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Safety of Herpes Zoster Vaccine in the Shingles Prevention StudyA Randomized Trial

Michael S. Simberkoff, MD; Robert D. Arbeit, MD; Gary R. Johnson, MS; Michael N. Oxman, MD; Kathy D. Boardman, RPh;

Heather M. Williams, RN; Myron J. Levin, MD; Kenneth E. Schmader, MD; Lawrence D. Gelb, MD; Susan Keay, MD, PhD;

Kathleen Neuzil, MD; Richard N. Greenberg, MD; Marie R. Griffin, MD; Larry E. Davis, MD; Vicki A. Morrison, MD; and

Paula W. Annunziato, MD, for the Shingles Prevention Study Group

Background: The herpes zoster vaccine is effective in preventingherpes zoster and postherpetic neuralgia in immunocompetentolder adults. However, its safety has not been described in depth.

Objective: To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetentolder adults.

Design: Randomized, placebo-controlled trial with enrollment fromNovember 1998 to September 2001 and follow-up through April2004 (mean, 3.4 years). A Veterans Affairs Coordinating Centergenerated the permutated block randomization scheme, which wasstratified by site and age. Participants and follow-up study person-

nel were blinded to treatment assignments. (ClinicalTrials.gov reg-istration number: NCT00007501)

Setting: 22 U.S. academic centers.

Participants: 38 546 immunocompetent adults 60 years or older,including 6616 who participated in an adverse events substudy.

Intervention: Single dose of herpes zoster vaccine or placebo.

Measurements: Serious adverse events and rashes in all partici-pants and inoculation-site events in substudy participants during thefirst 42 days after inoculation. Thereafter, vaccination-related seri-ous adverse events and deaths were monitored in all participants,and hospitalizations were monitored in substudy participants.

Results: After inoculation, 255 (1.4%) vaccine recipients and 254(1.4%) placebo recipients reported serious adverse events. Localinoculation-site side effects were reported by 1604 (48%) vaccinerecipients and 539 (16%) placebo recipients in the substudy. Atotal of 977 (56.6%) of the vaccine recipients reporting local sideeffects were aged 60 to 69 years, and 627 (39.2%) were olderthan 70 years. After inoculation, herpes zoster occurred in 7 vaccinerecipients versus 24 placebo recipients. Long-term follow-up (mean,3.39 years) showed that rates of hospitalization or death did notdiffer between vaccine and placebo recipients.

Limitations: Participants in the substudy were not randomly se-lected. Confirmation of reported serious adverse events with med-

ical record data was not always obtained.

Conclusion: Herpes zoster vaccine is well tolerated in older, immuno-competent adults.

Primary Funding Source: Cooperative Studies Program, Depart-ment of Veterans Affairs, Office of Research and Development;grants from Merck to the Veterans Affairs Cooperative StudiesProgram; and the James R. and Jesse V. Scott Fund for ShinglesResearch.

Ann Intern Med. 2010;152:545-554. www.annals.org

For author affiliations, see end of text.

Herpes zoster occurs with increasing frequency and sever-ity with increasing age (1, 2). It is often associated withpain and discomfort that may interfere with functional statusand quality of life during the acute phase. Herpes zoster painand discomfort may persist for weeks, months, or even years.This debilitating complication, known as postherpetic neural-

gia, results in significant decrements in quality of life andability to perform activities of daily living (24). Antiviraltherapy has limited effect on the frequency and severity ofpostherpetic neuralgia. Therefore, a safe and effective vaccineto prevent herpes zoster and postherpetic neuralgia in olderadults at greatest risk is highly desirable.

We and others (5, 6) have reported that live attenuatedOka/Merck herpes zoster vaccine (Merck & Co., White-house Station, New Jersey) is immunogenic in populations

who have had varicella-zoster virus (VZV) infection, in-cluding older adults, and in persons lacking VZV antibody(6). Veterans Affairs Cooperative Study 403 (SPS [ShinglesPrevention Study]) (7, 8) showed that herpes zoster vaccine

was effective in preventing herpes zoster and postherpeticneuralgia in persons 60 years or older. Health care provid-ers and patients need detailed information about the safetyand tolerability, as well as efficacy, of a new vaccine to

make informed decisions about its use. Determining thesafety profile of herpes zoster vaccine was a major studyobjective. We present a comprehensive analysis of ourobservations.

METHODSDesign Overview

The methods have been published elsewhere (7). Thestudy was a randomized, placebo-controlled trial of herpes

See also:

Print

Editors Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546

Editorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 609

Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555

Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-20

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Appendix Tables

Appendix Figures

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Annals of Internal Medicine Article

www.annals.org 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 545

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zoster vaccine designed to test the vaccines safety andefficacy. All participants and follow-up study personnel,except for personnel administering the vaccine, were blindedto treatment throughout the study until data were re-viewed for accuracy and the database was locked. Thestudy was approved by the Human Rights Committee ofthe West Haven Department of Veterans Affairs Co-operative Studies Program Coordinating Center, WestHaven, Connecticut, and by the institutional reviewboard at each site.

Setting and Participants

The study was conducted at 22 academic medical cen-ters in the United States between 1998 and 2004. Weenrolled immunocompetent adults 60 years or older with ahistory of chickenpox or more than 30 years of residence inthe continental United States and no history of herpeszoster. The mean follow-up was 3.4 years.

Randomization and Intervention

At each site, we stratified consenting eligible partici-pants by age (60 to 69 years or 70 years) and randomlyassigned them to receive investigational herpes zoster vac-cine or placebo. The Coordinating Center generated a per-mutated block randomization. Allocation to herpes zostervaccine and placebo was balanced in blocks of 6 vials andin both of the prespecified age strata for each of the 22study sites. Single-dose vials of herpes zoster vaccine (me-dian potency, 24 600 plaque-forming units per dose) andplacebo were maintained at 20 C. Vials were reconsti-tuted, and participants were inoculated subcutaneously inthe nondominant deltoid region within 30 minutes afterthe vial was removed from the freezer. Study personnel

who reconstituted the vials and inoculated the participantshad no subsequent contact with them and no subsequentrole in data collection or analysis.

