducted on all study-eligible participants 
who receive at least one vaccine. Each data analysis will be conducted on 
participants with available data, under the assumption of missing at random. 
(See Li et al. [20] on handling missing data in vaccine clinical trials.) 
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the primary 
Statistical Analysis Plan (SAP), which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to https://ClinicalTrials.gov. Outcomes of interest for secondary and 
exploratory objectives intended for subsequent publications are to be listed under “Other 
Outcome Measures.” 
 
10.2.1 Primary Outcome Measures  
 
For Group A Primary Analyses: 
 
10.2.1.1 
[Objectives 1.2.1 and 1.2.2] Seroprotection response defined as 
HBsAb ≥10 mIU/mL at 8 weeks after the two-dose series (week 12) in 
Arm 1 and at 4 weeks after the three-dose series (week 28) in Arms 2 
and 3. 
 
10.2.1.2 
[Objective 1.2.4] Reported AEs from study vaccination initiation to 
study discontinuation. 
 
For Group B Primary Analyses: 

 
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10.2.1.3 
[Objective 1.2.3] Seroprotection response defined as HBsAb ≥10 
mIU/mL at 4 weeks after the vaccination series (week 28). 
 
10.2.1.4 
[Objective 1.2.4] Reported AEs from study vaccination initiation to 
study discontinuation. 
 
10.2.2 Secondary Outcome Measures  
 
For Group A Secondary Analyses: 
 
10.2.2.1 
HBsAb titer at the following study visits in Arm 1: 
• 
Week 4 [Objective 1.3.6] 
• 
Week 8 [Objectives 1.3.3, 1.3.5, and 1.3.6] 
• 
Week 12 [Objectives 1.3.1, 1.3.3, 1.3.5, and 1.3.6] 
• 
Week 24 [Objective 1.3.6] 
• 
Week 28 [Objectives 1.3.3 and 1.3.5] 
• 
Week 52 [Objectives 1.3.3 and 1.3.5] 
• 
Week 72 [Objective 1.3.12] 
 
10.2.2.2 
Seroprotection response defined as HBsAb ≥10 mIU/mL at the 
following study visits in Arm 1: 
• 
Week 4 [Objective 1.3.6] 
• 
Week 8 [Objectives 1.3.3, 1.3.5, and 1.3.6] 
• 
Week 12 [Objectives 1.3.3, 1.3.5, and 1.3.6] 
• 
Week 24 [Objective 1.3.6] 
• 
Week 28 [Objectives 1.3.3 and 1.3.5] 
• 
Week 52 [Objectives 1.3.3 and 1.3.5] 
• 
Week 72 [Objective 1.3.12] 
 
10.2.2.3 
HBsAb titer at the following study visits in Arm 2: 
• 
Week 4 [Objective 1.3.6] 
• 
Week 8 [Objective 1.3.6] 
• 
Week 12 [Objective 1.3.6] 
• 
Week 24 [Objective 1.3.6] 
• 
Week 28 [Objectives 1.3.2 and 1.3.5] 
• 
Week 32 [Objectives 1.3.4 and 1.3.5] 
• 
Week 48 [Objectives 1.3.4 and 1.3.5] 
• 
Week 72 [Objectives 1.3.4, 1.3.5, and 1.3.12] 
 
10.2.2.4 
Seroprotection response defined as HBsAb ≥10 mIU/mL at the 
following study visits in Arm 2: 
• 
Week 4 [Objective 1.3.6] 
• 
Week 8 [Objective 1.3.6] 
• 
Week 12 [Objective 1.3.6] 

 
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• 
Week 24 [Objective 1.3.6] 
• 
Week 28 [Objective 1.3.5] 
• 
Week 32 [Objectives 1.3.4 and 1.3.5] 
• 
Week 48 [Objectives 1.3.4 and 1.3.5] 
• 
Week 72 [Objectives 1.3.4, 1.3.5, and 1.3.12] 
 
10.2.2.5 
HBsAb titer at the following study visits in Arm 3:  
• 
Week 4 [Objective 1.3.6] 
• 
Week 8 [Objective 1.3.6] 
• 
Week 12 [Objective 1.3.6] 
• 
Week 24 [Objective 1.3.6] 
• 
Week 28 [Objectives 1.3.1, 1.3.2, and 1.3.3] 
• 
Week 32 [Objectives 1.3.3 and 1.3.4] 
• 
Week 48 [Objectives 1.3.3 and 1.3.4] 
• 
Week 72 [Objectives 1.3.3 and 1.3.4] 
 
10.2.2.6 
Seroprotection response defined as HBsAb ≥10 mIU/mL at the 
following study visits in Arm 3: 
• 
Week 4 [Objective 1.3.6] 
• 
Week 8 [Objective 1.3.6] 
• 
Week 12 [Objective 1.3.6] 
• 
Week 24 [Objective 1.3.6] 
• 
Week 28 [Objective 1.3.3] 
• 
Week 32 [Objectives 1.3.3 and 1.3.4] 
• 
Week 48 [Objectives 1.3.3 and 1.3.4] 
• 
Week 72 [Objectives 1.3.3 and 1.3.4] 
 
10.2.2.7 
Grade ≥2 AEs within 4 weeks after each injection [Objective 1.3.10] 
 
For Group B Secondary Analyses: 
 
10.2.2.8 
HBsAb titer at the following study visits: 
• 
Weeks 4, 8, 12, and 24 [Objective 1.3.9] 
• 
Week 28 [Objective 1.3.7] 
• 
Weeks 32, 48, and 72 [Objective 1.3.8] 
 
10.2.2.9 
Seroprotection response defined as HBsAb ≥10 mIU/mL at the 
following study visits: 
• 
Weeks 4, 8, 12, and 24 [Objective 1.3.9] 
• 
Weeks 32, 48, and 72 [Objective 1.3.8] 
 
10.2.2.10 Grade ≥2 AEs within 4 weeks after each injection [Objective 1.3.10] 
 
For Exploratory Analyses Combining Groups A and B: 
 

 
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10.2.2.11 HBsAb titer at the following study visits in Group A, Arm 2, and Group 
B [Objective 1.4.1]: Weeks 4, 8, 12, 24, 28, 32, 48, and 72 
 
10.2.2.12 Seroprotection response defined as HBsAb ≥10 mIU/mL at the 
following study visits in Group A, Arm 2, and Group B [Objective 
1.4.1]: Weeks 4, 8, 12, 24, 28, 32, 48, and 72 
 
10.2.3 Other Outcome Measures  
 
10.2.3.1 
HBV surface antigen-specific B and T-cell responses 
 
10.2.3.2 
Innate immune soluble factors 
 
10.2.3.3 
Genes and adaptive cell phenotypes (to be identified when the assay 
is determined) 
 
10.2.3.4 
Cell-associated HIV-1 RNA in CD4+ T-cells 
 
10.2.3.5 
Frequency of latently infected cells 
 
10.2.3.6 
Total DNA levels  
 
10.2.3.7 
HIV-1 specific immune responses, T-cell activation, expression of 
exhaustion markers on T-cells and other levels of HIV-specific 
immunity and activation (biomarkers to be defined when the assays 
are identified).  
 
10.3 
Randomization and Stratification 
 
At study entry, Group A participants will be randomized in 1:1:1 ratio to Arms 1, 2, and 3. 
Randomization will use permuted blocks and balancing by main site. Group A will be 
stratified by sex assigned at birth (male versus female) and diabetes diagnosis status 
(yes versus no). 
 
All Group B participants will be assigned to receive three doses of HEPLISAV-B. 
 
10.4 
Sample Size and Accrual  
 
10.4.1 Group A (Non-responder, N=561) 
 
Group A consists of individuals who have prior history of HBV vaccination but are 
considered non-responders. There are two primary objectives, and the Group A 
overall type I error rate of 5% is preserved by applying the Bonferroni correction 
to allocate a type I error rate of 2.5% to each primary analysis.  
 
Accrual of about 45 participants per month on the average is anticipated. 
Complete enrollment in about 12.5 months in Group A is anticipated. 

