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Vaccine 28 (2010) 4204–4209

Contents lists available at ScienceDirect

Vaccine

journa l homepage: www.e lsev ier .com/ locate /vacc ine

afety, tolerability, and immunogenicity of zoster vaccine in subjects with aistory of herpes zoster

ichard Millsa, Stephen K. Tyringb, Myron J. Levinc, Janie Parrinod, Xiaoming Lid,athleen E. Colld, Jon E. Stekd,∗, Katia Schliengerd, Ivan S.F. Chand, Jeffrey L. Silberd

Palmetto Medical Research, Mount Pleasant, SC, United StatesUniversity of Texas Health Science Center, Houston, TX, United StatesUniversity of Colorado Denver and Health Sciences Center, Denver, CO, United StatesMerck Research Laboratories, P.O. Box 1000, North Wales, PA 19454, United States

r t i c l e i n f o

rticle history:eceived 15 May 2009eceived in revised form 29 March 2010ccepted 5 April 2010vailable online 21 April 2010

eywords:oster vaccineerpes zosterpELISAafetymmunogenicity

a b s t r a c t

Background: Prior clinical studies of zoster vaccine enrolled subjects without a history of herpes zoster(HZ), so there are limited data on safety and immunogenicity in vaccinees with a prior history of HZ. Thisstudy was conducted to evaluate the safety and immunogenicity of zoster vaccine recipients who had aprior episode of HZ.Methods: A total of 101 subjects ≥50 years of age with a prior history of HZ were enrolled. They werestratified by number of years since their HZ (5 to 9 years and ≥10 years, in an approximate 2:1 ratio),and randomized 1:1 to one of two vaccination groups. On day 1, Group I was administered zoster vaccineand Group II received placebo. At week 4, Group I received placebo and Group II received zoster vaccine.Subjects were followed for adverse experiences (AEs), exposure to varicella or HZ, and development of anyvaricella/varicella-like or HZ/HZ-like rashes, for 28 days after each injection. Blood samples were obtainedprior to study injection on day 1 and week 4, and at week 8. Serum was assessed for varicella-zoster virus(VZV) antibody concentration by glycoprotein enzyme-linked immunosorbent assay.Results: No serious AEs were reported within the 28-day safety follow-up period following any vaccina-tion. Although a higher percentage of subjects reported injection-site AEs after receiving zoster vaccinethan did placebo recipients, the proportion of subjects reporting systemic clinical AEs was similar in bothgroups. Zoster vaccine induced a VZV antibody response at 4 weeks post-vaccination. The estimatedgeometric mean titer (GMT) ratio (vaccine/placebo) was 2.07 (95% CI: 1.48, 2.88). The geometric mean

fold-rise (GMFR) from prevaccination to week 4 post-vaccination was 2.1 in zoster vaccine recipients,versus 1.0 in placebo recipients.Conclusions: In HZ history-positive adults ≥50 years of age, zoster vaccine: (1) was well tolerated; and (2)significantly boosted the level of VZV antibody from baseline to 4 weeks post-vaccination as measuredby GMT and GMFR. These data support the Advisory Committee on Immunization Practices’ recommen-dation for routine zoster vaccination for all immunocompetent persons ≥60 years of age irrespective of HZ history.

. Introduction

Herpes zoster ([HZ]; shingles) is a neurocutaneous infectionaused by the reactivation of the varicella-zoster virus (VZV), whichas remained latent in the spinal dorsal root or cranial sensory gan-

lia since an episode of chickenpox (varicella) earlier in life [1,2].OSTAVAX® (zoster vaccine live) [3], a vaccine for prevention ofZ and its complications in older adults, is licensed in the U.S.,uropean Union, and other countries [4,5], and is recommended

∗ Corresponding author. Tel.: +1 484 344 2837.E-mail address: jon stek@merck.com (J.E. Stek).

264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2010.04.003

© 2010 Elsevier Ltd. All rights reserved.

for universal vaccination of individuals 60 years of age and olderby the Advisory Committee on Immunization Practices (ACIP) ofthe U.S. Centers for Disease Control and Prevention (CDC) [6,7].