Follow-up Procedures and Outcome Measures

Participants and study personnel responsible forfollow-up assessments were blinded to treatment assign-ment. Participants were followed monthly, either byparticipant-initiated reports to a toll-free automated tele-phone response system or by direct calls from study site

personnel. In addition, all participants were questionedabout the occurrence of rashes and serious adverse eventsduring the 42 days after inoculation.

Early in the enrollment phase, approximately 300participants at each study site (6616 overall) were alsoenrolled in an adverse events substudy. Participation inthe substudy was voluntary and not randomized. Partic-ipants were asked to complete a detailed vaccinationreport card designed to capture all adverse events thatoccurred during the first 42 days after inoculation. Thevaccination report card prompted persons to record oraltemperature for the first 21 days, erythema, swelling,

pain and tenderness, and rash at the inoculation site;any other inoculation-siterelated signs or symptoms;rashes away from the inoculation site; exacerbations ofpreexisting diseases; new local or systemic illnesses; hos-pitalizations; and any other event the patient consideredmedically important.

Serious adverse events, defined by concurrent U.S.Food and Drug Administration and International Com-mittee on Harmonization guidelines (9), were moni-tored throughout the study by both active and passivesurveillance. They were reported on study-specific Med-

Watch forms. During the first 42 days after inoculation,

all enrolled persons were followed actively for seriousadverse events. After that, investigators were instructedto report all deaths as well as any serious adverse eventconsidered to be possibly, probably, or definitely relatedto vaccination. In addition, persons in the substudy

were questioned monthly regarding hospitalizations. AllMedWatch forms were reviewed by the CooperativeStudies Program Research Pharmacist, the NationalStudy Coordinator, the Study Chairman, SPS personnelat the Coordinating Center, and personnel at Merck(investigational new drug holder for the vaccine). Weresolved any questions by querying the site that reported

the serious adverse event.Each adverse event was recorded on a specific study

form and, before the study was unblinded, was coded bythe site by using a controlled vocabulary system (CodingSymbols from a Thesaurus of Adverse Reaction Terms[COSTART]) (10). Three investigators blindly reviewedall serious adverse events reported during the 42 daysafter inoculation and assigned each event to 1 of 6pathophysiologic categories. Appendix Table 1 (avail-able at www.annals.org) defines these categories. Dis-crepancies in assignment were resolved by discussionamong these investigators.

Context

The herpes zoster vaccine helps prevent herpes zoster andpostherpetic neuralgia in older adults, but is it safe?

Contribution

This secondary report from a very large trial showed that

few vaccine and placebo recipients, and equal numbers inboth groups, reported serious adverse events (1.4%).

More vaccine recipients than placebo recipients (48% vs.16%) reported inoculation-site side effects, such as red-ness and tenderness. Inoculation-site side effects were

more common in persons aged 60 to 69 years than inpersons older than 70 years.

Implication

Herpes zoster vaccine causes minor local inoculation-siteadverse effects but no more serious adverse events thandoes placebo.

The Editors

Article Safety of Herpes Zoster Vaccine

546 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 www.annals.org

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Statistical Analysis

All data were stored and analyzed at the CoordinatingCenter. We performed analyses by using SAS statisticalsoftware (SAS Institute, Cary, North Carolina). We calcu-lated the rates of adverse events during the first 42 daysafter inoculation by dividing the number of persons withthe event by the number of persons with safety follow-up.

We calculated risk differences between groups (vaccine placebo) and 95% CIs by using an asymptotic method forthe difference between 2 proportions; for analyses of treat-ment differences, including both age cohorts, we weightedthe proportions by the number of participants with safetyfollow-up in each age stratum at the 22 sites (11). Wecalculated rates of serious adverse events, hospitalization, ordeath occurring at any time during follow-up by dividingthe number of persons with at least 1 event by the numberof person-years of safety follow-up. Cumulative event rates

were calculated by using product-limit estimates for time-to-event data and compared treatment groups and age

strata by using a log-rank test stratified by site. We per-formed post hoc analyses of severity and duration in par-ticipants who had an adverse event. Duration of adverseevents was compared between groups by using the Wil-coxon rank-sum test, and severity of adverse events wascompared between groups by using the CochranMantelHaenszel chi-square test statistic stratified by age and site.

We used the time to the first occurrence of a serious ad-verse event in each person for the time-to-event analyses.

When assessing severity of inoculation site or systemic ad-verse events, we used the report of the most severe adverseevent per person, rather than the first report. We did not

prespecify within-age stratum comparisons of risk betweentreatments; however, we performed them in response toquestions to the study group on the safety of the vaccine inmore elderly persons.

Role of the Funding Source

The trial was funded by the Cooperative Studies Pro-gram of the Department of Veterans Affairs, Office of Re-search and Development, and by a grant to the Veterans

Affairs Cooperative Studies Program from Merck. Merckwas involved in review of all completed MedWatch formsbut not in coding the adverse events, contacting the sites,performing the statistical analyses reported here, preparing

the manuscript, or submitting the manuscript for publica-tion. An executive committee that included 2 nonvotingmembers employed by Merck was primarily responsible forthe conduct of the study.

RESULTSA total of 38 546 older adults participated in this

study (Figure 1). During the first 42 days after vaccination,we obtained safety follow-up data from 37 388 (97%) par-ticipants. A total of 6575 (99%) of the 6616 substudyparticipants completed the vaccination report card. Morethan 95% of the 38 546 trial participants were followed to

the end of the study and completed a closeout interview(mean safety follow-up, 3.39 years; range, 1 day to 5.40years). In persons without closeout interviews, 1598(4.1%) were known to have died, 132 (0.3%) withdrew,and 113 (0.3%) were lost to follow-up. The proportion ofpersons completing safety surveillance and the reasons for

or rates of incomplete follow-up did not differ betweengroups.In all participants, the frequency and distribution of

vesicular rashes occurring during the first 42 days aftervaccination differed between vaccine and placebo recip-ients. A varicella-like rash, defined as 1 or more un-grouped vesicles, occurred at the inoculation site morefrequently in vaccine recipients than placebo recipients(0.11% vs. 0.04%); however, rates of rashes occurringelsewhere were similar (0.10% vs. 0.07%). The varicella-like rashes occurring at the inoculation site typicallyconsisted of small numbers of vesicles, did not spread,

