Effects of Chronic Viral Infection on Immune Response to Zoster Vaccination

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.

Inclusion Criteria:

- Willing to receive the herpes zoster vaccine

- Volunteer chronically infected with HCV (as demonstrated by serology testing and have
a viral load >1000 copies) without treatment

- Healthy volunteer without significant medical problems

Exclusion Criteria:

- Received any vaccine within a month prior to study vaccine

- Previous Zoster infection as an adult, >18 years

- HIV or Hepatitis B virus infection in the HCV and healthy arms

- 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 particpation 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

- Male or female < 50 and > 70 years of age

- Is pregnant or lactating

- Clinical, laboratory, or biopsy evidence of cirrhosis

- Allergy to gelatin and/or neomycin

- ALT and/or AST > 3.5 times the ULN

- Immunosuppressed or immunodeficient individuals including those with a history of
primary or acquired immunodeficiency states, leukemia, lymphoma or other malignant
neoplasms affecting the bone marrow or lymphatic system and those on immunosuppressive
therapy

- Individuals with active untreated tuberculosis

- Prior Varicella vaccination

- HCV volunteers who have a viral load of <1000 copies