 
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10.4.1.1 
Non-inferiority Design (Arm 1 and Arm 3 Comparison) 
 
For the primary objective to show that SPR proportion in Arm 1 is non-
inferior to the SPR proportion in Arm 3 within the non-inferiority margin of 
10%, we assume that 70% in the control arm (Arm 3) will achieve SPR. 
We assume the proportion of participants achieving SPR with two doses 
of HEPLISAV-B (Arm 1) will be higher at 75%. As a non-inferiority design, 
this comparison is powered to show that the SPR proportion in Arm 1 is 
not lower than that of Arm 3 (control) by more than the pre-specified non-
inferiority margin of 10%. A sample size of 168 each in Arm 1 and Arm 3 
achieves 80% power to detect a difference between the two proportions 
of less than 10%, in a one-sided test with type I error of 1.25% using 
normal approximation. Assuming no more than about 10% missing data 
for SPR, which includes loss to follow-up within each study arm prior to 
the primary outcome visit, the study sample size is increased to 187 per 
study arm. Table 10.4.1.1-1 below shows sample sizes for various 
scenarios for the Arm 1 and Arm 3 non-inferiority comparison with a non-
inferiority margin of 10%. Arm 1 is anticipated to have better SPR 
proportion than Arm 3 (control), and scenarios where Arm 1 has worse 
response are not considered here. 
 
Table 10.4.1.1-1: Group A (non-responder) Non-inferiority Comparison between Arms 1 
and 3 with One-sided 1.25% (corresponds to two-sided type I error of 
2.5%) after Bonferroni Correction 
ENGERIX-B 
Seroprotection 
Response 
(Arm 3, 
Control) 
HEPLISAV-B 
Seroprotection 
Response 
(Arm 1) 
Difference 
(Arm 3 minus 
Arm 1) 
Targeted 
Sample 
Size per 
Arm 
Planned 
Sample Size 
per Arm (10% 
loss-inflated) 
0.65 
0.65 
0.70 
0.75 
0 
-0.05 
-0.10 
N=433 
N=185 
N=99 
N=482 
N=206 
N=110 
0.70 
0.70 
0.75 
0.80 
0 
-0.05 
-0.10 
N=400 
N=168 
N=88 
N=445 
N=187 
N=98 
0.75 
0.75 
0.80 
0.85 
0 
-0.05 
-0.10 
N=357 
N=147 
N=75 
N=397 
N=164 
N=84 
 
Figure 10.4.1.1-1 shows possible results of the non-inferiority 
comparison under the design assumptions of 70% SPR in Arm 3 and 
75% SPR in Arm 1. The figure presents the SPR differences (SPR 
proportion in Arm 3 minus SPR proportion in Arm 1) as point 
estimates (in solid circles) with two-sided 97.5% confidence intervals 
with a sample size of 168 each in Arm 1 and Arm 3. For the purpose 

 
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of illustrating potential outcomes in this non-inferiority design, potential 
multiple interim looks and stratification factors are not incorporated in 
the confidence interval estimation. The confidence intervals that lie 
entirely below the margin of 10% will be deemed non-inferior. Figure 
10.4.1.1-1 shows that about 80% of the confidence intervals lie below 
the margin of 10%. 
 
 
*Simulation trials were ranked by the estimate of the SPR difference between Arms 1 and 3. 
The vertical line at -0.05 represents the assumed SPR difference (Arm 3 - Arm 1), the vertical line 
at 0 represents no difference in SPR between Arm 3 and Arm 1, and the vertical line at 0.10 
represents the 10% non-inferiority margin. 
Figure 10.4.1.1-1: Simulated Point Estimates and 97.5% Confidence Intervals for 
the Arm 1 SPR Difference from Arm 3 under the Design Assumptions 
 
No formal interim efficacy analysis to conclude non-inferiority of Arm 1 
compared to Arm 3 (control) is planned for the first primary objective, and 
sample size adjustment for interim efficacy monitoring is not made. 
Guidelines on interim monitoring for Arm 1 are described below in section 
10.5. The proposed sample size for Arm 1 and Arm 3 is 187 for each.  
 
10.4.1.2 
Superiority Design (Arm 2 and Arm 3 Comparison) 
 
For the primary objective to compare SPR proportion at 4 weeks after 
the vaccination series between Arm 2 and Arm 3 (control), an 
increase of 15% is assumed in the proportion of participants achieving 

 
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SPR with three doses of HEPLISAV-B (Arm 2). With the sample sizes 
of 147 participants in each study arm, there is 80% power to detect a 
difference as significant in a two-sided test at a significance level of 
2.5% using normal approximation. Table 10.4.1.2-1 shows sample 
sizes for various scenarios for the Arm 2 and Arm 3 comparison. 
 
Table 10.4.1.2-1: Group A (non-responder) Comparison between Arms 2 and 3 
with Two-sided Type I Error of 2.5% after Bonferroni Correction 
ENGERIX-B 
Seroprotection 
Response 
(Arm 3) 
HEPLISAV-B 
Seroprotection 
Response 
(Arm 2) 
Difference 
(Arm 2 minus 
Arm 3) 
Targeted 
Sample 
Size per 
Arm 
0.65 
0.80 
0.85 
0.15 
0.20 
N=168 
N=88 
0.70 
0.85 
0.90 
0.15 
0.20 
N=147 
N=75 
0.75 
0.85 
0.90 
0.95 
0.10 
0.15 
0.20 
N=303 
N=121 
N=60 
 
Formal interim efficacy analyses are planned for the Arm 2 and Arm 3 
comparison, should the study enrollment allow such interim analyses 
to be useful to affect the conduct of the study. Assuming no more than 
three interim analyses for the study and applying the O’Brien and 
Fleming approach to preserve the two-sided type I error rate at 2.5%, 
Arm 2 and Arm 3 sample sizes should be at least 149 per study arm. 
Assuming no more than about 10% loss in the SPR data within each 
study arm, the targeted study sample size is 166 each for Arm 2 and 
Arm 3 to retain 80% power. To maintain 1:1:1 randomization across 
Arms 1, 2, and 3 throughout enrollment, the sample size in Arm 2 is 
increased to 187. Therefore, the power for the comparison between 
Arm 2 and Arm 3 is higher than 80%. 
 
10.4.2 Group B (Naïve to HBV vaccination, N=73) 
 
Group B consists of individuals who have no known prior history of HBV 
vaccination. The study is powered to conclude that the proportion achieving SPR 
is greater than 55%. Assuming a response proportion of 75%, a sample size of 
65 would provide at least 90% power in a two-sided test using normal 
approximation at a targeted significance level of 5%. Assuming at most 10% 
missing data, including loss to follow-up prior to the primary outcome visit, the 
study sample size is increased to 73. Table 10.4.2-1 below shows sample sizes 
for various responses, where the null rate for response is 55%. 
 
Table 10.4.2-1: Group B (Naïve to HBV Vaccination) 
HEPLISAV-B 
Difference 
Targeted Sample Size  
Total Sample Size 

 
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Seroprotection 
from Null 
(Includes 10% LFU) 
0.70 
0.15 
N=113 
N=126 
0.75 
0.20 
N=65 
N=73 
0.80 
0.25 
N=44 
N=49 
 
The table below shows two-sided 95% confidence intervals for the various 
potential sample SPR proportions, using the Wilson method and the targeted 
analysis sample size of 65. 
 
Table 10.4.2-2: Group B Confidence Intervals 
Sample SPR proportion  
95% CI 
67.7% (44/65) 
(55.6%, 77.8%) 
70.8% (46/65) 
(58.8%, 80.4%) 
73.8% (48/65) 
(62.0%, 83.0%) 
76.9% (50/65) 
(65.4%, 85.5%) 
80.0% (52/65) 
(68.7%, 87.9%) 
 
Accrual of about six participants per month on the average is anticipated. 
Complete enrollment in about 12 months in Group B is anticipated. 
 
10.5 
Data and Safety Monitoring  
 
10.5.1 Interim Monitoring Guidelines 
 
The study will be monitored by the core protocol team and the independent 
DAIDS-appointed DSMB. The initial interim data review by the DSMB will occur 
no later than one year after the enrollment of the first participant in the study in 
either Group A or B. 
 
10.5.1.1 
Group A 
 
(1) Primary Outcome Analysis Comparison Between Arms 1 and 3 
 
Regarding the first primary objective in Group A, early interim 
efficacy analysis to conclude non-inferiority of Arm 1 compared to 
the control, Arm 3, will not occur. Long-term antibody results are 
also needed to guide the recommendation of the two-dose 
HEPLISAV-B vaccine series. 
 