and were transient (mean duration, 5.4 days in vaccinerecipients and 6.7 days in placebo recipients). Varicella-like rashes away from the inoculation site tended to lastlonger than inoculation-site rashes (mean duration, 17.6days [range, 3 to 110 days] in vaccine recipients and18.6 days [range, 1 to 92 days] in placebo recipients).Of the nonherpes zoster rashes, 11 were evaluated bycentral polymerase chain reaction (PCR) assay, and 5

were evaluated by local virus culture. All results werenegative for both wild-type and Oka vaccine strainVZV. One vaccine recipient had a disseminatedvaricella-like rash on day 18 that was assessed as proba-bly related to the inoculation but was not suspected tobe herpes zoster. During the 42 days after inoculation,herpes zosterlike rashes (defined as multiple vesicles ina dermatomal distribution) occurred more often in pla-cebo recipients than vaccine recipients. Of these, herpeszoster was confirmed in 24 placebo recipients and 7vaccine recipients. Specimens were available from all but1 case in each treatment group, and all 29 tested posi-tive for wild-type VZV DNA by PCR assay. Nonetested positive for the Oka vaccine strain VZV.

In substudy participants, the most common adverseevents at the inoculation site were erythema, swelling, andpain and tenderness (Table 1). For both treatment groups,

inoculation-site adverse events were more common inyounger persons than in older persons (Table 1). Mostevents were mild or moderate in severity (Table 2). Ery-thema and swelling at the inoculation site were the onlyevents in which the intensity was statistically significantlygreater in vaccine recipients than in placebo recipients.However, fewer than 1% of vaccine recipients reportedthem as severe. Erythema, swelling, pain and tenderness,and warmth at the inoculation site persisted for longer invaccine recipients than placebo recipients (Appendix Table2, available at www.annals.org). Erythema was the onlylocal adverse event that persisted longer in younger vaccine

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Figure 1. Safety monitoring in the Shingles Prevention Study.

Entire study follow-up

1673 (96.6%) Completed 1663 (96.3%)

45 (2.6%) Died 48 (2.8%)

7 (0.4%) Withdrew 11 (0.3%)

7 (0.4%) Lost 5 (0.3%)

42-d safety follow-up

1726 (99.7%) Completed 1709 (99.0%)

6 (0.3%) No contact 18 (1.0%)

Herpes zoster

vaccine

(n = 1732)

Aged 6069 y

(n = 3459 [53.8%])

Adverse event substudy*

Placebo

(n = 1727)

Enrolled in the adverse event substudy (n = 6616)


1493 (92.6%) Completed 1428 (92.5%)

99 (6.1%) Died 106 (2.8%)

12 (0.7%) Withdrew 7 (0.3%)

9 (0.6%) Lost 3 (0.3%)


1600 (99.2%) Completed 1540 (96.8%)

13 (0.8%) No contact 4 (0.3%)

Herpes zoster

vaccine

(n = 1613)

Aged 70 y

(n = 3157 [46.2%])

Placebo

(n = 1544)


10 109 (97.4%) Completed 10 073 (97.4%)

218 (2.1%) Died 246 (2.4%)

23 (0.2%) Withdrew 29 (0.3%)

28 (0.3%) Lost 21 (0.2%)


10 100 (97.3%) Completed 10 095 (97.4%)278 (2.7%) No contact 274 (2.6%)

Herpes zoster

vaccine

(n = 10 378)

Aged 6069 y

(n = 20 747 [53.8%])

Total study population

Placebo

(n = 10 369)

Participants enrolled (n = 38 546)


8250 (92.8%) Completed 8284 (93.0%)

575 (6.5%) Died 549 (6.2%)

42 (0.5%) Withdrew 55 (0.6%)

25 (0.3%) Lost 19 (0.2%)


8571 (96.4%) Completed 8622 (96.8%)321 (3.6%) No contact 285 (3.2%)

Herpes zoster

vaccine

(n = 8892)

Aged 70 y

(n = 17 799 [46.2%])

Adverse event substudy

(n = 6616 [17.2%])

Placebo

(n = 8907)

* Enrollment into the adverse event substudy was independent of blinded random assignment to receive vaccine or placebo. During the first year of thestudy, we completed a convenience sample of 300 participants per site, with a target of 50% in each age group.



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recipients than older recipients (data not shown). Pruritusat the inoculation site occurred more frequently in vaccinerecipients than placebo recipients in both age strata (Table1) and persisted longer in vaccine recipients than inplacebo recipients (Appendix Table 2). Inoculation-siteevents occurred sooner after vaccination in placebo recipi-

ents than vaccine recipients (mean, 1.7 vs. 2.3 days; P

0.001), whereas the time to the first systemic adverse event(mean, 15.9 vs. 15.2 days) and the duration of systemicadverse events (mean, 14.8 vs. 19.1 days) were similar invaccine and placebo recipients (data not shown).

During the first 42 days after inoculation, serious ad-verse events were reported in 1.4% of all participants ineach group (Table 3). The point estimates for risk differ-ence between treatment groups were 0.12% or less whenanalyzed overall, by prespecified age strata, or by COSTARTbody system (Table 3). Rates of serious adverse events in-creased with age at similar rates in vaccine recipients andplacebo recipients. A time-to-event analysis by age groupfor the whole study population showed no statistically sig-

nificant difference between vaccine recipients and placeborecipients (Figure 2).

We performed a post hoc analysis for serious ad-verse events that occurred during the 42 days after in-oculation in all participants 80 years or older (Table 3).Follow-up of serious adverse events was available for

96.6% (1220 of 1263) of vaccine recipients and 96.6%(1289 of 1335) of placebo recipients in this age group.The overall rate of serious adverse events did not statis-tically significantly differ by treatment group in partic-ipants 80 years or older (risk difference, 0.6 percentagepoints [95% CI, 0.5 percentage points to 1.7 percent-age points]), and there were no statistically significantdifferences between groups for any body system (COSTART)or Physiologic Diagnostic Category classification (data notshown).

