TLR-9 Adjuvanted Vaccination for Chronic Hepatitis B

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Hepatitis B Vaccine Recombinant, Adjuvanted Intramuscular Solution [HEPLISAV-B]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to participate in this study, an individual must meet all the following criteria: >18 years old Diagnosed with CHB infection, without HIV, hepatitis C nor hepatitis D co-infections Currently receiving OAV with HBV VL <100 IU/ml for ≥ 12 months Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, and other study procedures. 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: Pregnancy or breast feeding. 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. 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). Administration of any blood products within 3 months prior to randomization. Participation in a study with an investigational study product or device within 30 days of randomization. Has allergies to any hepatitis B and/or yeast-based vaccines. Subjects meeting any of the following laboratory parameters at screening: ALT greater than 3 times the upper limit of normal Elevated total bilirubin WITH direct bilirubin greater than 2 times upper limit of normal 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. Have any chronic or acute or unstable conditions that the investigator considers a contraindication to study participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention - vaccination<br>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]<br>* one 0.5ml intramuscular injection on day 0 and week 4.<br>|
| No Intervention: No vaccination<br>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?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine, CpG, hepatitis B, Toll-like receptor, hepatitis B surface antibody, HBsAb, anti-HBsAg, hepatitis B surface antigen, HBsAg, TLR9