Early stopping due to concerns on poor vaccine responses in Arm 
1 that may be deemed harmful may occur. For this purpose, the 
SPR estimates for the primary outcome measure will be provided 
with a two-sided 99.9% confidence interval around the difference 
in the proportion estimates (Arm 3 minus Arm 1). As a guideline, 
a lower bound of this confidence interval above 10% may be 
considered evidence towards poor response in Arm 1 that 

 
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suggests potential harm. 
 
The DSMB will review the interim data and make 
recommendations. If the decision is made that Arm 1 should 
close early, the sample size of its comparator, Arm 3, may be 
adjusted as determined by the need for the second primary 
objective (comparison between Arm 2 and Arm 3). 
 
(2) Primary Outcome Analysis Comparison Between Arms 2 and 3 
 
Formal efficacy interim analyses are planned for the second 
primary objective on the comparison between Arm 2 and Arm 3 
(control arm), should the study enrollment allow such interim 
analyses to be useful to affect the conduct of the study. The 
initial interim efficacy analysis on the primary outcome for this 
comparison is aimed at when at least 40% of the SPR results at 
4 weeks after the vaccination series are available for analysis. 
The Lan-DeMets spending function for type I error (alpha) with 
O’Brien-Fleming type boundaries will be employed. With this 
approach, two-sided type I error rate for efficacy at the 0.025 
level will be preserved regardless of the number and timing of 
the analysis. If the confidence interval at the interim look lies 
entirely above zero and the interim data review identifies no 
concerns, early stopping of Arm 2 to conclude Arm 2 superiority 
may occur. 
 
Early stopping due to concerns about poor vaccine responses in 
Arm 2 may also occur. For this purpose, the SPR estimates for 
the primary outcome measure will be provided with a two-sided 
99.9% confidence interval around the difference in the proportion 
estimates (Arm 3 minus Arm 2), similar to the assessment of 
potential harm in Arm 1 discussed above. As a guideline, a lower 
bound of this confidence interval above 10% may be considered 
as evidence towards poor response in Arm 2 to suggest potential 
harm. 
 
The DSMB will review the interim data and make recommendations. 
The DSMB will weigh the benefits of closing early against the 
benefits of continuing the study to accumulate additional safety data 
in this study population. If the decision is made that Arm 2 should 
close early, the sample size of its comparator, Arm 3, may be 
adjusted as determined by the need for the first primary objective 
(comparison between Arm 1 and Arm 3). 
 
10.5.1.2 
Group B 
 
An interim efficacy analysis to conclude early that the estimated 

 
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single-arm SPR proportion at 4 weeks after the vaccination series 
exceeds the null proportion (55%) will not be conducted.  
Establishing a good precision around the SPR estimate and 
collecting safety information on a reasonable number of study 
participants living with HIV without prior HBV vaccination are 
important in Group B. 
 
Early stopping due to concerns about poor vaccine responses 
may occur. If the study enrollment allows interim analysis on the 
SPR proportion to be useful to affect the conduct of the study, a 
two-sided 99.9% confidence interval may be provided with the 
proportion estimate, and the interval upperbound below 45% 
(10% lower than the null proportion) may be used as guidance. 
 
10.5.2 Analysis Plan  
 
For the interim analyses, Newcombe confidence intervals on SPR differences 
from control (Arm 3) will be provided for comparisons in Group A. For the SPR 
comparisons with Arm 3 in the assessment of potential harm in continuing Arm 1 
or Arm 2, two-sided 99.9% confidence intervals will be provided. For the efficacy 
assessments for the comparison between Arms 2 and 3, repeated confidence 
interval approach using a Lan-DeMets alpha spending function with O’Brien-
Fleming-type boundaries for the efficacy interim looks is planned.  
 
A Wilson confidence interval around SPR estimate will be provided for Group B, 
if the timing of the review warrants such look. If so, a two-sided 95% confidence 
interval will be provided. If an interim look occurs, no adjustment will be made to 
the type I error (alpha) for the final analysis, since Group B consists of a small, 
single-arm study to provide information on the SPR estimate with a reasonable 
precision. 
 
10.6 
Analyses 
 
All study analyses will be conducted separately in Groups A and B, unless otherwise 
noted. A detailed SAP will be developed before clinical trial initiation. The following 
provides a brief description of analyses that address the primary and secondary 
objectives. All available data on participants who initiated the vaccination series will be 
analyzed. 
 
10.6.1 Group A 
 
Primary Outcome Analyses on Vaccine Response 
For each of the two primary objectives on vaccine response, the primary 
outcome on the SPR at 8 weeks after the two-dose vaccination series (Arm 1, 
week 12) and at 4 weeks after the three-dose vaccination series (Arms 2 and 3, 
week 28) will be analyzed as a binary variable. To preserve the overall type I 
error rate at 5%, a Bonferroni correction will be applied for two comparisons. 

 
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A two-sided 97.5% confidence interval will be provided for the estimated 
proportion difference between Arm 1 and Arm 3 (Arm 3 minus Arm 1). If an 
interim look with a 99.9% confidence interval occurs to assess potential harm, 
the alpha level for the final analysis will not be adjusted, since 0.1% alpha 
spending in the interim look would have minimal effect on the final confidence 
interval. A score-based approach similar to the Wilson method for proportion 
differences (known as Newcombe method) will be used to estimate a stratified 
confidence interval. If the resulting confidence interval lies entirely below the non-
inferiority margin of 10%, then non-inferiority of Arm 1 compared to Arm 3 
(control) will be concluded. 
 
Superiority of Arm 1 compared to Arm 3 will be concluded if the confidence 
interval lies entirely below zero.  
 
For the comparison between Arm 2 and Arm 3, a two-sided 97.5% stratified 
confidence interval will be provided for the estimated proportion difference 
between Arm 2 and Arm 3 (Arm 2 minus Arm 3). A score-based method of 
Newcombe will be used, accounting for stratified randomization. A repeated 
confidence interval approach using a Lan-DeMets alpha spending function 
with an O’Brien-Fleming approach that accounts for the repeated analyses due 
to interim monitoring will be provided. If the resulting confidence interval lies 
entirely above zero, then superiority of Arm 2 compared to Arm 3 (control) will be 
concluded. 
 
For both comparisons, additional analyses may be conducted where missing 
SPR is imputed if both antibody results immediately prior to and after the missed 
visit are <10 mIU/mL, or if both are ≥10 mIU/mL. 
 
Primary Analysis on Safety 
To address the study objectives on safety, the proportion of participants with AEs 
will be summarized with a two-sided 95% confidence interval in each study arm 
using the Wilson method. The outcome in 10.2.1.2 will be used, and the worst 
graded event per participant over time will be used. In addition, proportion 
estimates at the end of study will be calculated using the Kaplan-Meier method 
with Greenwood’s formula for the variance. Descriptive summaries of events and 
the number of participants experiencing the events will be provided by grade. All 
diagnoses reported as AEs will be described. The confidence intervals on AEs  
will be provided without adjustment for stratification factors. They will also be 
provided by sex, if there are sufficient numbers of events where such estimation 
is meaningful. 
 
Secondary Outcome Analyses 
The following secondary analyses on SPR will be conducted using a two-sided 
type I error rate of 2.5% without further correction for multiple analyses. This type 
I error was chosen to provide confidence intervals of widths comparable to the 
primary outcome analyses. 

 
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The SPR at additional study weeks will be analyzed as a binary variable. The 
SPR proportion will be estimated for each analysis group (study arm or combined 
study arms). A two-sided 97.5% confidence interval around the difference in 
proportions will be calculated using a score-based approach similar to the Wilson 
method (known as Newcombe method). These will also be stratified confidence 
intervals, similar to the primary analysis approach. The secondary objectives on 
the SPR comparisons will be addressed using this analysis approach. 
 
For the secondary objectives on the analysis of the antibody titer as a continuous 
measure, a two-sided type I error rate of 5% without correction for multiple 
analyses will be used. The geometric mean titer will be calculated for each 
analysis group (study arm or combined study arms) and compared using a t-test. 
A two-sided 95% confidence interval around the difference in the geometric 
means will be calculated assuming t-distribution of log10-transformed antibody 
titer. The confidence intervals will be provided across stratification factors and 
within stratum. 
 
