B-Enhancement of HBV Vaccination in Persons Living With HIV (BEe-HIVe): Evaluation of HEPLISAV-B (BEe-HIVe)

The purpose of this study was to evaluate response to and safety of the HBV vaccine HEPLISAV-B in two study populations of people living with HIV: prior HBV vaccine recipients who are deemed non-responders and individuals who are naïve to HBV vaccination.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Hepatitis B
• Intervention / Treatment: Biological: HEPLISAV-B; Biological: ENGERIX-B

Detailed Description

This phase III/IV study evaluated the response to and safety of the HBV vaccine HEPLISAV-B in two study populations of people 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 analyses were conducted as separate evaluations of the two study populations for all primary and secondary objectives.

Group A (HBV vaccine non-responders)

The study was designed as an open-label three-arm study to evaluate whether:

1. HEPLISAV-B vaccination given as a two-dose series achieves non-inferior seroprotection response (SPR) compared to standard dose ENGERIX-B.
2. HEPLISAV-B vaccination given as a three-dose series achieves superior SPR compared to standard dose ENGERIX-B.

Participants were randomized in 1:1:1 ratio to the following study arms, stratified by sex at birth (male vs. female) and diabetes diagnosis status (yes vs. no):

2-CpG: Two doses of HEPLISAV-B at weeks 0 and 4.

3-CpG: Three doses of HEPLISAV-B at weeks 0, 4, and 24.

3-alum: Three doses of ENGERIX-B at weeks 0, 4, and 24.

The target sample size in Group A was 561 participants, 187 participants in each arm.

Group B (Naïve to HBV vaccination)

Group B study was a single arm evaluation of vaccine response and safety of three doses of HEPLISAV-B. The target sample size was 73 participants.

In both groups, participants were scheduled to attend several study visits through Week 72. All participants were to remain on their antiretroviral therapy (ART), not provided by the study, throughout the study. Visits included physical examinations and blood collection. For 7 days after each vaccination, participants were asked to record temperature and any reactions they experienced.

• Study Type: Interventional
• Enrollment (Actual): 638
• Phase: Phase 3

Contacts and Locations

Study Locations

• Botswana
  • South-East District
    • Gaborone, South-East District, Botswana
      • Gaborone CRS
• Brazil
  • Rio De Janeiro, Brazil, 21040-360
    • Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 91350
      • Hospital Nossa Senhora da Conceicao CRS
• Kenya
  • Rift Valley
    • Kericho, Rift Valley, Kenya, 20200
      • Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
• Malawi
  • Blantyre, Malawi
    • Blantyre CRS
• Philippines
  • Silang, Philippines, 4118
    • De La Salle Health Science Institute Angelo King Medical Research Center
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2092
      • Wits Helen Joseph Hospital CRS (Wits HJH CRS), Perth Road, Westdene
  • Kwa Zulu Natal
    • Durban, Kwa Zulu Natal, South Africa, 4052
      • Durban International Clinical Research Site CRS
  • Soweto
    • Johannesburg, Soweto, South Africa, 1862
      • Soweto ACTG CRS
• Thailand
  • Bangkok, Thailand, 10330
    • Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
• Uganda
  • Kampala, Uganda, 10005
    • Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35222
      • Alabama CRS
  • California
    • Los Angeles, California, United States, 90035-4709
      • UCLA CARE Center CRS
    • San Diego, California, United States, 92103
      • UCSD Antiviral Research Center
    • San Francisco, California, United States, 94110
      • Ucsf Hiv/Aids Crs
    • Torrance, California, United States, 90502
      • Harbor-UCLA CRS
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS
  • District of Columbia
    • Washington, District of Columbia, United States, 20005
      • Whitman-Walker Health CRS
  • Georgia
    • Atlanta, Georgia, United States, 30308-2012
      • The Ponce de Leon Center CRS
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital CRS (MGH CRS)
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1010
      • Washington University Therapeutics (WT) CRS
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School Clinical Research Center CRS
  • New York
    • New York, New York, United States, 10032
      • Columbia P&S CRS
    • New York, New York, United States, 10065
      • Weill Cornell Uptown CRS
    • New York, New York, United States, 10010
      • Weill Cornell Chelsea CRS
    • Rochester, New York, United States, 14642
      • University of Rochester Adult HIV Therapeutic Strategies Network CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Chapel Hill CRS
    • Greensboro, North Carolina, United States, 27401
      • Greensboro CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Cincinnati Clinical Research Site
    • Cleveland, Ohio, United States, 44106
      • Case Clinical Research Site
    • Columbus, Ohio, United States, 43210
      • Ohio State University CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Therapeutics CRS
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh CRS
  • Tennessee
    • Nashville, Tennessee, United States, 47183
      • Vanderbilt Therapeutics (VT) CRS
  • Texas
    • Houston, Texas, United States, 77009
      • Houston AIDS Research Team CRS
  • Washington
    • Seattle, Washington, United States, 98104-9929
      • University of Washington AIDS CRS
• Vietnam
  • Hanoi
    • Đống Đa, Hanoi, Vietnam, 10000
      • Hanoi Medical University CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria, Groups A and B