The pivotal efficacy trial (Shingles Prevention Study [SPS])demonstrated that zoster vaccine reduced the incidence of HZ by51% and of post-herpetic neuralgia (PHN) by 67% in adults ≥60years of age, with a 61% relative reduction of burden of illness asso-ciated with HZ pain in vaccinees who developed HZ, presumably

through boosting VZV-specific immune responses [8,9]. Zoster vac-cine boosted VZV-specific cellular and humoral immune responsesfrom baseline to 6 weeks post-vaccination, including antibodyresponses assessed by glycoprotein enzyme-linked immunosor-bent assay (gpELISA) [10].

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The ACIP recommends that zoster vaccine can be administeredo adults of the appropriate age without regard to HZ history [7],ut there is little data to document the response of vaccinees withrior HZ to the vaccine. One reason for this recommendation is thatelf-reporting of prior illness or vaccination status in older adultss frequently unreliable. For example, one study of self-reportedneumococcal vaccination status in adults ≥65 years of age foundhat positive and negative predictive values were only 78% and 61%,espectively [11]. Another study of patient reports of cardiovascu-ar disease compared with patient medical records found positiveredictive values of 31% (medical problem or surgery related torteries to the head, arms, or legs or the aorta) to 78% (high bloodressure) and negative predictive values of 90% (high cholesterol)o 95% (medical problem or surgery related to arteries to the head,rms, or legs or the aorta) [12]. For individuals who may have annclear history of HZ, especially if the HZ occurred in the distantast, questions are expected to be raised by physicians and patientsegarding the use of zoster vaccine.

The purpose of this study (NCT00322231) was to determine theafety profile and immunogenicity of zoster vaccine in individualsho experienced a prior episode of HZ. Favorable data in personsith a confirmed history of HZ will support the ACIP recommenda-

ion, and will help address questions regarding administration ofoster vaccine to individuals whose HZ history is unclear.

. Methods

.1. Study population

Healthy subjects ≥50 years of age with a physician-documentedistory of HZ (≥5 years prior to study entry) were eligible for thetudy. Subjects were excluded if they had an episode of HZ <5 yearsefore study entry; ≥2 prior episodes of HZ; previous vaccinationith any VZV-containing vaccine; immune deficiency associatedith illness or medical treatments; received blood products withinmonths prior to the first study dose through 8 weeks after enroll-ent; had hypersensitivity or anaphylactic reactions to gelatin or

eomycin; currently were using any form of non-topical antiviralherapy; received any live vaccine 4 weeks prior to the first studyose or during the study period or received any inactivated vaccinedays prior to the first study dose or during the study period; or hadhistory of alcohol or drug abuse. The protocol was approved by

he Ethical Review Committee of each participating site and writ-en informed consent was obtained from each subject prior to entrynto the study.

.2. Vaccine

The lyophilized zoster vaccine (∼89,000 plaque-forming unitsPFU]/dose at release) and placebo were supplied to the study cen-ers in 0.7-mL single-dose vials and stored at −15 ◦C or colder.accine and placebo were reconstituted with sterile diluent imme-iately prior to administration, and were indistinguishable fromach other. All subjects received a single 0.65-mL subcutaneousnjection of either zoster vaccine or placebo.

.3. Study design

This was a randomized, double blind, placebo controlled,rossover, multicenter (9 sites) study conducted in the Unitedtates between May 2006 and July 2007 to examine the safety, tol-

rability, and immunogenicity of zoster vaccine administered toubjects with a history of HZ. A total of 101 subjects, ≥50 years ofge with a history of HZ ≥5 years prior to screening, were enrollednd randomized in a 1:1 ratio to one of two vaccination groups.nrollment in each group was stratified in an approximate 2:1 ratio

(2010) 4204–4209 4205

by number of years since their episode of HZ (5 to 9 years and ≥10years). On day 1, subjects in Group 1 were administered zoster vac-cine and subjects in Group 2 received placebo. At week 4, subjectsin Group 1 received placebo and subjects in Group 2 received zostervaccine.