To address the study objective on post-injection AEs, the proportion of 
participants with events will be summarized with a two-sided 95% confidence 
interval in each study arm using the Wilson method. For these analyses, the 
worst graded event per participant over the specified time after each injection will 
be used. In addition, descriptive tables summarizing the events and the number 
of participants experiencing the events will be provided. The confidence intervals 
on the post-injection events will be provided across stratification factors.  
 
Furthermore, descriptive summaries will be provided on the participants who 
discontinue the vaccination series early, categorized by the reasons for 
discontinuation. Similar summaries will be provided on the participants who 
discontinue the study early. 
 
While the study has not been powered for testing the sex or race effect on the 
success of HEPLISAV-B vaccination using the primary outcome, logistic 
regression models that include sex and race will be analyzed and reported as 
secondary analyses. Logistic regression models will also be used to assess other 
demographic or baseline clinical characteristics associated with vaccine 
response. 
 
10.6.2 Group B 
 
Primary Outcome Analysis on Vaccine Response 
The primary outcome on the SPR at 4 weeks after the vaccination series will be 
assessed by estimating the proportion of participants who achieve SPR. A two-
sided 95% confidence interval around the observed SPR proportion will be 
provided using the Wilson score method for binomial variables. If the confidence 
interval lies above 55%, then it will be concluded that the SPR proportion is  

 
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greater than 55%. If an interim look occurs, no adjustment will be made to the 
type I error (alpha) for the final analysis. Group B consists of a small, single-arm 
study to provide information on the SPR estimate with a reasonable precision. 
 
Primary Analysis on Safety 
To address the objective on safety, the proportion of participants with AEs will be 
summarized with a two-sided 95% confidence interval using the Wilson method. 
For Objective 1.2.4, the outcome described in 10.2.1.4 will be used. For the 
analysis, the worst graded event per participant over time will be used. In 
addition, descriptive tables summarizing the events and the number of 
participants experiencing the events will be provided by grade. Diagnoses 
reported as AEs will be described. 
 
Secondary Outcome Analyses 
Each secondary analysis will be conducted using a two-sided type I error rate of 
5% without correction for multiple analyses. 
 
The SPR at additional study weeks will be analyzed as a binary variable. A two-
sided 95% confidence interval around the observed SPR proportion will be 
provided using the Wilson score method for binomial variables.  
 
To address objectives related to antibody titer as a continuous measure, the 
geometric mean titers will be calculated with two-sided 95% confidence intervals, 
assuming t-distribution of log10-transformed antibody titer.  
 
To address the study objective on post-injection AEs, the proportion of 
participants with events will be summarized with a two-sided 95% confidence 
interval using the Wilson method. For the analysis, the worst graded event per 
participant over the specified time will be used. In addition, descriptive tables 
summarizing the events and the number of participants experiencing the events 
will be provided. Diagnoses reported as AEs will be described. 
 
Furthermore, descriptive summaries will be provided on the participants who 
discontinue the vaccination series early, categorized by the reasons for 
discontinuation. Similar summaries will be provided on the participants who 
discontinue the study early. 
 
While the study has not been powered for testing the sex or race effect on the 
success of HEPLISAV-B vaccination using the primary outcome, the proportions 
of subgroups defined by sex and race who achieve the primary outcome will be 
estimated with confidence intervals and reported as secondary analyses. 
 
11.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 

 
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12.0 
DATA COLLECTION AND MONITORING  
 
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon randomization/registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to ensure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for this 
purpose by NIAID. Remote monitoring visits may be performed in place of, or in 
addition to onsite visits to ensure the safety of study participants and data 
integrity [45]. The site must make available study documents for site monitors to 
review utilizing a secure platform that is HIPAA and 21 CFR Part 11 compliant. The 
Data Management Center will configure Medidata Remote Source Review (RSR) 
and make it available to all sites. We encourage Sites to use the DMC provided 
Medidata RSR platform but other potential platform options include: Veeva 
SiteVault, site-controlled SharePoint or cloud-based portal, and direct access to 
Electronic Medical Record (EMR). Other secure platforms that are 21 CFR Part 11 
compliant may be utilized, as allowed by the DAIDS Office of Clinical Site 
Oversight (OCSO). 
  
12.4 
Reporting Protocol Deviations 
 
The site principal investigator and staff are responsible for identifying and 
reporting deviations. If protocol deviations are identified, corrective actions are to 
be developed by the site and implemented promptly. Protocol deviations must be 
reported to the IRB/EC per their guidelines. 
 
Refer to the MOPS for the definition of protocol deviation and instructions for 
completing the study protocol deviation eCRF.  
 

 
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13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Appendices I and II) and any 
subsequent modifications will be reviewed and approved by the IRB or EC responsible 
for oversight of the study. The informed consent will be obtained from the participant and 
documented as per the site’s Informed Consent Process SOP. A signed consent form 
will be obtained from the participant (or legal guardian, or person with power of attorney 
for participants who cannot consent for themselves). The consent form will describe the 
purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the participant or legal guardian, 
and this fact will be documented in the participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties, or the 
industry supporter or designee.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other government agencies as part of their duties to ensure that research participants 
are protected, or the industry supporter. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission.  
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 

 
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All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  

 
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16.0 
REFERENCES 
 
1. 
Sun HY, Sheng WH, Tsai MS, Lee KY, Chang SY, Hung CC. Hepatitis B virus 
coinfection in human immunodeficiency virus-infected patients: a review. World J 
Gastroenterol 2014;20:14598-614. 
2. 
Mena G, Garcia-Basteiro AL, Bayas JM. Hepatitis B and A vaccination in HIV-infected 
adults: a review. Hum Vaccin Immunother 2015;11:2582-98. 
3. 
Launay O, van der Vliet D, Rosenberg AR, et al. Safety and immunogenicity of 4 
intramuscular double doses and 4 intradermal low doses vs standard hepatitis B 
vaccine regimen in adults with HIV-1: a randomized controlled trial. JAMA 
2011;305:1432-40. 
4. 
Launay O, Rosenberg AR, Rey D, et al. Long-term immune response to hepatitis B 
virus vaccination regimens in adults with human immunodeficiency virus 1: secondary 
analysis of a randomized clinical trial. JAMA Intern Med 2016;176:603-10. 
5. 
Irungu E, Mugo N, Ngure K, et al. Immune response to hepatitis B virus vaccination 
among HIV-1 infected and uninfected adults in Kenya. J Infect Dis 2013;207:402-10. 
6. 
Pettit NN, DePestel DD, Malani PN, Riddell J 4th. Factors associated with 
seroconversion after standard dose hepatitis B vaccination and high-dose 
revaccination among HIV-infected patients. HIV Clin Trials 2010;11:332-9. 
7. 
Wood RC, MacDonald KL, White KE, et al. Risk factors for lack of detectable antibody 
following hepatitis B vaccination of Minnesota health care workers. JAMA 
1993;270:2935-9. 
8. 
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 licensed hepatitis B vaccine in patients with chronic kidney 
disease. Vaccine 2013;31:5306-13. 
9. 
Cooper CL, Davis HL, Angel JB, et al. CPG 7909 adjuvant improves hepatitis B virus 
vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 
2005;19:1473-9. 
10. Cooper CL, Angel JB, Seguin I, Davis HL, Cameron DW. CPG 7909 adjuvant plus 
hepatitis B virus vaccination in HIV-infected adults achieves long-term seroprotection 
for up to 5 years. Clin Infect Dis 2008;46:1310-14.  
11. Hyer R, McGuire DK, Xing B, et al. Safety of a two-dose investigational hepatitis B 
vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant in adults. Vaccine 
2018;36:2604-11. 
12. Bruxvoort K, Slezak J, Qian L, et al. Association between 2
-dose vs 3 -dose 
hepatitis B vaccine and acute myocardial infarction.
 JAMA  2022;327:1260-8. 
doi:10.1001/jama.2022.2540  
13. Rey D, Piroth L, Wendling MJ, et al. Safety and immunogenicity of double-dose versus 
standard-dose hepatitis B revaccination in non-responding adults with HIV-1 (ANRS 
HB04 B-BOOST): a multicentre, open-label, randomised controlled trial. Lancet Infect 
Dis 2015;15:1283-91. 