• HIV-1 infection
• On current HIV-1 antiretroviral therapy (ART)
• CD4+ T-cell count ≥100 cells/mm^3
• HIV-1 RNA <1000 copies/mL

Inclusion Criteria, Group A only

• Serum Hepatitis B antibody <10 mlU/mL, non-reactive (negative), or indeterminate
• Documentation of HBV vaccination >168 days prior to study entry

Inclusion Criterion, Group B only

• Serum Hepatitis B antibody non-reactive (negative) within 45 days prior to study entry

Exclusion Criteria, Groups A and B

• Infection or prior exposure to HBV
• Serum HBsAb level ≥10 mlU/mL or positive at screening or any other time prior to screening
• Presence of any active or acute AIDS-defining opportunistic infections
• Solid organ transplantation
• History of ascites, encephalopathy, or variceal hemorrhage
• Diagnosis of chronic kidney disease (CKD) stage G4
• Cancer diagnosis within 5 years
• Currently receiving chemotherapy
• Chronic use and/or receipt of systemically administered immunosuppressive
• Known allergy/sensitivity or any hypersensitivity to any HBV vaccine or yeast
• Active, serious infection other than HIV-1
• Receipt of any inactivated virus vaccine within 14 days

• Receipt of any of the following within 45 days prior to study entry:

  • Live virus vaccine
  • Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF)
  • Any other investigational medicinal agent
• Receipt of immunoglobulin or blood products within 90 days prior to study entry
• Receipt of an injection of DNA plasmids or oligonucleotides within 60 days prior to study entry

Exclusion Criteria, Group A only

• Hepatitis B virus vaccination ≤168 days prior to study entry
• Receipt of HEPLISAV-B vaccine at any time prior to study entry