Blood samples were drawn on day 1, week 4, and week 8 post-enrollment and tested for VZV antibody titer by gpELISA. Lesionsamples were to be collected from all rashes that developed duringthe study and evaluated by VZV polymerase chain reaction (PCR)assay for the presence of vaccine strain VZV DNA.

2.4. Study objectives

This was an estimation study with no hypothesis testing. Theprimary objective was to determine whether zoster vaccine wasgenerally well tolerated when administered to HZ history-positiveadults ≥50 years of age. The secondary objective was to determinewhether zoster vaccine was immunogenic when administered toHZ history-positive adults.

2.5. Safety surveillance

Subjects were followed for injection-site and systemic adverseexperiences (AEs), VZV-like rash, and exposure to varicella/HZ for28 days after each injection. Safety and tolerability were assessedby using a Vaccination Report Card (VRC). The subject recorded themaximum size (in inches) of erythema and swelling, and the maxi-mum severity of pain or tenderness (based on a scale of none, mild,moderate, and severe) for injection-site reactions. The site investi-gator evaluated each AE as to seriousness, action taken, maximumintensity (excluding injection-site AEs during days 1 to 5 followingeach vaccination), duration, and relationship to vaccine. All VRCswere reviewed to ensure that all varicella, varicella-like, HZ, orHZ-like rashes and serious AEs were recorded.

2.6. Immunogenicity measurements

Immune response to zoster vaccine was based on VZV gpELISAantibody geometric mean titer (GMT) 4 weeks after administrationof zoster vaccine and the geometric mean fold-rise (GMFR) fromprevaccination to 4 weeks after administration of zoster vaccine.For immunogenicity evaluation, Group 1 subjects who receivedplacebo at week 4 were excluded from immunogenicity analysisat week 8 in order to avoid a carry-over effect of zoster vaccine thatwas administered on day 1.

2.7. Statistical methods

2.7.1. SafetySafety and tolerability was assessed by statistical and clinical

review of safety data collected for 28 days after each injection. Thenumber and proportion (%) of subjects with specific AEs, risk dif-ferences, and the associated 95% confidence intervals (CIs) wereprovided by vaccination group (vaccine or placebo). These sum-maries combined clinical safety information from the two vaccinegroups according to the clinical material subjects received. In accor-dance with the crossover design, in which each subject served ashis/her own control, the risk differences between the two groups(vaccine versus placebo) and the associated two-sided 95% CIs werecalculated based on the method of correlated binomial data [13].

2.7.2. ImmunogenicityThe VZV gpELISA GMT at prevaccination and 4 weeks after

each injection, and corresponding GMFR, in VZV gpELISA anti-body responses were summarized, along with 95% CIs, based on

4206 R. Mills et al. / Vaccine 28 (2010) 4204–4209

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Fig. 1. Sub

he per-protocol population by vaccination group (vaccine ver-us placebo). In addition, the GMT ratio (vaccine/placebo) and its5% CI were provided based on a longitudinal regression model14] adjusting for prevaccination antibody titers and using naturalog-transformed antibody titers. Data for subjects in Group 1, whoeceived placebo at week 4, were excluded from immunogenicitynalysis at week 8, in order to avoid the impact of a carry-over effectf zoster vaccine.

. Results

.1. Participant accounting and demographics

As shown in Fig. 1, 100% (51/51) of the subjects randomizedo Group 1 and 98.0% (49/50) of subjects randomized to Group

completed all study visits. After randomization, one subject inroup 2 was discontinued from the study after withdrawing con-ent prior to receipt of zoster vaccine at dose 2. Subjects in both

Table 1Demographics.