 
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14. Dörner T, Radbruch A. Selecting B cells and plasma cells to memory. J Exp Med 
2005;201:497-9. 
15. FDA. FDA Advisory Committee Briefing Document. HEPLISAV-BTM. Vaccines and 
Related Biological Products Advisory Committee, July 28, 2017. Dynavax Technologies 
Corporation. Accessed at: https://www.fda.gov/media/106639/download. 
16. Winckelmann AA, Munk-Petersen LV, Rasmussen TA, et al. Administration of a Toll-
like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-
infected patients. PLoS One 2013;8:e62074. Print 2013. 
17. Vibholm L, Schleimann MH, Højen JF, et al. Short-course Toll-like receptor 9 agonist 
treatment impacts innate immunity and plasma viremia in individuals with human 
immunodeficiency virus infection. Clin Infect Dis 2017;64:1686-95.  
18. Council for International Organizations of Medical Sciences (CIOMS) and World 
Health Organization (WHO). International Ethical Guidelines for Health-related 
Research Involving Humans. Geneva: Council for International Organizations of 
Medical Sciences (CIOMS), 2016. Retrieved from: https://cioms.ch/wp-
content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf  
19. Freidlin B, Korn EL, Gray R. A general inefficacy interim monitoring rule for 
randomized clinical trials. Clin Trials 2010;7:197-208 
20. Li X, Wang WW, Liu GF, Chan IS. Handling missing data in vaccine clinical trials for 
immunogenicity and safety evaluation. J Biopharm Stat 2011;21:294-310. 
21. FDA Guidance on Conduct of Clinical Trials of Medical Products During the 
COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and 
Institutional Review Boards. March 2020; Updated on August 30, 2021. Accessed 
at: https://www.fda.gov/media/136238/download. 

 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For protocol: 
A5379 B-ENHANCEMENT OF HBV VACCINATION IN PERSONS LIVING WITH HIV (BEe-
HIVe): Evaluation of HEPLISAV-B  
 
FINAL Version 3.0, 13Dec20222 
 
SHORT TITLE FOR THE STUDY: BEe-HIVe 
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to find out whether a hepatitis B vaccine 
called HEPLISAV-B is more effective at preventing hepatitis B infection in 
adults living with HIV than the current standard hepatitis B vaccine called 
ENGERIX-B. Vaccine side effects will also be studied. 
 
STUDY  
TREATMENT 
There will be treatment provided in this study. Participants will receive 
either HEPLISAV-B or ENGERIX-B. Both vaccines are approved by the 
United States Food and Drug Administration (FDA). Each vaccine will be 
given as a shot (injection) in the muscle of your upper arm. Some 
participants in the study will receive two shots of HEPLISAV-B (the dosing 
approved by the FDA), some participants will receive three shots of 
HEPLISAV-B, which is an investigational (experimental) dosing schedule, 
and some participants will receive three shots of ENGERIX-B (the dosing 
approved by the FDA). You will continue taking your anti-HIV medications 
that are prescribed by your doctor while you are in this study. The anti-
HIV medications will not be provided to you in this study. 
 
NUMBER OF  
PARTICIPANTS 
There are two treatment groups of people, for a total of 634 participants. 
 
LENGTH OF  
STUDY  
Participants will be on study for 72 weeks (almost 1.5 years).  
Overall, you may have up to 10 study visits. 
 
REQUIRED  
ACTIVITIES 
Blood collections 
At all visits, some blood will be collected from a vein in your arm.  
• 
At all visits, your blood will be stored. 
 

 
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Special procedures  
• 
At 2 or 3 visits, you will have a vaccine shot. 
• 
You will be contacted by telephone, text message, or e-mail 
throughout the study. 
 
RISKS 
The following are possible: 
• 
Pain, soreness, redness, swelling, and hardening where you had your 
vaccine shot. 
• 
Fainting, fatigue, dizziness, headache, generally not feeling well, 
fever, and muscle pain. 
• 
Allergic reaction including fever, chills, headache, rash, itchy skin, low 
or high blood pressure, or difficulty breathing. 
• 
Risks related to blood draws and social harm. 
 
BENEFITS 
If you take part in this study, there may be a direct benefit to you if you 
respond to either vaccine. It is also possible that you receive no benefit 
from being in this study. 
 
OTHER CHOICES 
Instead of being in this study you have the choice of receiving approved 
HBV vaccine as part of regular care from your doctor or participating in 
and receiving a different experimental HBV vaccine, if you qualify. 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are living with human 
immunodeficiency virus (HIV) (the virus that causes AIDS). This study is sponsored by the 
National Institutes of Health (NIH). The doctor in charge of this study at this site is: (insert name 
of Principal Investigator). Before you decide if you want to be a part of this study, we want you 
to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
This study is looking at hepatitis B virus (HBV) vaccination in adults 18 to 70 years of age living 
with HIV around the world. Hepatitis B is a serious viral infection that affects the liver and is 
transmitted through blood and body fluids. A vaccine (a shot of medicine given through a 
needle) can prevent HBV, but vaccines are not used to cure HBV. 
 
Vaccinating people living with HIV against HBV does not always work in preventing them from 
getting HBV, especially in people with weak immune systems or difficulty fighting infections. 
Prevention of HBV in individuals living with HIV has primarily been done by giving people three 

 
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shots over 6 months. A new vaccine approved by the United States Food and Drug 
Administration (FDA), called HEPLISAV-B, has been shown to provide a better response in 
people who have not responded well to the older HBV vaccines. The purpose of this study is to 
see whether this new vaccine, HEPLISAV-B, will be more effective in adults living with HIV than 
the current standard vaccine, ENGERIX-B also approved by the FDA. Some participants in the 
study will receive two shots of the HEPLISAV-B vaccine (the dosing approved by the FDA), 
some participants will receive three shots of the HEPLISAV-B vaccine (an (investigational 
[experimental] dosing schedule), and some participants will receive three shots of ENGERIX-B 
(the dosing approved by the FDA). Vaccine adverse reactions (side effects) will also be studied. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
There are two groups of individuals in this study. One group will include individuals who have 
received a previous HBV vaccination but did not respond well to the vaccine (Group A). The 
other group will include individuals who have never received a HBV vaccination (Group B). If 
you are in Group A, you have an equal chance of receiving either two shots of HEPLISAV-B, 
three shots of HEPLISAV-B, or three shots of ENGERIX-B (current standard HBV vaccine). You 
will not be able to choose which of these three options you will receive during this study; 
however, you and the study staff will know which vaccine dose you are receiving. If you are in 
Group B, you will receive three shots of HEPLISAV-B. Each vaccine will be given as a shot 
(injection) in the muscle of your upper arm. You will continue taking your anti-HIV medications 
that are prescribed by your doctor while you are in this study. The anti-HIV medications will not 
be provided to you in this study. 
 
Screening 
If you would like to be in this study, after you have read and signed this informed consent form, 
you will come to the clinic for a screening visit to make sure you meet the requirements for 
joining the study. This visit will take about 1 hour. At this visit: 
• 
Your HIV status will be confirmed. 
• 
You will be asked questions about your medical history and any medications you are taking 
or have taken in the past. 
• 
You will have a complete physical exam, including vital signs (temperature, pulse, 
respiration rate, and blood pressure). 
• 
You may be tested to see if you have HBV. 
• 
You may have approximately 42 mL (about 3 tablespoons) of blood collected (refer to 
Attachment A for more details). 
• 
You will decide if you want to participate in an optional visit that will occur within 16-28 hours 
after your first vaccine shot. [For non-US sites: remove] 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG study. As 
part of your screening visit, some demographic (for example, age, gender, race), clinical (for 
example, disease condition, diagnosis), and laboratory (for example, CD4+ cell count, viral load) 
information will be collected from you. We also collect information on whether you use (or have 
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We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may help determine whether there are patterns and/or 
common reasons why people do not join a study. 
 