Exclusion Criterion, Group B only

• Known HBV vaccination prior to study entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A, 2-CpG: HEPLISAV-B (two injections); Participants were prescribed 0.5 mL of HEPLISAV-B (hepatitis B vaccine with a cytosine phosphoguanine adjuvant) by intramuscular (IM) injection at Weeks 0 and 4.	Biological: HEPLISAV-B; Administered by IM injection
Experimental: Group A, 3-CpG: HEPLISAV-B (three injections); Participants were prescribed 0.5 mL of HEPLISAV-B (hepatitis B vaccine with a cytosine phosphoguanine adjuvant) by IM injection at Weeks 0, 4, and 24.	Biological: HEPLISAV-B; Administered by IM injection
Active Comparator: Group A, 3-alum: ENGERIX-B (three injections); Participants were prescribed 1 mL of ENGERIX-B (conventional hepatitis B vaccine with an aluminum hydroxide adjuvant) by IM injection at Weeks 0, 4, and 24.	Biological: ENGERIX-B; Administered by IM injection
Experimental: Group B: HEPLISAV-B (three injections); Participants were prescribed 0.5 mL of HEPLISAV-B (hepatitis B vaccine with a cytosine phosphoguanine adjuvant) by IM injection at Weeks 0, 4, and 24.	Biological: HEPLISAV-B; Administered by IM injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Primary Seroprotection Response	Primary seroprotection response was defined as antibody titer against hepatitis B surface antigen (anti-HBs) ≥10 mIU/mL at 8 weeks after 2-dose vaccination series and at 4 weeks after 3-dose vaccination series. If the completion of the vaccine series was delayed (a delay of ≤4 weeks was allowed), the trial protocol specified obtaining an antibody result at 8 weeks for the 2-dose series or at 4 weeks for the 3-dose series after vaccine completion for use in the primary outcome analysis. The study was designed separately for the two study populations (Groups A and B), and the analysis was conducted separately, as prespecified in the study protocol and Statistical Analysis Plan (SAP). In Group A, two-sided 97.5% confidence intervals (CI) were specified for the SPR differences between study arms (presented in the Statistical Analyses sections below). In Group B, two-sided 95% Wilson CI around the single-arm estimate was specified (presented in the Data Table below).	Week 12 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and in Group B
Percentage of Participants With Adverse Events (AEs)	The protocol required reporting of (1) Grade ≥2 AEs, (2) AEs that led to a change in study treatment regardless of grade, (3) AEs meeting serious AE (SAE) definition or expedited AE (EAE) reporting requirement, (4) Grade ≥1 local and systemic injection reactions within 7 days of any study vaccine injection, (5) medically attended adverse events (MAAE) regardless of grade, and (6) potential immune-mediated AEs regardless of grade. Grading was per DAIDS AE Grading Table (Version 2.1): Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening) and 5 (death). DAIDS EAE Manual (V1.0) was used. Wilson method was used for confidence intervals.	From study entry to study discontinuation (Week 72 or premature discontinuation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Seroprotection Response	Seroprotection response (SPR) was defined as antibody titer against hepatitis B surface antigen (anti-HBs) ≥10 mIU/mL. Study visit weeks are according to protocol-specified visit windows; anti-HBs results outside visit windows were not included. These are snapshots at scheduled visits irrespective of delayed vaccinations, unlike the visits defined in Primary Outcome 1. The study was designed separately for the two study populations (Groups A and B), and the analysis was conducted separately, as prespecified in the study protocol and Statistical Analysis Plan (SAP). In Group A, two-sided 97.5% confidence intervals (CI) were specified for the SPR differences between study arms (presented in the Statistical Analyses sections below). In Group B, two-sided 95% Wilson CIs around the single-arm estimates were specified (presented in the Data Table below).	Weeks 4, 8, 12, 24, 28, 32 (Group A 3-CpG and 3-alum and Group B), 48 (Group A 3-CpG and 3-alum and Group B), 52 (Group A 2-CpG) and 72. The visit schedule differed between the study arms.
Count of Participants by Anti-HBs Titer Categories	Count of participants by antibody titer against hepatitis B surface antigen (anti-HBs), categorized using cutoffs at 5, 10, 100 and 1000 mIU/mL. The testing assay lower limit of quantitation was 5 mIU/mL and upper limit 1000 mIU/mL. Study visit weeks are according to protocol-specified visit windows; anti-HBs results outside visit windows were not included. Because high proportions of participants achieved anti-HBs above the assay upper limit of quantitation, the planned geometric mean analysis was not conducted. Instead, anti-HBs were summarized according to the categories shown in the Data Table below.	Weeks 4, 8, 12, 24, 28, 32 (Group A 3-CpG and 3-alum and Group B), 48 (Group A 3-CpG and 3-alum and Group B), 52 (Group A 2-CpG) and 72. The visit schedule differed between the study arms.
Percentage of Participants With Grade ≥2 AEs Post-vaccination Adverse Events	The protocol required reporting of (1) Grade ≥2 AEs, (2) AEs that led to a change in study treatment regardless of grade, (3) AEs meeting serious AE (SAE) definition or expedited AE (EAE) reporting requirement, (4) Grade ≥1 local and systemic injection reactions within 7 days of any study vaccine injection, (5) medically attended adverse events (MAAE) regardless of grade, and (6) potential immune-mediated AEs regardless of grade. This outcome is limited to the Grade ≥2 AEs that occurred within 4 weeks after any study vaccination. Grading was per DAIDS AE Grading Table (Version 2.1): Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening) and 5 (death). DAIDS EAE Manual (V1.0) was used. Wilson method was used for confidence intervals.	From study vaccination initiation to 4 weeks after last study vaccination (Week 8 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and Group B)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Primary Seroprotection Response by Sex	Subgroup analysis of the primary seroprotection response outcome measure (as described in the Primary Outcome Measure 1 above) by sex. Descriptive summary of the SPR by subgroups; the study was not powered for testing the success of HEPLISAV-B vaccination within subgroups.	Week 12 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and in Group B
Percentage of Participants With Primary Seroprotection Response by Race	Subgroup analysis of the primary seroprotection response outcome measure (as described in the Primary Outcome Measure 1 above) by race. Descriptive summary of the SPR by subgroups; the study was not powered for testing the success of HEPLISAV-B vaccination within subgroups.	Week 12 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and in Group B