In substudy participants, the overall rate of serious ad-verse events during the 42 days after inoculation was 1.6%(Table 4). As reported elsewhere (7), the rate of seriousadverse events was higher in vaccine recipients than in pla-

Table 1. Adverse Events at the Inoculation Site in Substudy Participants

Variable Aged 60 to 69 Years Aged >70 Years Risk DifferenceBetween Age Strata inVaccine Recipients(95% CI), percentagepoints*

Herpes ZosterVaccine Group

Placebo Group Risk Difference(95% CI),percentage points*

Herpes ZosterVaccine Group

Placebo Group Risk Difference(95% CI),percentage points*

Number Risk,%

Number Risk,%

Number Risk,%

Number Risk,%

Enrolled persons 1732 1727 1613 1544

Persons withsafetyfollow-up

1726 1709 1600 1540

Persons withoutsafetyfollow-up

6 18 13 4

Persons with 1inoculation-site adverseevent

977 56.6 326 19.1 37.7 (34.6 to 40.6) 627 39.2 213 13.8 25.4 (22.5 to 28.4) 16.4 (13.1 to 19.8)

Adverse eventprompted foron the VRC

Erythema 718 41.6 136 8.0 33.8 (31.2 to 36.5) 470 29.4 91 5.9 23.6 (21.1 to 26.2) 11.1 (8.0 to 14.3)

Swelling 559 32.4 92 5.4 27.1 (24.7 to 29.6) 312 19.5 55 3.6 16.0 (13.9 to 18.2) 12.2 (9.2 to 15.1)

Pain/tenderness 743 43.0 174 10.2 32.9 (30.2 to 35.7) 404 25.3 104 6.8 18.5 (16.0 to 21.0) 17.1 (13.9 to 20.2)

Rash 12 0.7 1 0.1 0.6 (0.2 to 1.2) 8 0.5 5 0.3 0.2 (0.4 to 0.7) 0.2 (0.5 to 0.8)

Self-reportedadverse event

Pruritus 164 9.5 18 1.1 8.5 (7.1 to 10.1) 73 4.6 15 1.0 3.6 (2.5 to 4.8) 4.6 (2.9 to 6.4)

Hematoma 23 1.3 31 1.8 0.5 (1.3 to 0.4) 30 1.9 15 1.0 0.9 (0.1 to 1.8) 0.5 (1.5 to 0.3)

Mass 22 1.3 1 0.1 1.2 (0.7 to 1.9) 8 0.5 1 0.1 0.4 (0.1 to 1.0) 0.8 (0.2 to 1.6)

Warmth 39 2.3 7 0.4 1.9 (1.1 to 2.8) 18 1.1 4 0.3 0.9 (0.3 to 1.6) 1.0 (0.2 to 2.0)

Other adverseevent

20 1.2 10 0.6 0.6 (0.1 to 1.3) 13 0.8 5 0.3 0.5 (0.1 to 1.1) 0.3 (0.4 to 1.1)

VRC vaccination report card.* We calculated the risk difference by subtracting the estimated risk for the placebo group from the estimated risk for the herpes zoster vaccine group. We computed the CIfor the risk difference and the Pvalue for testing whether the risk difference is different from 0 on the basis of an asymptotic method for difference of 2 binomial proportions.

We stratified all analyses by site. Risk differences and 95% CIs are provided for events prompted for on the VRC and for self-reported events with an incidence rate 1%. We calculated the risk as the percentage of persons with 1 adverse event in persons with follow-up in each age group. P 0.001. P 0.050. Reported in 0.1% of persons.



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cebo recipients (1.9% vs. 1.3%; P 0.038, analysis strat-ified by age and site). Although some serious adverse eventsoccurred more often in vaccine recipients than in placeborecipients (for example, cardiovascular body system classi-fication in 20 vs. 12 persons, respectively), none of thedifferences at or below the level of body system was statis-tically significant (7). Because of limitations in diagnosticclassifications based on body system, we further analyzedall serious adverse events that occurred during the first 42days after vaccination by using pathophysiologic criteria(Appendix Table 1). We subclassified serious adverseevents related to vascular disease on the basis of whetherthey were consistent with acute vascular pathology (for ex-ample, myocardial infarction, strokes) or with functionaldisturbance associated with underlying vascular disease (forexample, congestive heart failure). The overall rates of vas-cular events (that is, vascular [pathology] plus vascular[functional]) were nearly identical between vaccine recipi-

ents and placebo recipients in the total study population(99 [0.5%] vs. 101 [0.6%]) (Table 3). When each categoryof vascular pathophysiology was considered separately,there were small numerical differences between treatmentgroups that were neither statistically significant nor clini-cally meaningful (Table 3). We observed similar results

when we analyzed serious adverse events in the substudy(Table 4).

Over the course of the entire study, rates of death inthe total SPS population (Appendix Figure 1, available at

www.annals.org) and rates of hospitalization in the sub-study (Appendix Figure 2, available at www.annals.org)

were greater in the older age stratum than in the youngerage stratum. However, rates for each treatment group, bothoverall and by age strata, were essentially identical and didnot vary appreciably over the course of the study. Of note,the death rate in study participants was substantially lowerthan that reported by the U.S. National Health Statistics

Table 2. Severity of Inoculation-Site Adverse Events in Substudy Participants

Inoculation-SiteAdverse Event

Persons With Adverse Event, n (%) P Value forDifferencein Severity*Herpes Zoster

Vaccine GroupPlacebo Group

Erythema 1188 (100) 227 (100) 0.001

Mild 924 (77.8) 218 (96.0)Moderate 209 (17.6) 7 (3.1)

Severe 55 (4.6) 2 (0.9)

Swelling 871 (100) 147 (100) 0.001

Mild 678 (77.8) 139 (94.6)

Moderate 157 (18.0) 7 (4.8)

Severe 36 (4.1) 1 (0.7)

Pain 1147 (100) 278 (100) 0.064

Mild 1053 (91.8) 266 (95.7)

Moderate 91 (7.9) 12 (4.3)

Severe 3 (0.3) 0 (0.0)