Entry  
If you are eligible for the study and still interested in participating, you will come in for the entry 
visit. This visit will take about 1.5 hours. At this visit: 
• 
You will be asked questions about your medical history and any medications you are taking 
or have taken in the past. 
• 
You will have a brief physical exam. 
• 
You may have approximately 135 mL (about 9 tablespoons) of blood collected (refer to 
Attachment A for more details). 
• 
Your blood will be stored for testing at the end of the study. 
• 
If you are able to get pregnant, some of your blood or urine will be collected to test for 
pregnancy. If the pregnancy test is positive, you will not proceed with entry into the study 
and not receive the vaccine. 
• 
You will either receive one shot of HEPLISAV-B or ENGERIX-B. 
• 
You will take home a diary card. 
 
Optional visit after your first vaccine shot [For non-US sites: remove this visit] 
This visit will only be for some participants in Group A, and is optional. After your first vaccine 
shot, you may come back within 16-28 hours for another visit the next morning. This visit will 
take about 30 minutes. At this visit: 
• 
You will have approximately 105 mL (7 tablespoons) of blood collected (refer to Attachment A 
for more details). 
 
Other Study Visits 
You will be asked to come in up to 8 more times throughout the study. These visits will last 
about 1 hour. At most of these visits: 
• 
You will have a brief physical exam. 
• 
You will have as little as 5 mL (about 1 teaspoon) to as much as 132 mL (9 tablespoons) of 
blood collected at any one visit (refer to Attachment A for more details). 
• 
If you are able to become pregnant, you will have a pregnancy test and the result must be 
negative within 2 days prior to receiving a study vaccine dose. You will also have a 
pregnancy test at your last study visit. Options about staying on the study if you become 
pregnant are explained elsewhere in the consent. 
• 
Your blood will be stored for testing at the end of the study. Some participants in Group A 
will have extra blood stored. 
• 
If you are receiving three shots of HEPLISAV-B, you will receive one shot at two of these 
visits. 
• 
If you are receiving three shots of ENGERIX-B, you will receive one shot at two of these 
visits. 
• 
If you are receiving two shots of HEPLISAV-B, you will receive one shot at one of these 
visits.  

 
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• 
Site staff will remind you that it is important that you receive all the shots. It will improve your 
chance of responding to the vaccine.  
• 
At the visits when you receive the vaccination, you will be given a diary card. 
• 
You will bring the diary card back to the clinic at the visit after the vaccination. 
• 
You will be contacted by the study staff a few times between visits. 
 
Remote Data Collection 
Sometimes the study staff may need to conduct a scheduled visit with you remotely (for 
example, by telephone, or via telehealth). This could happen for any of the reasons listed 
below: 
• 
You are not able to attend a visit in person (for example, because you are not feeling 
well or you are in lockdown or quarantine). 
• 
The site is temporarily unable to conduct non-essential visits in the clinic (for example, 
because of a problem at the facility or because of a public health emergency). 
 
Regardless of the reason, the study staff will attempt to contact you and obtain as much 
of the required information from you as is possible. Further, the in-person visit will be 
rescheduled.  
 
Details of how often the study visits will occur and information about the procedures are 
explained in Attachment A, as part of this consent. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood will be stored and used for study-required (immunologic, virologic, and 
standard genetic) testing.  
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you. If you are enrolling in this study at 
a site outside the US, you must know that biologic samples collected from you may be shipped 
and stored outside of the country from which they are collected. 
 
The testing described above (immunologic, virologic, and genetic) is required by this study. If you 
do not agree to the storage or testing that has been described above, you cannot join this study.  
  
Please refer to Attachment B to consent for use of your samples in other studies. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 634 people will take part in this study. 
 
 

 
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HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 72 weeks (almost 1.5 years).  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled  
• 
A Data and Safety Monitoring Board (DSMB) recommends that the study be stopped early 
(A DSMB is an outside group of experts who monitor the study.) 
• 
You are not able to start the study vaccine 
 
The study doctor may also need to take you off the vaccination series without your permission if: 
• 
You have an allergic reaction or other severe reaction to either of the study vaccines 
• 
You have a new or worsened immune-mediated adverse event. These may include 
conditions such as gastrointestinal, liver, metabolic, musculoskeletal, neuroinflammatory, 
and skin disorders and vasculitides. Study staff can tell you about these. 
• 
You need a treatment that you may not take while getting the vaccine you have been 
assigned to take. 
• 
If you miss the 2nd dose in the allowed timeframe for a two-dose series. 
• 
If you miss the 3rd dose in the allowed timeframe for a three-dose series. 
 
If you must stop the study vaccine before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
If I have to permanently stop the study-provided vaccine before completing/receiving all doses, 
or once I leave the study, how would the vaccine be provided? 
During the study: 
 
If you must permanently stop the study-provided vaccine before completing/receiving all doses, 
the study staff will discuss other options that may be used to complete your vaccination. 
 
After the study: 
 
If you completed all the vaccine shots, receiving more shots would not be necessary. If you do 
not finish the vaccine series during the study and this would be of benefit to you, the study staff 
will discuss how you may be able to obtain the vaccine. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The vaccines used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these vaccines. These lists include the 
more serious or common side effects with a known or possible relationship. If you have questions 
concerning the additional study vaccine side effects, please ask the medical staff at your site. 

 
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There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study vaccines. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Before it was approved by the FDA, HEPLISAV-B was tested in more than 9500 people. Overall, the 
side effects were similar to the side effects seen with other vaccines. In one study, people who got 
HEPLISAV-B had a heart attack more often than people who got ENGERIX-B. However, the heart 
attacks were rare. After careful review by experts, no relationship between the heart attacks and 
HEPLISAV-B was found. Since FDA approval, Dynavax, the manufacturer of HEPLISAV-B, has been 
conducting a large observational study of 30,000 people who received HEPLISAV-B and 30,000 people 
who received ENGERIX-B to evaluate heart attacks and the theoretical concern that vaccines can 
cause autoimmune disease (a condition in which the immune system mistakenly attacks the body). The 
final study results showed no relationship between heart attacks and HEPLISAV-B. 
 
Vaccine-related Hypersensitivity (allergic reaction) 
Fever 
Chills 
Headache 
Rash 
Itchy skin 
Low or high blood pressure 
Difficulty breathing 
 
Related to Vaccine Injections (shots) 
Injection site pain 
Injection site soreness 
Redness around the injection site 
Injection site hardening/mass 
Injection site swelling 
Fainting  
 
HEPLISAV-B Risks 
Fatigue 
Headache 
Malaise (generally not feeling well) 
Fever 
Muscle pain 
 
ENGERIX-B Risks 
Fatigue 
Dizziness 
Headache 
Fever 
 

 
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Risks of Blood Draws 
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 
enters the body, lightheadedness, and in rare cases, fainting, or infection.  
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV status 
secret from people close to you. This may lead to unwelcome discussions about or reactions to 
your HIV status. Please talk with the study staff if you have any concerns about this. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
At this time there are no studies done in humans that show that HEPLISAV-B is safe for unborn 
babies; information gathered on people who received the vaccine whilst pregnant is not enough 
to figure out if it is safe for the unborn babies. Studies done in animals have not shown any such 
harms. If you are having sex that could lead to pregnancy, you must take precautions to not 
become pregnant. 
 
If you can become pregnant, you and your partner must use reliable birth control that you can 
discuss with the study staff. At least one of the following methods MUST be used for the 
duration of the study: 
• 
Condoms (male or female) with or without a spermicide  
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
 
If you can become pregnant, you must have a pregnancy test before you enter this study and a 
few times during the study. These tests must show that you are not pregnant. If you think you 
may be pregnant at any other time during the study, tell your study staff right away. The study 
staff will talk to you about your choices. 
 
It is not known if HEPLISAV-B or ENGERIX-B, pass through breast milk. Therefore, 
breastfeeding individuals will not be enrolled in this study.  
 
 
WHAT IF I BECOME PREGNANT DURING THE STUDY? 
 
If you become pregnant during the study, you will have the option to stay in the study and either 
continue the vaccination series or not continue. Before you decide what you want to do, the study 
staff will counsel you about your options and the risks involved. You will need to complete a 
separate Pregnancy Consent Form to stay in the study and continue with the vaccination series.  
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study). If you are 
taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to an 
international database that collects information about pregnancies in people taking anti-HIV 

 
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drugs. This report will not use your name or other information that could be used to identify you.  
 