Group 1 aZOSTAVAX®/Placebo

(N = 51)

n (%)

GenderMale 15 (29.4Female 36 (70.6

Age (years)50–59 10 (19.6≥60 41 (80.4Mean 68.3SD 9.9Median 68Range 51–93

RaceWhite 47 (92.2Black 3 (5.9)Asian 1 (2.0)Hispanic 0 (0.0)

N = number of subjects randomized in the vaccination group. n = number oa Indicates order of receipt.

counting.

groups were generally comparable with respect to baseline charac-teristics (Table 1), except there were a higher percentage of femalesin Group 1 (70.6%) than in Group 2 (48.0%). The mean age at enroll-ment was 68.3 years for Group 1 and 67.4 years for Group 2. Theoverall study group was mostly Caucasian, with a higher percentageof females (59.4%) than males (40.6%). All subjects in both groupshad one or more underlying medical conditions, the most com-mon being hypertension (59.4%) and hypercholesterolemia (46.5%).Over 90% of the subjects in both vaccination groups were receiv-ing one or more medication at baseline and during study treatment.The most frequently reported concomitant medications were lipid-reducing agents (∼60%), analgesics (∼57%), and renin-angiotensininhibitors (∼47%).

3.2. Safety

All subjects who had safety data were included in the safetysummary (Table 2). No subjects reported a serious AE during

Group 2 aPlacebo/ZOSTAVAX®

(N = 50)

n (%)

) 26 (52.0)) 24 (48.0)

) 10 (20.0)) 40 (80.0)

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) 42 (84.0)3 (6.0)3 (6.0)2 (4.0)

f subjects contributing to each category.

R. Mills et al. / Vaccine 28 (2010) 4204–4209 4207

Table 2Clinical adverse experience (AE) summary – days 1–28 post-vaccinationa.

ZOSTAVAX® Placebo

n (%) n (%)

Overall per-protocol summaryNumber of subjects 100 101Subjects with follow-up 98 (98.0) 96 (95.0)With one or more AE 51 (52.0) 17 (17.7)

Injection-site AEsb 45 (45.9) 4 (4.2)Systemic AEs 15 (15.3) 13 (13.5)

With vaccine-related systemic AEsc 2 (2.0) 0 (0.0)With serious AEs 0 (0.0) 0 (0.0)

Serious vaccine-related AEs 0 (0.0) 0 (0.0)Who died 0 (0.0) 0 (0.0)

Discontinued due to a vaccine-related AE 0 (0.0) 0 (0.0)

Subjects with 5–9 years since prior HZ episodes (stratum I)Number of subjects 70 71Subjects with follow-up 68 (97.1) 66 (93.0)With one or more AE 37 (54.4) 15 (22.7)

Injection-site AEsb 32 (47.1) 3 (4.5)Systemic AEs 9 (13.2) 12 (18.2)

With vaccine-related systemic AEsc 1 (1.5) 0 (0.0)

Subjects with ≥10 years since prior HZ episodes (stratum II)Number of subjects 30 30Subjects with follow-up 30 (100) 30 (100)With one or more AE 14 (46.7) 2 (6.7)

Injection-site AEsb 13 (43.3) 1 (3.3)Systemic AEs 6 (20.0) 1 (3.3)

With vaccine-related systemic AEsc 1 (3.3) 0 (0.0)

Subjects 50–59 years of ageNumber of subjects 20 20Subjects with follow-up 19 (95.0) 19 (95.0)With one or more AE 9 (47.4) 5 (26.3)

Injection-site AEsb 9 (47.4) 1 (5.3)Systemic AEs 1 (5.3) 4 (21.1)

With vaccine-related systemic AEsc 0 (0.0) 0 (0.0)

Subjects ≥60 years of ageNumber of subjects 80 81Subjects with follow-up 79 (98.8) 77 (95.1)With one or more AE 42 (53.2) 12 (15.6)

Injection-site AEsb 36 (45.6) 3 (3.9)Systemic AEs 14 (17.7) 9 (11.7)

With vaccine-related systemic AEsc 2 (2.5) 0 (0.0)

