TLR-9 Adjuvanted Vaccination for Chronic Hepatitis B (BOOST-9)

Augmentation of Humoral Immunity Using Toll-Like Receptor (TLR) 9 Adjuvanted HBV Surface Antigen to Enhance Anti-HBSAg Response

Unmethylated cystine-guanosine dinucleotide (CpG) motifs are pathogen-associated molecular patterns (PAMPs) associated with bacterial and viral-derived DNA that activate the innate and humoral immunity via toll-like receptor 9. This is a randomized controlled pilot study evaluating the clinical and immune correlates of a seroprotective immune response against a CpG-adjuvanted vaccine for hepatitis B.

Study Overview

• Status: Withdrawn
• Conditions: Hepatitis B
• Intervention / Treatment: Drug: Hepatitis B Vaccine Recombinant, Adjuvanted Intramuscular Solution [HEPLISAV-B]

Detailed Description

This is an open-label, randomized, pilot study to assess the effect of CpG-adjuvanted vaccination among people with chronic hepatitis B. This study will evaluate the effect of CpG-adjuvanted vaccination on B-cells that produce anti-HBsAg antibody.

The primary hypothesis is that TLR9 agonism with CpG-adjuvanted hepatitis B vaccine will increase the number of anti-HBsAg producing B-cells in people with chronic hepatitis B infection who are virally suppressed on nucleos(t)ide analogue (NUC) therapy.

In this study, 40 people with chronic hepatitis B virally suppressed on NUC therapy will be randomized in a 1:1 fashion to receive an 0.5ml intramuscular injection of HEPLISAV-B vaccine - an FDA approved vaccine for preventing hepatitis B infection. Participants randomized to receive the vaccine will receive a total of 2 injections, at day 0 and week 4. Participants will be evaluated at days 7, 14, 28, 35, 56, 96, 393 for adverse events, with and blood sample collections on days 0, 14, 28, 56, 196.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Institute of Human Virology, University of Maryland School of Medicine
  • Virginia
    • Falls Church, Virginia, United States, 22044
      • Dr Sang V Tran Internal Medicine Practice

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

In order to participate in this study, an individual must meet all the following criteria:

1. >18 years old
2. Diagnosed with CHB infection, without HIV, hepatitis C nor hepatitis D co-infections
3. Currently receiving OAV with HBV VL <100 IU/ml for ≥ 12 months
4. Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, and other study procedures.
5. Determined by medical history, targeted physical examination, and clinical judgement of the investigator to be in good health.

CHB infection is defined as any individual with documentation of the following in the past:

• Positive HBsAg and/or detectable HBV DNA test

Exclusion Criteria:

A participant will be ineligible to participate on this study if any of the following criteria are met:

1. Pregnancy or breast feeding.
2. Received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to Screening (for corticosteroids ≥ 20 mg/day of prednisone equivalent). Topical tacrolimus is allowed if not used within 14 days prior to Day 1.
3. Received or plans to receive live virus vaccines within 4 weeks, and inactivated vaccine within 2 weeks prior to randomization; or plans to receive a non-study vaccine within 28 days after any dose of study vaccine (with exception for seasonal influenza vaccine within 14 days of study vaccine).
4. Administration of any blood products within 3 months prior to randomization.
5. Participation in a study with an investigational study product or device within 30 days of randomization.
6. Has allergies to any hepatitis B and/or yeast-based vaccines.

7. Subjects meeting any of the following laboratory parameters at screening:

   1. ALT greater than 3 times the upper limit of normal
   2. Elevated total bilirubin WITH direct bilirubin greater than 2 times upper limit of normal
8. Is acutely ill or febrile 72 hours prior to or at vaccine dosing (fever defined as ≥ 38.0°C/100.4°F). Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator.
9. Have any chronic or acute or unstable conditions that the investigator considers a contraindication to study participation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention - vaccination; HEPLISAV-B is available in pre-filled, single-dose 0.5 mL vials. Each dose contains 20 μg of HBsAg and 3,000 μg of 1018 adjuvant. HEPLISAV-B is administered as an intramuscular injection in the deltoid region. Study subjects randomized to the vaccine group will receive a total of 2 injections, each administered at least 4 weeks apart - the same dosing schedule recommended for hepatitis B prevention. Once enrolled, participants will have study visits on days 0 (first injection), 14, 28, 56, and 196 with phone call follow ups on days 7, 35, and 393. Research blood samples will be collected at days 0, 14, 28, 56, 196.	Drug: Hepatitis B Vaccine Recombinant, Adjuvanted Intramuscular Solution [HEPLISAV-B]; one 0.5ml intramuscular injection on day 0 and week 4.
No Intervention: No vaccination; Participants randomized to the control group will have study visits on days 0, 14, 28, 56, and 196 with phone call follow ups on days 7, 35, and 393. Research blood samples will be collected at days 0, 14, 28, 56, 196.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and reactogenicity of the Hepatitis B Virus Surface Antigen, Recombinant (HEPLISAV-B; Dynavax Technologies Corporation) Vaccine in patients with chronic hepatitis B	Occurrence of local and systemic solicited adverse events	Baseline to 7 days following each vaccine dose
Occurrence of unsolicited adverse events	Unsolicited adverse events	from dose 1 to 28 days following each vaccine dose
Medically Attended Adverse Events	Occurrence of Medically Attended Adverse Events (MAAEs)	From first vaccine to 12 months after last vaccine on study.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatitis B surface antigen-specific antibodies	Change in hepatitis B surface antigen-specific antibody (anti-HBsAg)-producing B-cells	baseline to day 56
Anti-HBsAg Seroconversion	Number of patients with anti-HBsAg seroconversion	Day 0 through 12 months post vaccination

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Lydia Tang, MBChB, University of Maryland School of Medicine

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): July 1, 2024

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 9, 2021
• First Posted (Actual): April 14, 2021

Study Record Updates

• Last Update Posted (Actual): July 22, 2022
• Last Update Submitted That Met QC Criteria: July 19, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: vaccine; hepatitis B; HBsAg; Toll-like receptor; hepatitis B surface antibody; HBsAb; anti-HBsAg; hepatitis B surface antigen; TLR9; CpG
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A
• Other Study ID Numbers: HP-00095866

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No