You may volunteer to participate in the HEPLISAV-B pregnancy registry. Information that could 
identify you will be collected in that registry if you choose to enroll. You may call 1-844-443-
7734 to find out more about this registry. [For non-US sites: remove information about 
HEPLISAV-B pregnancy registry] 
 
For individuals who can become pregnant: 
 
____ (initials) I agree for my information to be included in the HEPLISAV-B pregnancy registry if 
I become pregnant. [For non-US sites: remove] 
 
OR 
____ (initials) I do not want to be included in the HEPLISAV-B pregnancy registry if I become 
pregnant. [For non-US sites: remove] 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you if you respond to the vaccine. 
This means you will be protected from getting HBV, but no guarantee can be made. It is also 
possible that you may receive no benefit from being in this study. Information learned from this 
study may help others who have HIV and HBV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
Receiving approved HBV vaccine as part of regular care from your doctor 
• 
Participating in and receiving a different experimental HBV vaccine, if you qualify 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, this research is covered by a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your participation. Also, any publication of this study will not use your name or identify you 
personally.  
 

 
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Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site), institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. The Certificate of Confidentiality does not prevent you from releasing information 
about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.  
 
For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. In 
addition to the efforts of the study staff to help keep your personal information private, this 
research is covered by a Certificate of Confidentiality from the US Federal Government. The 
Certificate of Confidentiality may not provide protections for your data in your country. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site), institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees. The Certificate of Confidentiality does not prevent you from 
releasing information about yourself and your participation in the study. Even with the Certificate 
of Confidentiality, if the study staff learns of possible child abuse and/or neglect or a risk of harm 
to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on https://ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
 
All information collected about you as part of the study will be sent securely to the ACTG 
statistical and data management center in the United States for combining with 
information from other study participants and statistical analysis of study results. Your 
name and other personal identifiers will not be sent. Your research site is responsible for 
sending your information in accordance with the laws, regulations, and policies of your 
country and research site. 
 
 

 
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WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study. The study vaccine will be provided at no cost during this study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Insert site-specific information on compensation to study participants.] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries.  
 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry Clinical Trials Insurance (CTI), this must be indicated in 
the informed consent.] Please note that, for all sites (not as part of an either/or statement 
with CTI), the NIH does not have a mechanism to provide direct compensation for 
research-related injury.  
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study. 
OR  
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH, regardless of whether 
CTI is available.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. At the end of the study, you will be told when study 
results may be available and how to learn about them. Individual results related to your safety 
and significant clinical findings requiring medical attention and follow up will be provided to you 
and your treating medical provider. 
 
If you do not have the capacity to consent, your legally authorized representative may consent 
on your behalf. During the course of the study, if you become able to consent, informed consent 

 
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will be obtained from you. At that time you can decide whether you want to stay in the study or 
not.  
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Number of above 
 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
__________________________________ 
Participant’s Legally Authorized 
Legally Authorized Representative 
Representative (print) 
Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 

 
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ATTACHMENT A: STUDY VISITS AND PROCEDURES 
 
Section A: Study Visits 
 
Table 1: Expected Study Visit Schedule for Participants Receiving Three Shots of a Vaccine 
Procedure 
Screening 
Entry 
On-study (visit weeks) 
End Study 
Early 
1st visit after 1st 
vaccine shot* 
4 
8 
12 
24 
28 
32 
48 
72 
HIV confirmed 
✓ 
 
 
Not applicable 
 
Questions about your 
health and medications you 
are taking 
✓ 
✓ 
 
At all visits 
✓ 
Physical exam 
✓ 
✓ 
 
At all visits 
✓ 
Blood collected 
✓ 
✓ 
✓ 
At all visits 
✓ 
Pregnancy test 
 
✓ 
 
At a few visits 
✓ 
Blood stored 
 
✓ 
✓ 
At all visits 
✓ 
HEPLISAV-B vaccine 
 
✓ 
 
At two study visits 
 
ENGERIX-B vaccine 
 
✓ 
 
At two study visits 
 
Observation after vaccine 
 
✓ 
 
At two visits 
 
Diary card given to you 
 
✓ 
 
At two visits 
 
Bring diary card back to 
clinic 
 
 
 
At a few visits 
 
Telephone, text message, 
or e-mail contact 
 
 
 
Between a few visits 
 
 
*1st visit after 1st vaccine shot is only for some participants and is optional [For non-US sites: remove this visit from the table and this footnote.] 

 
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Table 2: Expected Study Visit Schedule for Participants Receiving Two Shots of a Vaccine 
 
Section B: Explanation of Visit Schedule 
 
Screening: This visit will take place not more than 45 days before you enter the 
study. 
 
Entry: This visit will take place at least 24 hours after your screening visit. 
 
On-study: 
First visit after your first vaccine shot: This visit is optional. You will have blood 
collected and stored. This visit will take place the next day after you receive your 
first vaccine shot. Not all participants will have to do this visit. [For non-US sites: 
remove this visit.] 
 
Next 72 weeks after study entry: you will have up to 10 study visits. You will 
continue to take your anti-HIV medications, which are not provided by the study. 
 
Week 72 visit: This will be your final study visit. 
 
Section C: Explanation of Procedures 
 
Physical exam: You will have a complete physical exam at screening and then only 
a brief physical exam at other visits.  
 
Procedure 
Screening 
Entry 
On-study (visit weeks) 
End Study 
Early 
4 
8 
12 
24 
28 
52 
72 
HIV confirmed 
✓ 
 
Not applicable 
 
Questions about your health and 
medications you are taking 
✓ 
✓ 
At all visits 
✓ 
Physical exam 
✓ 
✓ 
At all visits 
✓ 
Blood collected 
✓ 
✓ 
At all visits 
✓ 
Pregnancy test 
 
✓ 
At a few visits 
✓ 
Blood stored 
 
✓ 
At all visits 
✓ 
HEPLISAV-B vaccine 
 
✓ 
At one visit 
 
Observation after vaccine 
 
✓ 
At one visit 
 
Diary card given to you 
 
✓ 
At one visit 
 
Bring diary card back to clinic 
 
 
At a few visits 
 
Telephone, text message, or e-mail 
contact 
 
 
Between a few visits 
 

 
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Blood collected: Blood will be collected from a vein in your arm at all visits for 
research tests that may include liver function tests, your HIV viral load (a measure of 
the amount of HIV in your blood), your CD4+ T-cell count (a measure of the strength 
of your immune system, the system that helps your body fight infections), HBsAb (a 
measure of how much HBV antibodies are in your body), and standard genetic 
testing. You will also have your blood stored at most visits. Some participants in 
Group A will have extra blood stored. 
 
Pregnancy test: If you are able to become pregnant, you will have a pregnancy test, 
using either a blood sample or a urine sample. A pregnancy test will be done a few 
times throughout the study and any time you think you may be pregnant. 
 
HEPLISAV-B or ENGERIX-B vaccination: You will have either three shots total of 
HEPLISAV-B or ENGERIX-B at three different time points (when you enter the study 
and 4 and 24 weeks after) or two shots total of HEPLISAV-B at two different time 
points (when you enter the study and 4 weeks after). Each vaccine will be given as 
a shot in the muscle of your upper arm. During these visits, you will be observed for 
30 minutes after the shot in case you have a reaction to the shot. Your temperature 
will be measured. 
 
Diary card: You will be provided with a diary card, a ruler, and a thermometer at the 
visits you receive the vaccination. You will take the diary card home. For 7 days 
after you receive the vaccination, you will record any reactions you had to the 
vaccine (pain, redness, or swelling near where you had the shot, not feeling well, 
headache, body aches, and feeling tired). You will also measure and record your 
temperature in the evenings. You will be asked to bring the diary card back to the 
clinic at your next visit.  
 
Telephone, e-mail, or text message contact: You will be contacted by telephone, 
text message, or e-mail to remind you to complete the diary card and to bring it to 
your next study visit. 
 
 

 
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ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
 
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples.” The 
ACTG will only allow your extra samples to be used in other studies if you agree to this. If you 
have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository located in the United States. 
 
There is no limit on how long your extra samples will be stored. [Site: Revise the previous 
sentence to insert limits if your regulatory authority imposes them.] 
 