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= number of subjects in each category. The same subject may appear in different ca AEs were collected after each dose of the relevant vaccination.b All injection-site AEs were considered vaccine-related.c Determined by the investigator to be possibly, probably, or definitely related to

he 28-day safety follow-up period post-vaccination; no subjectsiscontinued due to an AE. One serious AE of tachy–brady syn-rome was reported beyond the safety follow-up period at day 33ost-vaccination 2, following receipt of placebo. This was deter-ined by the investigator to be definitely not related to the study

accine.The proportion of subjects reporting systemic AEs was similar

nd low following receipt of either zoster vaccine (15.3%) or placebo13.5%). Two vaccine-related systemic AEs were reported, both inroup 2 subjects following administration of zoster vaccine (dose): pain and myalgia of moderate intensity; and axillary pain ofild intensity. The rate of reported injection-site AEs was higher

n vaccine recipients (45.9%) than in placebo recipients (4.2%). Theost frequently reported injection-site AEs in vaccine recipientsere erythema (33.7%), pain (36.7%), and swelling (26.5%). All AE

ates were generally similar regardless of time (5 to 9 years versus10 years) since prior HZ episode or age (50 to 59 years versus ≥60ears).

One varicelliform rash was noted in both the zoster vaccineroup and in the placebo group; specimens from these rashes wereot obtained for PCR testing. No other varicella, varicella-like, HZ,r HZ-like rashes were reported during the study. No subjectseported exposure to varicella or HZ.

ries, but counted only once in each category.

accine.

3.3. Immunogenicity

Table 3 summarizes the VZV gpELISA antibody response by ran-domization stratum (time since prior HZ episode: 5 to 9 years and≥10 years), by age group (50 to 59 years and ≥60 years), and for allsubjects combined. Among adults ≥50 years of age, zoster vaccineinduced an increase in VZV gpELISA antibody at 4 weeks post-vaccination with an estimated GMT ratio (vaccine/placebo) of 2.07(95% CI: 1.48, 2.88), which was significantly (p < 0.001) higher thanthat induced by placebo. The GMFR from prevaccination to week 4post-vaccination was higher in the vaccine recipients when com-pared with the placebo-only recipients, regardless of stratum orage group (Table 3).

4. Discussion

Immunogenicity data from previous zoster vaccine clinical tri-

als, with populations that excluded subjects with a history ofHZ, indicate that older adults have readily detectable high base-line VZV gpELISA titers [8,9,15,16]. Immunogenicity data obtainedfrom a substudy of the SPS showed that despite these VZVgpELISA antibody levels (GMT was 278.8) at baseline among

4208 R. Mills et al. / Vaccine 28 (2010) 4204–4209

Table 3VZV gpELISA antibody titer summary.

Endpoint Time point ZOSTAVAX® (N = 100) Placeboa (N = 50)

n Response (95% CI) n Response (95% CI)

All subjects combinedGMT Prevaccination 97 376 (315, 448) 45 390 (289, 526)GMT 4 weeks post-vaccination 97 810 (688, 953) 48 391 (292, 524)GMFR 4 weeks post-vaccination 95 2.1 (1.8, 2.4) 45 1.0 (0.9, 1.1)

Subjects with 5–9 years since prior HZ episodes (stratum I)GMT Prevaccination 67 414 (331, 518) 31 409 (276, 606)GMT 4 weeks post-vaccination 68 888 (719, 1098) 33 451 (307, 663)GMFR 4 weeks post-vaccination 66 2.1 (1.8, 2.5) 31 1.1 (1.0,1.2)

Subjects with ≥10 years since prior HZ episodes (stratum II)GMT Prevaccination 30 302 (231, 395) 14 351 (218, 565)GMT 4 weeks post-vaccination 29 653 (524, 812) 15 286 (189, 433)GMFR 4 weeks post-vaccination 29 2.2 (1.7, 2.8) 14 0.8 (0.7, 1.0)

Subjects 50–59 years of ageGMT Prevaccination 19 304 (182, 508) 8 265 (112, 625)GMT 4 weeks post-vaccination 19 884 (622, 1257) 9 304 (122, 756)GMFR 4 weeks post-vaccination 18 2.8 (1.8, 4.4) 8 1.0 (0.7, 1.3)

