Effects of Persistent Innate Immune Activation on Vaccine Efficacy

Study Overview
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Brief Summary
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This study will investigate the effects of chronic HCV infection and corresponding innate immune activation on the immune response to HBV vaccination. We will recruit chronic HCV patients and healthy control patients for HBV vaccination. We will use RNA Sequencing (RNA-Seq), a relatively new technology for simultaneously measuring the expression of all genes, to determine patients' innate immune status, and learn how this innate immune signature is related to HBV vaccine response. We will then explore the mechanisms by which chronic HCV infection affects different immune cells and functions that are known to be important for an effective HBV vaccine response. These studies will enhance our understanding of the immune effects of chronic viral infection, establish factors that determine effective vaccine responses, and help guide vaccination strategies for HCV patients and other individuals with chronic inflammatory disease.

Detailed Description
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Vaccines have been responsible for preventing millions of deaths and extending the average human lifespan. Effective vaccines stimulate the cells of the immune system to activate genes and associated functions that bring about protective immunity. If we can better understand the factors that influence vaccine success versus failure, we may be able to improve current vaccines and/or develop new vaccines against prevalent infectious diseases. Certain groups of people do not respond well to particular vaccines. For example, vaccines can be less effective in immunocompromised patients, elderly individuals, and people with chronic inflammatory diseases. Often it is these groups of people that have the greatest need for protection against infectious disease. People chronically infected with hepatitis C virus (HCV) are at increased risk of serious liver disease. As a result, they should receive the hepatitis B virus (HBV) vaccine, which can protect them from infection by HBV, another virus that targets the liver. However, people chronically infected with HCV do not respond to the HBV vaccine as effectively as healthy people without HCV. Chronic HCV infection is not thought to cause general problems with the immune system, and the reasons for this poor vaccine response are poorly understood. Previous work has shown that chronic HCV infection leads to production of chemical (innate immune) signals that can affect function of the immune system, but it is currently unknown how this might impact vaccination.

Official Title
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Effects of Persistent Innate Immune Activation on Vaccine Efficacy

Conditions
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Hepatitis C Infection

Intervention / Treatment
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* Drug: Recombivax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to receive three doses of an FDA-approved Hepatitis B vaccine Volunteer chronically infected with HCV (as demonstrated by serology and/or viral load laboratory studies) Healthy volunteer without significant medical problems Exclusion Criteria: Received any vaccine within a month prior to study vaccine Positive serum antibody against Hep B surface antigen and/or core Hep B core antigen HIV positive For HCV-negative, healthy volunteers: History of HCV infection or positive HCV antibody test Participation in another clinical study of an investigational product currently or within the past 90 days, or expected participation during this study In the opinion of the investigator, the volunteer is unlikely to comply with the study protocol Any clinically significant abnormality or medical history or physical examination including history of immunodeficiency or autoimmune disease (in addition to HCV infection, for HCV group) Currently taking systemic steroids or other immunomodulatory medications including anticancer medications and antiviral medications Any clinically significant acute or chronic medical condition requiring care by a primary care provider (e.g., diabetes, coronary artery disease, rheumatologic illness, malignancy, substance abuse) that, in the opinion of the investigator, would preclude participation Unable to continue participation for 156 weeks History of previous Hepatitis B vaccination(s) Male or female < 18 and > 62 years of age Is pregnant or lactating History of Hepatitis B infection Clinical, laboratory, or biopsy evidence of cirrhosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 62 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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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Recombivax in HCV infected individuals<br>Recombivax vaccine administered IM to HCV-infected individuals | Drug: Recombivax<br>* Injection of Recombivax HBV vaccine administered IM, at 0, 1, and 6 months after enrollment<br>* Other names: Hepatitis B vaccine;|
| Active Comparator: Recombivax in healthy volunteers<br>Recombivax vaccine administered IM to healthy individuals | Drug: Recombivax<br>* Injection of Recombivax HBV vaccine administered IM, at 0, 1, and 6 months after enrollment<br>* Other names: Hepatitis B vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBV Vaccine Response Versus Non-response Status | Titers of anti-hepatitis B surface antigen antibody measured at 8 months Luminex assay for multiplex cytokine/chemokine panel measured at 8 months RNA-Seq with analysis focus on curated ISG list measured at 8 months | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and Functional Status of Anti-HBsAg Antibody-producing B Cells Post-vaccination Doses Over Time | ELISPOT assays will measured at 8 months | 8 months | 
| Frequency and Functional Status of HBsAg-specific CD4+ Helper T Cells | Flow cytometry assays measured at 8 months | 8 months | 
| Functional Response of Monocytes Stimulated ex Vivo With Vaccine Antigen and/or Adjuvant | Isolated from patient PBMCs measured at 8 months | 8 months | 
| Gene Expression Profile of Conventional Dendritic Cells Measured by RNA-Seq | Isolated from patient PBMCs measured at 8 months | 8 months |