Effects of Chronic Viral Infection on Immune Response to Zoster Vaccination

Overview

This study aims to identify the innate and adaptive immune response to zoster vaccination. Half of the participants will be individuals with chronic hepatitis C, while the other half with healthy volunteers.The innate immune signature elicited by Zoster vaccination will be characterized by RNA-seq analysis of pre- and post-vaccination RNA from whole blood. We will compare fold changes in gene expression profiles pre- versus post-vaccination in each individual, as well as between the two arms of the study. RNA-seq will be used to assess innate immune activation by evaluating the changes to the expression levels of interferon-stimulated genes pre- and post-vaccination. Adaptive immune response will be determined by the traditional correlates of protection used in previous Zoster clinical studies in addition to flow cytometry24. Correlates of protection include antibody response, interferon gamma production and the frequency of responder cells post- vaccination24. For antibody production, we will perform Zoster glycoprotein ELISA (gpELISA) targeting IgG/IgM. The number and frequency of responder cells will be characterized by flow cytometry.

Chronic HCV infection is associated with persistent innate immune activation and dampened cellular immune responses. Interferons (IFNs) are key mediators of the antiviral innate immune response, initiating the expression of interferon-stimulated genes (ISG) with numerous host protective effector functions. However, in chronic HCV, high pre-therapy expression of ISG and persistent activation of the innate immune system negatively predicts the response to IFN-based therapies and failure of viral clearance8. In addition, HCV persistence is also associated with HCV-specific-CD8+ T cell exhaustion. HCV-specific CD8+ T cell exhaustion is characterized by diminished ex vivo polyfunctionality, upregulation of negative costimulatory cell modulators and, decreased cellular proliferation and IFN production10,12. This phenotype is associated with the development of short-term effector CD8+ T cells rather than durable, long-term memory CD8+ T cells. Chronic bystander infections (e.g. chronic HCV), characterized by persistent inflammation have been linked to bystander (non-HCV specific) CD8+ T cell dysfunction. Bystander CD8+ T cell dysfunction significantly impairs the expansion of memory CD8+ T cells and could prevent the development of secondary immunological memory to new antigens and/or vaccines11,13. Clinically, chronic HCV has been associated with impaired immune response to Hepatitis B vaccination13,14,15. Only 40% to 60% of individuals with chronic HCV achieve seroprotective titers following HBV vaccination versus 90% to 95% in healthy subjects13,14. Specific immune defects responsible for HBV vaccine failure in HCV-infected patients are unknown at present. However, some studies have suggested that the blunting of the immune response to HBV vaccination is associated with lymphocyte dysfunction and upregulation of PD-1 expression on CD4+ T cells in HBV vaccine non-responders13,15. In the United States, 99.5% of adults over 40 years have been infected with the Varicella zoster virus (VZV) and are at risk of Zoster virus reactivation (shingles) and its complications. Unilateral, painful, blistering rashes along dermatomes characterize shingles. Complications associated with shingles include acute or chronic pain, osteonecrosis, zoster ophthalmicus with visual impairment, increased risk of blindness and a 4-fold risk of cerebral vasculitis-associated stroke)1,2. Overall, complications of shingles have a negative impact on the quality of life and activities of daily living21,22. Zoster vaccine live (Zostavax®, Merck) is recommended for the prevention of shingles. Zoster vaccine is a live, attenuated vaccine that is licensed by the FDA for individuals older than 50 years without an underlying immune deficiency (HIV, malignancies, immunosuppression and transplantation). In non-immunocompromised individuals, Zoster vaccine decreases shingles by 51% in individuals between ages 60 - 89 years and 70% in individuals between 50 - 59 years of age. Chronic infections such as TB, malaria and chronic Hepatitis C virus (HCV) have been associated with increased susceptibility to other pathogens and decreased vaccination efficacy3-6. Although chronic HCV infection is not considered a clinically immunocompromised state, it is associated with persistent immune activation and decreased vaccination response7. Zostavax is routinely administered to chronic HCV patients. However, at present, no other study has documented the immune responses elicited by Zoster vaccination in this population. This study aims to identify the innate and adaptive immune signatures elicited by zoster vaccination in chronic HCV and healthy volunteers. Unrecognized suboptimal vaccine response in individuals with chronic immune dysregulated states (chronic bystander viral infections (HBV, HCV and HIV with CD4 \>200), diabetes, advancing age, cancers and transplantation) could be potentially devastating and costly.