Subjects ≥60 years of ageGMT Prevaccination 78 395 (329, 475) 37 424 (306, 588)GMT 4 weeks post-vaccination 78 793 (658, 956) 39 415 (303, 568)

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= number of subjects vaccinated. n = number of subjects contributing to the immua Immunogenicity was assessed for placebo recipients only in Group 2.

accinees, zoster vaccine was immunogenic with a GMFR of.7 at 6 weeks post-vaccination [9]. The SPS also establishedhat the 6 week post-vaccination VZV antibody response mea-ured by gpELISA (individual titer and fold-rise) and measuresf cell-mediated immunity, correlated with protection againstZ [9].

The population with prior HZ enrolled in this study had numeri-ally higher baseline VZV gpELISA antibody levels (GMT: 376, zosteraccine; 390 placebo) on average than the population without priorZ enrolled in the SPS (GMT: 278 zoster vaccine; 291 placebo). Theost-vaccination VZV antibody response was measured at 4 weeks

n this study, which was 2 weeks earlier than in the SPS. Zosteraccine induced a GMFR of 2.1 at 4 weeks post-vaccination in sub-ects with prior HZ, demonstrating that regardless of a subject’s HZistory zoster vaccine elicited an immunologic antibody boost. Theaseline GMTs in subjects with an episode of HZ ≥10 years prioras numerically lower than in subjects with an episode of HZ 5

o 9 years prior, suggesting that the strong boost in VZV-specificmmune response provided by an HZ episode continued to wanever time. The VZV gpELISA GMT 4 weeks after zoster vaccine wasignificantly higher than in placebo recipients. The VZV gpELISAMFR from prevaccination to 4 weeks post-vaccination was higher

n the zoster vaccine group than in placebo recipients regardlessf time since prior HZ episode or age group. In addition, consistentith results from previous studies, subjects in the 50 to 59 years

ld age group had a greater GMFR than subjects in the ≥60 years ofge group [15–17].

Zoster vaccine was generally well tolerated with no signifi-ant AEs during the 28-day safety follow-up phase. The rates ofnjection-site AEs in subjects with prior HZ (45.9%) were compara-le to that observed in the SPS (48.3%), in which subjects with priorZ were excluded [8]; the rates of injection-site AEs for placebo

ecipients were 4.2% and 16.6% in the two studies, respectively.Routine vaccination of all persons aged ≥60 years, including

hose who report a previous episode of HZ, with one dose of zosteraccine is recommended by the ACIP [6]; however, the optimal timeor vaccination has not been established. Data from this clinicalrial confirm that zoster vaccine is safe and immunogenic whendministered to persons with a prior history of HZ.

2.0 (1.7, 2.3) 37 1.0 (0.9, 1.1)

icity summary. VZV antibody GMT is in gpELISA units/mL.

Financial disclosure

Other than employees of Merck & Co., Inc. (as indicated on thetitle page), all authors have been investigators for the sponsor.Employees may hold stock and/or stock options in the company.R. Mills has no additional disclosures. S. Tyring has been a consul-tant to Merck and has served as a speaker for Merck products. M.Levin has been a consultant to Merck, has served as a speaker forMerck products, and shares in the patent for ZOSTAVAX®.

Acknowledgements

The authors would like to thank all the study participants andstaff at the study sites and the ZOSTAVAX® Protocol 014 investiga-tors who made this study possible.

ZOSTAVAX® Protocol 014 Study GroupR. Cain, L. Gilderman, J. Lawless, F. Maggiacomo, M. Nunez, and

B. Venkateswaralu.Contributions: Mills, Tyring, and Levin: enrollment of subjects

and/or data collection, analysis and interpretation of data, andpreparation of manuscript. Parrino, Li, Coll, and Stek: analysis andinterpretation of data, and preparation of manuscript. Schlienger,Chan, and Silber: study concept and design, analysis and interpre-tation of data, and preparation of manuscript. Funding: This studywas funded by Merck & Co., Inc. The sponsor formally reviewed apenultimate draft. All co-authors approved the final version of themanuscript.

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