Heplisav-B Revaccination for Hepatitis B Vaccine Nonresponders

Study Overview
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Brief Summary
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The goal of this natural history study is to examine the immune responses to the Heplisav-B vaccine in Veterans living with HIV who were non-responders to prior HBV vaccination. A comparison group of HBV vaccine nonresponders without HIV infection will be enrolled to characterize the HIV-associated immune alterations that affect vaccine response. The investigators hypothesize that TLR9-mediated innate immune stimulation with Heplisav will elicit HBV seroprotection despite prior vaccination failures in persons living with HIV, compared to HIV uninfected individuals. Participants eligible for Heplisav-B vaccination will be asked to provide blood samples at multiple timepoints before and after their vaccination.

Detailed Description
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HIV-positive individuals are at increased risk of morbidity and mortality from Hepatitis B co-infection, due to shared routes of transmission, increased likelihood of developing chronic infection (as opposed to spontaneous clearance), and increased immune dysregulation leading to accelerated disease progression, and so current guidelines recommend the routine vaccination of HIV-positive individuals against HBV. However, because achieved seroprotection rates (SPR) are historically lower than in HIV-negative individuals, post-vaccination serologic testing is recommended for this group and re-vaccination (with increased dose or additional doses) should be attempted for those who were non-responders to the initial vaccine. Heplisav-B is a HBV vaccine adjuvanted with a TLR9 agonist that has shown improved SPR among groups with reduced response rates to classic alum-adjuvanted vaccines, such as those with CKD, obesity, or diabetes. The investigators propose to evaluate immunological mechanisms of protection in Veterans who were non-responders to prior HBV vaccination now receiving Heplisav vaccinations. The investigators will enroll a comparison group of HIV-negative individuals to characterize the HIV-associated immune alterations that modulate vaccine response. The investigators hypothesize that TLR9-mediated innate immune stimulation with Heplisav will elicit HBV seroprotection despite prior vaccination failures in persons living with HIV, compared to HIV uninfected individuals. By assessing innate immune responses and B cell immunophenotypes at baseline, post-vaccination, and at long-term followup in Veterans with and without HIV the investigators will assess the mechanisms by which the immunostimulatory effects of TLR9 agonists may overcome the immune dysfunction in these patients.

Official Title
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Heplisav-B Revaccination for Hepatitis B Vaccine Nonresponders

Conditions
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HIV Infections, Hepatitis B, Vaccine Response Impaired

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 by age of screening If HIV positive, either: Suppressed on a stable, ARV regimen for >4 weeks with CD4 count >100. HIV VL suppressed <50 copies/mL, although single isolated VL >50 not excluded. OR Untreated ≥ 8 weeks with CD4 count >100 Prior HBV vaccine (other than Heplisav) with last dose >30 days prior to screening and anti-HBSAg ≤10 IU/mL measured >30days from last vaccine dose. (No exclusion for HBV CAb positive.) Ability to provide informed consent and adhere to clinic visits (in the judgment of both the participant and the provider) No history of adverse reaction to HBV vaccines or components thereof If HCV Ab positive: undetectable HCV viral load and >12 weeks from completion of any HCV therapy. Exclusion Criteria: History of allergic reaction to HBV vaccines or components (including yeast) HBsAb titer >10 IU/mL on screening evaluation Clinically significant illness (other than HIV) that may, in the opinion of the investigator, interfere with the subject treatment, or adherence to protocol. This may include but is not limited to a history of transplant, decompensated cirrhosis, or malignancy that may interfere with host immunity. Poor venous access interfering with blood sample collection Any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent. No exclusion will be made for chronic renal disease or ESRD

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 109 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV infected<br> | |
| HIV uninfected<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in B cell functional responses | Characterize the change in B cell functional responses by ELISpot on day 30 compared to baseline | Day 30 | 
| Change in B cell functional responses | Characterize the change in B cell functional responses by ELISpot on day 60 compared to baseline | Day 60 | 
| Change in B cell functional responses | Characterize the change in B cell functional responses by ELISpot on day 365 compared to baseline | Day 365 | 
| Change in B cell phenotypic responses | Characterize the change in B cell phenotypic responses by flow cytometry on day 365 compared to baseline | Day 30 | 
| Change in B cell phenotypic responses | Characterize the change in B cell phenotypic responses by flow cytometry on day 365 compared to baseline | Day 60 | 
| Change in B cell phenotypic responses | Characterize the change in B cell phenotypic responses by flow cytometry on day 365 compared to baseline | Day 365 | 
| Cytokine profile | Change in cytokine profile on day 1 compared to baseline | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatitis B surface antibody responses | Characterization of the hepatitis B surface antibody titers on day 30 compared to baseline | Day 30 | 
| Hepatitis B surface antibody responses | Characterization of the hepatitis B surface antibody titers on day 60 compared to baseline | Day 60 | 
| Hepatitis B surface antibody responses | Characterization of the hepatitis B surface antibody titers on day 365 compared to baseline | Day 365 | 
| Hepatitis B surface antibody response rates | Characterization of the hepatitis B surface antibody response rates on day 30 compared to baseline | Day 30 | 
| Hepatitis B surface antibody response rates | Characterization of the hepatitis B surface antibody response rates on day 60 compared to baseline | Day 60 | 
| Hepatitis B surface antibody response rates | Characterization of the hepatitis B surface antibody response rates on day 365 compared to baseline | Day 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heplisav-B, HIV, vaccine