Rash 20 (100) 6 (100) 0.54

Mild 17 (85.0) 4 (33.3)

Moderate 3 (10.0) 2 (66.7)

Pruritus 237 (100) 33 (100) 0.28

Mild 208 (87.8) 30 (90.9)

Moderate 27 (11.4) 2 (6.1)

Severe 2 (0.8) 1 (3.0)

Hematoma 53 (100) 46 (100) 0.42

Mild 46 (86.8) 41 (89.1)

Moderate 5 (9.4) 5 (10.9)

Severe 2 (3.8) 0 (0.0)

Mass 30 (100) 2 (100) 0.60

Mild 25 (83.3) 2 (100.0)

Moderate 5 (16.7) 0 (0.0)

Warmth 57 (100) 11 (100) 0.94

Mild 52 (91.2) 10 (90.9)Moderate 5 (8.8) 1 (9.1)

* For differences in distribution of intensity of the event between treatment groups (CochranMantelHaenszel chi-square test statistic controlling for age group and site). For erythema, but not for any other individual inoculation-site event, there was a significant effect of age on intensity in recipients of herpes zoster vaccine ( P 0.048;data not shown).



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for the general U.S. population 60 years or older (12).When we stratified the study population into 5-year agegroups to match the U.S. National Health Statistics data,the mortality rate in each age group was less than half(43% to 49%) of that reported for the general population.This is predictable given the enrollment procedures, which

excluded persons expected to have limited life expectancyor comorbid conditions associated with high risk for herpeszoster complications (for example, known immunosup-pression), to ensure the safety of study participants andadequate duration of follow-up.

DISCUSSIONAs shown elsewhere by the SPS (7), 1 dose of herpes

zoster vaccine reduced the burden of illness due to herpeszoster, as well as the incidence of postherpetic neuralgiaand herpes zoster. Our report further demonstrates that

herpes zoster vaccine had remarkably low rates of acutelocal reactions and, across the study population, had nodetectable effect on the rates of serious adverse events dur-ing the 42 days after inoculation or on the rates of deathduring the entire mean 3.39 years of follow-up.

An important safety consideration for any live atten-

uated virus vaccine is that the vaccine not cause thedisease it is designed to prevent. We reviewed all rashesreported by study participants during the 42 days afterinoculation. Vesicular rashes at the injection site weremore common in vaccine recipients than in placebo re-cipients, but overall these events were infrequent andlimited in extent and duration. Neither wild-type norOka vaccine strain VZV was shown in these injection-site lesions, either by culture or PCR assay, and there

were no documented episodes of disseminated vesiculardisease caused by vaccine virus.

Table 3. Rates of Serious Adverse Events Occurring From Day 0 to 42 After Inoculation in the Total Study Population

Variable Herpes Zoster Vaccine Group* Placebo Group Risk Difference (95% CI),percentage points

P Value

Persons WithAny SeriousAdverseEvents, n

Persons With>1 SeriousAdverseEvents, n (%)

Persons WithAny SeriousAdverseEvents, n

Persons With>1 SeriousAdverseEvents, n (%)

Enrolled persons 324 255 (1.37) 320 254 (1.36) 0.01 (0.23 to 0.25) 0.93

Age

60 to 69 y 135 113 (1.12) 125 101 (1.00) 0.12 (0.17 to 0.40) 0.41

70 y 189 142 (1.66) 195 153 (1.78) 0.12 (0.51 to 0.27) 0.55

70 to 80 y 150 115 (1.57) 165 132 (1.80) 0.23 (0.65 to 0.19) 0.2880 y 39 27 (2.24) 30 21 (1.64) 0.60 (0.49 to 1.74) 0.28

Body system (COSTART)

General body 48 43 (0.23) 46 45 (0.24) 0.01 (0.11 to 0.09) 0.84

Cardiovascular 96 81 (0.43) 86 72 (0.38) 0.05 (0.08 to 0.18) 0.45

Digestive 41 35 (0.19) 57 43 (0.23) 0.04 (0.14 to 0.05) 0.37

Endocrine 1 1 (0.01) 4 3 (0.02) 0.01 (0.05 to 0.02) 0.32

Hemic and lymphatic 5 5 (0.03) 2 2 (0.01) 0.02 (0.02 to 0.06) 0.25

Metabolic/nutritional 5 5 (0.03) 3 2 (0.01) 0.02 (0.02 to 0.06) 0.25

Musculoskeletal 15 14 (0.08) 15 14 (0.07) 0.00 (0.06 to 0.06) 0.99

Nervous system 35 32 (0.17) 34 34 (0.18) 0.01 (0.10 to 0.08) 0.82

Respiratory 30 28 (0.15) 25 23 (0.12) 0.03 (0.05 to 0.11) 0.48

Skin 28 27 (0.14) 31 30 (0.16) 0.02 (0.10 to 0.07) 0.70

Sight/sense 4 4 (0.02) 0 0 (0.00) 0.02 (0.00 to 0.06) 0.045

Genitourinary 16 16 (0.09) 17 17 (0.09) 0.01 (0.07 to 0.06) 0.86

Diagnostic group

Vascular (pathology) 79 60 (0.32) 77 67 (0.36) 0.04 (0.16 to 0.12) 0.55

Vascular (functional) 45 39 (0.21) 39 34 (0.18) 0.03 (0.06 to 0.12) 0.54

Cancer 52 49 (0.26) 46 46 (0.25) 0.02 (0.09 to 0.12) 0.76

Infection 35 28 (0.15) 30 19 (0.10) 0.05 (0.03 to 0.13) 0.186

Accident 16 13 (0.07) 13 12 (0.06) 0.01 (0.05 to 0.07) 0.83

Allergic reaction 3 3 (0.02) 4 3 (0.02) 0.00 (0.04 to 0.04) 1.00

Autoimmune disorder 2 2 (0.01) 2 2 (0.01) 0.00 (0.03 to 0.03) 0.99

Other 92 61 (0.33) 109 71 (0.38) 0.05 (0.18 to 0.07) 0.39

COSTART Coding Symbols from a Thesaurus of Adverse Reaction Terms.* 19 270 participants enrolled, 18 671 participants with safety follow-up. 19 276 participants enrolled, 18 717 participants with safety follow-up. At time of enrollment. Not a prespecified age stratum or a prespecified analysis. Appendix Table 1 (available at www.annals.org) defines the diagnostic groups.