When a researcher wants to use your samples and information, his or her research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review the plan. [Site: If review by your institution’s IRB/EC/RE is also 
required, insert a sentence stating this.] IRBs/ECs protect the rights and well-being of people in 
research. If the research plan is approved, the ACTG will send your samples to the researcher’s 
location. This means that researchers who are not part of the protocol team may use your 
samples without asking you again for your consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific discovery or 
product based on the use of your samples. If this happens, there is no plan to share any money 
with you. The researcher is not likely to ever know who you are. 
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the staff any questions that you have before you indicate your selection. 
 
Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) and used 
for ACTG-approved HIV-related research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples.  
 
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my samples. 
 
 

 
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Research with Human Genetic Testing  
The ACTG has two different studies that collect samples for genetic testing. 
 
If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed Consent to 
Use Stored Human Biological Materials (HBM) for Currently Unspecified Analyses. 
 
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like to participate in one of these studies if it is being done 
where you live. If you would like to participate, you will sign a separate consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign and date 
a consent form for A5128 or A5243. 
 
 
 
 

 
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APPENDIX II: SAMPLE INFORMED CONSENT FOR PARTICIPANTS WHO BECOME 
PREGNANT WHILE ON STUDY 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
 
For protocol: 
A5379 B-ENHANCEMENT OF HBV VACCINATION IN PERSONS LIVING WITH HIV (BEe-
HIVe): Evaluation of HEPLISAV-B  
 
FINAL Version 3.0, 13Dec20222 
 
 
SHORT TITLE FOR THE STUDY: BEe-HIVe 
 
SUMMARY 
 
PURPOSE 
Because you are pregnant, you are being asked if you want to continue to 
take part in this research study.  
 
STUDY  
TREATMENT 
Treatment required is the same as the treatment stated in the main study 
A5379/BEe-HIVe consent form. 
 
NUMBER OF  
PARTICIPANTS 
There are two treatment groups of people, for a total of 634 participants. 
 
LENGTH OF  
STUDY 
Participants will be on study for 72 weeks (almost 1½ years). 
 
You will continue to have study visits and tests as stated in the main 
study A5379/BEe-HIVe consent form. 
 
REQUIRED  
ACTIVITIES 
The activities required are the same as the ones stated in the main study 
A5379/BEe-HIVe consent form.  
 
 
RISKS  
 
The following risks are possible: 
• 
Your body could respond differently to vaccines since you are 
pregnant. 
• 
There is no information on whether HEPLISAV-B poses a risk of harm 
to people who are pregnant or their unborn children. Animal studies 
suggest no such risk, but the results may not apply to humans.  

 
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• 
ENGERIX-B has been widely used in pregnancy, and the available 
information does not suggest that it poses a risk of harm to people 
who are pregnant or their unborn children. 
 
 
BENEFITS 
Continuing in the study and finishing your vaccination series may improve 
your chances of responding to the vaccine. This may be of benefit to you 
and your baby, but no guarantee can be made. 
 
 
OTHER CHOICES 
Instead of being in this study, you have the choice of discontinuing the 
vaccination series. 
 
 
INTRODUCTION 
 
Because you are now pregnant, you are being asked if you want to continue taking part in this 
research study. This study was designed so that people who were pregnant could not join the 
study. However, because you were already in the study when you became pregnant, you will be 
allowed to stay in the study whether you choose to continue the study vaccination during your 
pregnancy or not. 
 
This is a consent form. It gives you more information about this study and how it may affect your 
pregnancy and your baby. The study staff will talk with you about this information. You are free 
to ask questions about this study at any time. You may also talk with your own doctor about 
what is best for you and your baby. If you agree to stay in this study, you will be asked to sign 
this consent form. You will get a copy to keep.  
 
 
WHAT DO I HAVE TO DO IF I STAY IN THIS STUDY? 
 
If you choose to stay in this study, you will continue to have study visits and tests as stated in 
the main study A5379/BEe-HIVe consent form. 
 
You have the option to continue the study vaccine series (either HEPLISAV-B or ENGERIX-B). 
 
Care related to your pregnancy, the delivery of your baby, or the care of your baby will not be 
provided by this study. You must arrange for your care and your baby's care outside of this 
study. 
 
Long-term follow-up is recommended for a baby whose mother takes anti-HIV drugs during 
pregnancy. The study staff will talk with you about long-term follow-up and the possibility of 
enrolling your baby in a long-term follow-up study. 
 
 

 
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WHAT ARE THE RISKS RELATED TO STAYING IN THE STUDY? 
 
Now that you are pregnant, there are some possible risks you should know. These possible 
risks to you and your unborn baby are in addition to the risks that are described in the 
A5379/BEe-HIVe study consent you already signed. 
 
Risks to You and Your Unborn Baby if Staying on HEPLISAV-B or ENGERIX-B 
Your body could respond differently to vaccines since you are pregnant. 
 
HEPLISAV-B 
There is no information on whether HEPLISAV-B poses a risk of harm to people who are 
pregnant or their unborn children. Animal studies suggest no such risk, but the results may not 
apply to humans.  
 
ENGERIX-B  
ENGERIX-B has been widely used in pregnancy, and the available information does not 
suggest that it poses a risk of harm to people who are pregnant or their unborn children.  
 
 
ARE THERE BENEFITS TO STAYING IN THIS STUDY? 
 
If you continue to take part in this study, there may be a benefit to you and your baby, but no 
guarantee can be made. If you respond to the vaccine and become protected from infection with 
HBV, you can pass some of this protection to your baby until he or she builds up his or her own 
immunity. It is also possible that you and your baby will receive no benefit from continuing in this 
study. Information learned from this study may help others living with HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES STAYING ON THE VACCINATION SERIES? 
 
Instead of staying on the vaccination series, you have the choice of discontinuing the 
vaccination series. 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, this research is covered by a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your participation. Also, any publication of this study will not use your name or identify you 
personally.  
 

 
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Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties [insert name of site], institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. The Certificate of Confidentiality does not prevent you from releasing information 
about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by US law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. In 
addition to the efforts of the study staff to help keep your personal information private, this 
research is covered by a Certificate of Confidentiality from the US Federal Government. The 
Certificate of Confidentiality may not provide protections for your data in your country. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties [insert name of site], institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees. The Certificate of Confidentiality does not prevent you from 
releasing information about yourself and your participation in the study. Even with the Certificate 
of Confidentiality, if the study staff learns of possible child abuse and/or neglect or a risk of harm 
to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by US law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
All information collected about you as part of the study will be sent securely to the ACTG 
statistical and data management center in the United States for combining with 
information from other study participants and statistical analysis of study results. Your 
name and other personal identifiers will not be sent. Your research site is responsible for 
sending your information in accordance with the laws, regulations, and policies of your 
country and research site. 
 
 

 
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WHAT ARE THE COSTS TO ME? 
 
In addition to any costs that are described in the study consent you already signed, this study 
will not cover any cost related to your pregnancy, delivery of your baby, or care of your baby. 
 
 
WHAT HAPPENS IF MY BABY OR I AM INJURED? 
 
If your baby or you are injured as a result of being in this study, you will both be given 
immediate treatment for your injuries.  
 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry Clinical Trials Insurance (CTI), this must be indicated in 
the informed consent.] Please note that, for all sites (not as part of an either/or statement 
with CTI), the NIH does not have a mechanism to provide direct compensation for 
research-related injury.  
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study. 
OR  
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH, regardless of whether 
CTI is available.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Continuing to take part in this study is completely voluntary. You may choose not to continue in 
this study or you may leave this study at any time. Your decision will not have any impact on 
your participation in other studies conducted by NIH and will not result in any penalty or loss of 
benefits to which you are otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. At the end of the study, you will be told when study 
results may be available and how to learn about them. Individual results related to your safety 
and significant clinical findings requiring medical attention and follow up will be provided to you 
and your treating medical provider. 
 
____ (initials) I agree to stay in the study and continue receiving study vaccine series. 
 
OR 
____ (initials) I will stop study vaccine. 
 
 

 
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WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to continue in this study, please sign your name below. 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
__________________________________ 
Participant’s Legally Authorized 
Legally Authorized Representative 
Representative (print) 
Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate)