Elsevier

Vaccine

Volume 30, Issue 5, 20 January 2012, Pages 904-910
Vaccine

Safety, tolerability, and immunogenicity after 1 and 2 doses of zoster vaccine in healthy adults ≥60 years of age

https://doi.org/10.1016/j.vaccine.2011.11.096Get rights and content

Abstract

Background

Incidence and severity of herpes zoster (HZ) and postherpetic neuralgia increase with age, associated with age-related decrease in immunity to varicella-zoster virus (VZV). One dose of zoster vaccine (ZV) has demonstrated substantial protection against HZ; this study examined impact of a second dose of ZV.

Methods

Randomized, double-blind, multicenter study with 210 subjects ≥60 years old compared immunity and safety profiles after one and two doses of ZV, separated by 6 weeks, vs. placebo. Immunogenicity was evaluated using VZV interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay and VZV glycoprotein enzyme-linked immunosorbent antibody (gpELISA) assay. Adverse experiences (AEs) were recorded on a standardized Vaccination Report Card.

Results

No serious vaccine-related AEs occurred. VZV IFN-γ ELISPOT geometric mean count (GMC) of spot-forming cells per 106 peripheral blood mononuclear cells increased in the ZV group from 16.9 prevaccination to 49.5 and 32.8 at 2 and 6 weeks postdose 1, respectively. Two weeks, 6 weeks and 6 months postdose 2, GMC was 44.3, 42.9, and 36.5, respectively. GMC in the placebo group did not change during the study. The peak ELISPOT response occurred ∼2 weeks after each ZV dose. The gpELISA geometric mean titers (GMTs) in the ZV group were higher than in the placebo group at 6 weeks after each dose. Correlation between the IFN-γ ELISPOT and gpELISA assays was poor.

Conclusions

ZV was generally well-tolerated and immunogenic in adults ≥60 years old. A second dose of ZV was generally safe, but did not boost VZV-specific immunity beyond levels achieved postdose 1.

Highlights

► One dose of zoster vaccine (ZV) elicits substantial protection against HZ. ► This study examined impact of a second dose of ZV. ► ZV was generally well-tolerated and immunogenic in adults ≥60 years old. ► 2nd dose of ZV was generally safe, but did not boost VZV-specific immunity beyond postdose 1 levels.

Introduction

Herpes zoster (HZ; shingles) results from the reactivation of varicella-zoster virus (VZV) residing in the dorsal root or cranial sensory ganglia following the initial infection with VZV (chickenpox [varicella]). HZ is an often painful, unilateral, dermatomal, vesicular rash [1], [2]. ZOSTAVAX® (ZV; zoster vaccine live; Merck) is a vaccine for the prevention of HZ and its complications in individuals ≥60 years of age, that is licensed in the U.S., European Union, and other countries [3], [4] and recommended for vaccination of immune competent people ≥60 years old in the U.S. by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention [5], [6]. The U.S. Food and Drug Administration recently approved the use of ZV in individuals 50–59 years of age [7].

Many studies have demonstrated an age-related decline in VZV-specific cell-mediated immunity (CMI) measured by T lymphocyte proliferation assay (LPA) [8], [9], responder cell frequency (RCF) assay [10], [11], [12], [13], or interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay [14], whereas the levels of serum immunoglobulin antibody to VZV remain relatively constant [9], [10], [11], [12], [13], [14], [15]. These observations suggest that HZ develops in older individuals because their CMI to VZV falls below some critical threshold. The Shingles Prevention Study (SPS) demonstrated that ZV boosted CD4+ T-cell responses to VZV, reduced the incidence of HZ and postherpetic neuralgia (PHN) in adults ≥60 years of age, and lessened acute and chronic pain associated with HZ, presumably through the boosting of VZV-specific immune responses [12], [16].

The potential impact of a second dose of ZV is of interest, not only in terms of safety (e.g. inadvertent double dosing or subjects with a history of HZ), but also because of possible enhanced immunogenicity. This study (NCT00109122) examined the safety, tolerability, and immunogenicity after 1 and 2 doses of ZV in adults 60 years of age and older. Safety data for 42 days following both doses and immunogenicity data through 6 months after the second dose are summarized.

Section snippets

Study population

Healthy subjects ≥60 years of age with a history of varicella and no prior HZ were eligible. Subjects were excluded if they had previous vaccination with any VZV-containing vaccine, exposure to varicella or HZ within 4 weeks prior to study initiation, immune deficiency associated with illness or medical treatments (e.g. corticosteroids), neoplastic disease, receipt of blood products for 3 months prior to the first study dose, hypersensitivity or anaphylactic reactions to gelatin or neomycin

Participant accounting and demographics

Almost all subjects randomized to both treatment groups received two doses of ZV or placebo and had safety follow-up for 42 days after the second vaccination (Fig. 1). One subject in the ZV group was randomized, but not vaccinated, and was not included in the analyses. After receiving at least 1 dose of ZV or placebo, 7 subjects in the ZV group and 7 subjects in the placebo group were discontinued. Subjects in the treatment groups were comparable in age, ethnicity, and gender (Table 1). The

Discussion

The VZV IFN-γ ELISPOT GMCs in healthy adults ≥60 years of age at 2 and 6 weeks after each of two doses of ZV were higher in the ZV group than in the placebo group. Additional sampling of a subset of subjects determined that this VZV-CMI response after each dose of ZV peaked between 1 and 2 weeks after vaccination. The kinetics of these responses after ZV resembled the kinetics observed after HZ, presumably reflecting VZV-specific effector responses after presentation of VZV antigen [13], [21].

Acknowledgments

The authors would like to thank: (a) all the subjects who participated in this study and (b) Nickoya Bundick, Jodie Field, Robin Kaufhold, Rocio Marchese, and Melissa Wooters for contributions to study conduct.

Financial disclosure: Other than employees of Merck Sharp & Dohme Corp. (as indicated on the title page), all authors have been investigators for the sponsor. Dr. Levin is a consultant for Merck and shares intellectual property in the zoster vaccine. Employees may hold stock and/or stock

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  • Cited by (0)

    Data from this manuscript were presented in poster format at the 44th Annual Meeting of the Infectious Disease Society of America, Toronto, Canada, 2006; and the 12th Regional Conference of WONCA Europe, Florence, Italy, 2006.

    1

    JL was employed by Merck at the time of this research; now employed by Pfizer.

    2

    MJC was employed by Merck at the time of this research; now employed by International AIDS Vaccine Institute.

    3

    FPS was employed by Merck at the time of this research; now employed by Philimmune.

    4

    KS was employed by Merck at the time of this research; no current affiliation.

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