ZOSTAVAX® in Renal Transplant Patients

Infection with varicella-zoster virus (VZV) produces a life-long latent infection in sensory
ganglia. Reactivation of viral replication from latency results in a number of clinical
syndromes, most commonly herpes zoster, or shingles. Herpes zoster is typically a unilateral
vesicular rash in a dermatomal distribution accompanied by radicular pain that may be
severe. Immunocompromised persons are at higher risk for herpes zoster than immunocompetent
adults. The markedly increased risk of herpes zoster in organ transplant recipients suggests
that this population would benefit substantially if a similar strategy could be adopted. The
currently licensed zoster vaccine, ZOSTAVAX® (Zoster Vaccine Live), is not licensed for use
in immunosuppressed persons and in the United States for those less than 50 years of age. A
small Phase I study is important to address immunogenicity in patients with Chronic Kidney
Disease (CKD) prior to transplantation as well as safety and persistence of immune responses
following transplantation. This study is a multi-center, double blind, randomized,
placebo-controlled trial of ZOSTAVAX® immunization in subjects who will undergo renal
transplantation from a living donor or are wait-listed for a deceased donor no less than 4
weeks prior to transplantation. The primary objective of this study is to assess the safety
of ZOSTAVAX® when administered to subjects with CKD a minimum of 4 weeks prior to live donor
renal transplantation. This will be accomplished by comparing the rates of specific local
and systemic reactogenicity events and adverse events (AEs) between the vaccine and placebo
groups. Subjects likely to be suitable for renal transplant and who have an identified
living donor will be consented for screening serology for antibodies to VZV if such serology
is not standard of care or serostatus is not known. Subjects with positive VZV serology, an
identified living donor, and meeting inclusion and exclusion criteria will provide signed
informed consent for study enrollment. Subjects will be randomized to receive either active
vaccine (ZOSTAVAX®) [30 subjects] or placebo vaccine [10 subjects]. Blood will be drawn on
day 0 (day of vaccine) prior to vaccine administration for assessment of baseline humoral
and cellular immunity to VZV. Subjects will receive ZOSTAVAX® or placebo vaccination. At
approximately 5 weeks post-vaccination, subjects will have blood drawn for measurement of
humoral and cellular immune response. Subjects will undergo living donor renal transplant
with immunosuppression according to standard of care at each institution. All transplanted
subjects will receive anti-viral prophylaxis for 3 months post-transplant, consisting of
either valganciclovir (or ganciclovir) or acyclovir (or valacyclovir or famciclovir)
depending on risk of cytomegalovirus (CMV) disease. Subjects will be followed and treated by
the renal transplant team at each center according to local standard of care with
concomitant monitoring by the vaccine study teams. Subjects will have blood drawn for
humoral and cell-mediated immune assays at day 0, and week 5 post vaccination, and 6 months
and 12 months post-transplantation if they undergo transplantation. Parent protocol to
sub-study 09-0025.

Inclusion Criteria:

- Subjects must be willing and able to provide informed consent prior to study
procedures.

- Age 18 years or older at the time of vaccination.

- Chronic kidney disease (CKD) activated on the United Network for Organ Sharing (UNOS)
deceased donor waitlist or anticipating living donor renal transplant no sooner than
4 weeks following vaccination.

- Varicella Zoster Virus (VZV) seropositive by local laboratory or Center for Disease
Control (CDC) serologic testing

- Negative pregnancy test (women of childbearing age potential) performed at
enrollment- or within 48 hours prior. The use of contraception for women of
childbearing potential will be per renal transplant team's standard of care

Exclusion Criteria:

- Any pharmacologic immunosuppression at the time of enrollment, within one year prior
to enrollment, or between enrollment and transplant (e.g., for underlying autoimmune
disease or previous failed allograft). This includes prednisone at >/= 0.3 mg/kg/day
or steroid equivalent for > 10 days, any use of anti-metabolites (azathioprine,
mycophenolic acid, cytoxan), leflunomide, TNF-alpha inhibitors, calcineurin
inhibitors, mTOR inhibitors, IL-6 or IL-6 receptor inhibitors.

- Any transplant other than solitary kidney (e.g., no kidney/pancreas, kidney/liver
transplants). Second kidney transplants are permitted.

- Anticipated use of any post-transplant experimental immunosuppressive agent

- Prior ZOSTAVAX® or Varivax® vaccination

- Shingles or any other herpes zoster within 12 months of planned vaccination

- Receipt of any killed vaccines within 2 weeks prior and 4 weeks following study
vaccination or receipt of any live vaccines within 4 weeks prior and 6 weeks
following study vaccination

- Intercurrent illness at time of planned vaccination

- Inability to vaccinate in either arm (e.g. due to A-V fistula or graft)

- Known Human immunodeficiency virus (HIV) infection, Hepatitis C virus (HCV)
infection, or chronic hepatitis B determined from review of laboratory data obtained
from pre-transplant evaluation by renal transplant team. Note positive IgG hepatitis
B surface antibody alone (negative HBcAb and negative IgM) is indicative of vaccine
induced immunity and is not grounds for exclusion

- History of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other
components of the vaccine

- Asthma requiring systemic or inhaled steroid treatment within 12 months prior to
enrollment

- Allergy to ganciclovir, valgancyclovir, acyclovir, or famciclovir

- Panel Reactive Antibody (PRA) >/= 20 percent or donor-specific sensitization (by
solid phase assay or flow cytometry) or treatment with intravenous immunoglobulin
(IVIG) for desensitization prior to transplant

- History of primary or acquired immunodeficiency states.

- Routine use of anti-viral prophylaxis for Herpes Simplex Virus (HSV) at the time of
vaccination or within 3 months prior

- Any other condition that in the opinion of the investigator might interfere with the
subject's safety or ability to participate in the study

- Abnormal screening laboratory data resulting in a disqualification of transplant
candidacy. Abnormalities due to underlying disease (e.g., renal failure, anemia,
hyperlipidemia, cardiovascular disease, diabetes) are not exclusionary except as
denoted above for HIV, hepatitis B, hepatitis C, autoimmune disease.

- The subject is currently participating in a study that involves an experimental agent
(vaccine, drug, biologic, device, blood product, or medication) or has received an
experimental agent within 1 month prior to enrollment in this study, or expects to
receive another experimental agent during participation in this study.

- The subject has a diagnosis of schizophrenia, bi-polar disease, or other severe
(disabling) psychiatric diagnosis identified at the pre-transplant evaluation.

- The subject has been hospitalized within the past 5 years prior to enrollment for
psychiatric illness, history of suicide attempt or confinement for danger to self or
others identified at the pre-transplant evaluation.

- Dual listing at more than one transplant center.

- Unwilling to be temporarily inactivated on UNOS wait list for 4 weeks post
vaccination.