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The prespecified primary efficacy analysis excludedcases of herpes zoster that occurred during the first 30 days

after vaccination. However, in the safety analysis of all ve-sicular rashes during the first 42 days after inoculation,herpes zoster occurred more frequently in placebo recipi-ents than in vaccine recipients (24 vs. 7 confirmed cases,respectively), indicating not only that herpes zoster vaccinedid not cause herpes zoster but that it protected againstherpes zoster during this early period, as well as later. Theearly onset of vaccine-induced protection is consistent

with immunologic studies (13) indicating that VZV-seropositive, latently infected persons have an anamnesticresponse to herpes zoster vaccine.

Inoculation-site reactions were the primary differencein the rate of adverse events in recipients of herpes zostervaccine versus placebo in the immediate postinoculationperiod. These reactions were typically transient and rarelysevere. Overall, the reactions were similar to those observedin recipients of other vaccines recommended for olderadults (14). Inoculation-site reactions were statistically sig-nificantly more frequent and intense in younger vaccinerecipients than in older recipients. We reported elsewhere(5) that the immune response to herpes zoster vaccine wasmore vigorous in younger participants than in older par-ticipants. These findings suggest that the local side effectsof the herpes zoster vaccine may have been mediated byimmune responses to the attenuated vaccine virus.

Per protocol, during the 42 days after inoculation,there was active surveillance across the study for the occur-rence of serious adverse events, and nearly all persons wereexplicitly questioned. There were no differences or sugges-tive trends in the frequency or distribution of serious ad-verse events between vaccine and placebo recipients in the

total study population in any of the prespecified analyses,including by age strata, COSTART body system and sub-terms, and time-to-event analysis. The last is particularlycompelling because vaccine-associated serious adverse events

would be expected to show temporal clustering (15, 16).While our study was in progress, reports based on un-

controlled observations (1720) suggested that smallpoxvaccine was associated with acute cardiovascular adverseevents, including ischemia. One proposed mechanism(17) was that inflammatory mediators (for example,-interferon and tumor necrosis factor) generated duringthe immune response to that live virus vaccine might haveincreased the risk for acute vascular pathology. Therefore,

in addition to the prespecified safety analyses, we con-ducted 2 post hoc analyses to address concerns about anypossible vaccine-associated increase in the risk for vascularevents in older adults, who are the target population forherpes zoster vaccine. Rates of serious adverse events in the42 days after inoculation did not statistically significantlydiffer in vaccine and placebo recipients 80 years or older,potentially the most vulnerable trial participants. In addi-tion, while blinded to individual treatment assignments,

we classified each adverse event on the basis of inferredpathophysiology, with particular emphasis on cardiovas-cular and cerebrovascular events. These analyses also

found no statistically significant or clinically meaningfuldifferences between recipients of herpes zoster vaccineand placebo.

The substudy, which included approximately one sixthof the total study population, was designed to providedetailed information about relatively high-frequency,vaccination-related events (for example, inoculation-siteevents). Although participants were not selected at ran-dom, enrollment was well balanced by treatment in eachage stratum. The proportion of persons with 1 or moreserious adverse events was essentially the same in thesubstudy as in the total study population, indicatingthat ascertainment of the low-frequency but medicallyimportant events was similar in both populations. How-ever, in contrast to the total study population, seriousadverse events in the substudy were statistically morefrequent in vaccine recipients than in placebo recipients(P 0.038). This difference was not reflected in theprespecified analyses by age strata or by using theCOSTART classification method; specifically, there

were no statistically significant differences for specificevents or at the level of body system except for thesight/sense system, in which there were only 4 events.Our post hoc analysis, which was blinded and in whichserious adverse events were classified by pathophysio-

Figure 2. Time to first SAE from day 0 to day 42 for the total

study population.

CumulativeSAERate,%

Time to First SAE, d

Placebo, 6069 y

Herpes zoster vaccine, 6069 y

Placebo, 70 y


0 6 12 18 24 30 36 42

0

1

0.5

1.5

2

The cumulative rates of SAEs are shown for the time to the first SAEfrom days 0 to 42 after inoculation in all study participants. There is nosignificant treatment difference within age strata: For persons aged 60 to69 years, log-rankP 0.41; for persons 70 years or older, log-rank P0.56. Overall treatment comparison: log-rankP 0.94. Comparison ofage strata 60 to 69 years versus 70 years or older: log-rank P 0.001.SAE serious adverse event.



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logic category, also revealed no statistically significantdifferences in rates of these events in the recipients ofherpes zoster vaccine versus placebo in the substudy. Inaddition, beyond 42 days after inoculation, the treat-ment groups did not differ in any analysis. On the basisof all available data and analyses, we conclude that theobserved difference in rates of serious adverse events inthe vaccine recipients and placebo recipients in the sub-study, although statistically significant, represents achance occurrence in a selected subgroup and does notreflect vaccine-related events.

Our study has limitations. At enrollment, participantswere ambulatory and noninstitutionalized and 95% werewhite. We excluded severely debilitated older adults andthose with known immunosuppressive disease or treat-ment. The safety and efficacy of herpes zoster vaccine insuch populations are uncertain. Participants in the sub-study were not randomly selected. Serious adverse eventsnot treated at study sites were assessed by participants re-ports and, although efforts were made in every case, these

were not always confirmed by medical record review.In summary, our analyses showed that herpes zoster

vaccine was well tolerated and safe in older immunocom-petent adults. There was a modest increase in the rate of

acute inoculation-site events in vaccine recipients, but noincreased risk for herpes zoster itself and no pattern sug-gesting any serious adverse events were causally related tovaccination. Given the substantial protection that herpeszoster vaccine provides against the occurrence and morbid-ity of herpes zoster and, specifically, postherpetic neuralgia,

we believe that this safety profile supports the recommen-dation for routine use of herpes zoster vaccine in immuno-competent older adults, who are at increased risk for herpeszoster and its complications (21).