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Dynavax Technologies Corporation
• Investigators: Study Chair: Kenneth E. Sherman, MD, PhD, Cincinnati CRS; Study Chair: Kristen Marks, MD, Weill Cornell Chelsea CRS

Publications and helpful links

General Publications

• Marks KM, Kang M, Umbleja T, Avihingsanon A, Sugandhavesa P, Cox AL, Vigil K, Perazzo H, Price JC, Katsidzira L, Vernon C, Alston-Smith B, Sherman KE; ACTG 5379 Study Team. Immunogenicity and Safety of Hepatitis B Virus (HBV) Vaccine With a Toll-Like Receptor 9 Agonist Adjuvant in HBV Vaccine-Naive People With Human Immunodeficiency Virus. Clin Infect Dis. 2023 Aug 14;77(3):414-418. doi: 10.1093/cid/ciad201.
• Marks KM, Kang M, Umbleja T, Cox A, Vigil KJ, Ta NT, Omoz-Oarhe A, Perazzo H, Kosgei J, Hatlen T, Price J, Katsidzira L, Supparatpinyo K, Knowles K, Alston-Smith BL, Rathod P, Sherman KE; ACTG 5379 (BEe-HIVe) Study Team. HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial. JAMA. 2025 Jan 28;333(4):295-306. doi: 10.1001/jama.2024.24490.
• Kang M, Marks KM, Cox AL, Sherman KE. An efficient vaccine clinical trial: ACTG A5379 hepatitis B vaccine trial in persons with HIV. Vaccine. 2025 May 10;55:127028. doi: 10.1016/j.vaccine.2025.127028. Epub 2025 Mar 26.

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2020
• Primary Completion (Actual): August 13, 2024
• Study Completion (Actual): August 13, 2024

Study Registration Dates

• First Submitted: December 6, 2019
• First Submitted That Met QC Criteria: December 6, 2019
• First Posted (Actual): December 10, 2019

Study Record Updates

• Last Update Posted (Actual): July 20, 2025
• Last Update Submitted That Met QC Criteria: July 16, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: vaccination; seroprotection; cytosine phosphoguanine adjuvant
• Additional Relevant MeSH Terms: Blood-Borne Infections; Infections; Virus Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Viral, Human; Communicable Diseases; DNA Virus Infections; Hepadnaviridae Infections; Hepatitis; Hepatitis B
• Other Study ID Numbers: ACTG A5379; 38569 (Registry Identifier: DAIDS-ES Registry Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections network (ACTG) by NIH.

IPD Sharing Access Criteria

• With whom?

  • Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG.

• For what types of analyses?

  • To achieve aims in the proposal approved by the ACTG.

• By what mechanism will data be made available?

  • Researchers may submit a request for access to data using the ACTG "Data Request" form at: https://submit.mis.s-3.net/ Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No