From Veterans Affairs New York Harbor Healthcare System and NewYork University School of Medicine, New York, New York; Tufts Uni-

versity School of Medicine, Boston, Massachusetts; Veterans Affairs Co-

operative Studies Program Coordinating Center, West Haven, Connect-

icut; Veterans Affairs San Diego Healthcare System and University of

California, San Diego, San Diego, California; New Mexico Veterans

Affairs Health Care System, Albuquerque, New Mexico; National Can-

cer Institute, National Institutes of Health, Bethesda, Maryland; Univer-

sity of Colorado Denver, Aurora, Colorado; Geriatric Research Educa-

tion and Clinical Center (GRECC), Durham Veterans Affairs Medical

Center, Durham, North Carolina; St. Louis Veterans Affairs Medical

Center, St. Louis, Missouri; Baltimore Veterans Affairs Medical Center

and University of Maryland School of Medicine, Baltimore, Maryland;

University of Washington School of Medicine, Seattle, Washington;

Table 4. Rates of Serious Adverse Events Occurring From Day 0 to 42 After Inoculation in the Adverse Event Substudy

Variable Herpes Zoster Vaccine Group* Placebo Group Risk Difference (95% CI),percentage points

P Value

Persons WithAny Serious

AdverseEvents, n

Persons With>1 Serious

AdverseEvents, n (%)

Persons WithAny Serious

AdverseEvents, n

Persons With>1 Serious

AdverseEvents, n (%)

Enrolled persons 83 64 (1.93) 55 41 (1.29) 0.64 (0.04 to 1.28) 0.038

Body system (COSTART)

General body 11 10 (0.30) 7 7 (0.22) 0.08 (0.20 to 0.38) 0.50

Cardiovascular 22 20 (0.61) 16 12 (0.37) 0.24 (0.11 to 0.62) 0.161

Digestive 8 7 (0.21) 12 9 (0.29) 0.07 (0.37 to 0.20) 0.55

Endocrine 0 0 0 0

Hemic and lymphatic 2 2 (0.06) 0 0 0.06 (0.06 to 0.24) 0.164

Metabolic/nutritional 3 3 (0.09) 1 1 (0.03) 0.06 (0.10 to 0.26) 0.33

Musculoskeletal 5 5 (0.15) 1 1 (0.03) 0.12 (0.05 to 0.35) 0.122

Nervous system 15 12 (0.37) 6 6 (0.18) 0.19 (0.08 to 0.50) 0.146

Respiratory 4 4 (0.12) 5 5 (0.16) 0.04 (0.28 to 0.18) 0.66

Skin 6 5 (0.15) 4 3 (0.09) 0.06 (0.15 to 0.30) 0.50

Sight/sense 2 2 (0.06) 0 0 0.06 (0.06 to 0.24) 0.159

Genitourinary 5 5 (0.15) 2 2 (0.07) 0.08 (

0.12 to 0.31) 0.35

Diagnostic group

Vascular (pathology) 17 17 (0.52) 9 9 (0.27) 0.25 (0.06 to 0.61) 0.104

Vascular (functional) 10 10 (0.31) 9 8 (0.25) 0.05 (0.23 to 0.36) 0.67

Cancer 8 8 (0.24) 5 5 (0.15) 0.09 (0.16 to 0.36) 0.43

Infection 8 6 (0.18) 8 7 (0.22) 0.04 (0.31 to 0.22) 0.71

Accident 6 6 (0.18) 2 2 (0.06) 0.11 (0.08 to 0.36) 0.183

Allergic reaction 0 0 1 1 (0.03) 0.03 (0.19 to 0.08) 0.28

Autoimmune disorder 0 0 0 0

Other 18 17 (0.51) 13 9 (0.30) 0.21 (0.11 to 0.54) 0.178

COSTART Coding Symbols from a Thesaurus of Adverse Reaction Terms.* 3345 participants enrolled, 3326 participants with safety follow-up. 3271 participants enrolled, 3249 participants with safety follow-up. Appendix Table 1 (available at www.annals.org) defines the diagnostic groups.



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Lexington Veterans Affairs Medical Center, Lexington, Kentucky;GRECC, Veterans Affairs Tennessee Valley Healthcare System, and

Vanderbilt University School of Medicine, Nashville, Tennessee; Min-

neapolis Veterans Affairs Medical Center and University of Minnesota

School of Medicine, Minneapolis, Minnesota; and Merck, WhitehouseStation, New Jersey.

Some of the data from this article were presented at the 48th AnnualInternational Conference on Antimicrobial Agents and Chemotherapy/

Infectious Diseases Society of America 46th Annual Meeting, Washing-

ton, DC, 2528 October 2008.

Disclaimer: This study was conducted by the Cooperative Studies Pro-

gram of the Department of Veterans Affairs in collaboration with theNational Institute of Allergy and Infectious Diseases, National Institutes

of Health, and Merck.

Grant Support: By the Cooperative Studies Program of the Department

of Veterans Affairs, Office of Research and Development; Merck; and

the James R. and Jesse V. Scott Fund for Shingles Research.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNumM09-1222.

Reproducible Research Statement: Study protocol: Not available, but

additional methods information is available at www.nejm.org and www.clinicaltrials.gov. Statistical code and data set: Not available.

Requests for Single Reprints: Michael S. Simberkoff, MD, VeteransAffairs New York Harbor Healthcare System, 423 East 23rd Street, New

York, NY 10010; e-mail, [email protected].

Current author addresses and author contributions are available at www

.annals.org.

References1. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a newhypothesis. Proc R Soc Med. 1965;58:9-20. [PMID: 14267505]2. Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, Leplege A, et al.Characteristics of patients with herpes zoster on presentation to practitioners inFrance. Clin Infect Dis. 2001;33:62-9. [PMID: 11389496]3. Schmader KE, Sloane R, Pieper C, Coplan PM, Nikas A, Saddier P, et al.The impact of acute herpes zoster pain and discomfort on functional status andquality of life in older adults. Clin J Pain. 2007;23:490-6. [PMID: 17575488]4. van Seventer R, Sadosky A, Lucero M, Dukes E. A cross-sectional survey ofhealth state impairment and treatment patterns in patients with postherpeticneuralgia. Age Ageing. 2006;35:132-7. [PMID: 16431855]5. Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR,et al; Veterans Affairs Cooperative Studies Program Shingles Prevention Study

Investigators. Varicella-zoster virus-specific immune responses in elderly recipi-ents of a herpes zoster vaccine. J Infect Dis. 2008;197:825-35. [PMID:18419349]

6. Macaladad N, Marcano T, Guzman M, Moya J, Jurado F, Thompson M,et al. Safety and immunogenicity of a zoster vaccine in varicella-zoster virusseronegative and low-seropositive healthy adults. Vaccine. 2007;25:2139-44.[PMID: 17250932]7. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD,et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster andpostherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-84.[PMID: 15930418]

8. Oxman MN, Levin MJ; Shingles Prevention Study Group. Vaccinationagainst herpes zoster and postherpetic neuralgia. J Infect Dis. 2008;197 Suppl2:S228-36. [PMID: 18419402]9. ICH Clinical Safety Data Management Guidance: Definitions and Standards forExpedited Reporting. Accessed at www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129518.pdf on 9 March 2010.10. COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms.Fifth Edition. Rockville, MD: U.S. Food and Drug Administration. Report no.FDA/CDER-95/24. 1995.11. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med.1985;4:213-26. [PMID: 4023479]12. Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: Final Data for 2005.National Vital Statistics Reports. Hyattsville, MD: U.S. Department of Healthand Human Services, Centers for Disease Control and Prevention, National Cen-ter for Health Statistics, National Vital Statistics System; 2008. Accessed at http://cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_10.pdf on 9 March 2010.13. Arvin AM. Cell-mediated immunity to varicella-zoster virus. J Infect Dis.1992;166 Suppl 1:S35-41. [PMID: 1320649]14. Centers for Disease Control and Prevention. Update: vaccine side effects,adverse reactions, contraindications, and precautions. Recommendations of the

Advisory Committee on Immunization Practices (ACIP). MMWR RecommRep. 1996;45:1-35. [PMID: 8801442]15. Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO,Okoro CA, et al; Rotavirus Intussusception Investigation Team. Intussuscep-tion among infants given an oral rotavirus vaccine. N Engl J Med. 2001;344:564-72. [PMID: 11207352]16. Murphy BR, Morens DM, Simonsen L, Chanock RM, La Montagne JR,Kapikian AZ. Reappraisal of the association of intussusception with the licensedlive rotavirus vaccine challenges initial conclusions. J Infect Dis. 2003;187:1301-8. [PMID: 12696010]17. Centers for Disease Control and Prevention (CDC). Smallpox vaccine ad-

verse events among civiliansUnited States, March 4-10, 2003. MMWR MorbMortal Wkly Rep. 2003;52:201-3. [PMID: 12653459]18. Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, VernalisMN. Smallpox vaccination and myopericarditis: a clinical review. J Am CollCardiol. 2004;43:1503-10. [PMID: 15120802]19. Swerdlow DL, Roper MH, Morgan J, Schieber RA, Sperling LS, SniadackMM, et al; Smallpox Vaccine Cardiac Adverse Events Working Group. Isch-emic cardiac events during the Department of Health and Human ServicesSmallpox Vaccination Program, 2003. Clin Infect Dis. 2008;46 Suppl 3:S234-41. [PMID: 18284364]20. Sniadack MM, Neff LJ, Swerdlow DL, Schieber RA, McCauley MM,Mootrey GT. Follow-up of cardiovascular adverse events after smallpox vaccina-tion among civilians in the United States, 2003. Clin Infect Dis. 2008;46 Suppl3:S251-7. [PMID: 18284366]21. Harpaz R, Ortega-Sanchez IR, Seward JF; Centers for Disease Control and

Prevention. Prevention of Herpes Zoster: Recommendations of the AdvisoryCommittee on Immunization Practices (ACIP). Accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm?s_cidrr5705a1_e on 9 March 2010.



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Current Author Addresses: Dr. Simberkoff: Veterans Affairs New York

Harbor Healthcare System, 423 East 23rd Street, New York, NY 10010.

Dr. Arbeit: Division of Infectious Diseases, Tufts Medical Center, 800

Washington Street, Boston, MA 02111.

Mr. Johnson: Cooperative Studies Program Coordinating Center (151-

A), Veterans Affairs Connecticut Healthcare System, 950 Campbell Av-

enue, West Haven, CT 06516.

Dr. Oxman: Shingles Prevention Study (111F-1), Veterans Affairs Med-ical Center, 3350 La Jolla Village Drive, San Diego, CA 92161.

Ms. Boardman: Veterans Affairs Cooperative Studies Program, Phar-

macy Coordinating Center (151-I), Department of Veterans Affairs

Medical Center, 2401 Center Avenue Southeast, Albuquerque, NM

87106.

Ms. Williams: National Cancer Institute, Medical Oncology Branch,

Building 10, Room 12N226, 10 Center Drive, Bethesda, MD 20892.

Dr. Levin: University of Colorado, Pediatric Infectious Diseases, MS

C227, Building 401, 1784 Racine Street, Room R09-108, PO Box

6508, Aurora, CO 80045.

Dr. Schmader: Geriatric Research Education and Clinical Center (182),

Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC

27705.

Dr. Gelb: 370 Lyonnais Drive, Creve Coeur, MO 63141.

Dr. Keay: Veterans Affairs Medical Center, Room 3B-184, 10 North

Green Street, Baltimore, MD 21201.

Dr. Neuzil: PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA

98121.

Dr. Greenberg: University of Kentucky School of Medicine, Department

of Medicine, Room MN-672, 800 Rose Street, Lexington, KY 40536.

Dr. Griffin: Department of Preventive Medicine, Vanderbilt University

Medical Center, 1500 21st Avenue South, Village at Vanderbilt, Suite

2600, Nashville, TN 37212.

Dr. Davis: Veterans Affairs Medical Center, Research Service, Building

T12-A, 1501 San Pedro Southeast, Albuquerque, NM 87108.

Dr. Morrison: Hematology/Oncology and Infectious Disease Section,

Veterans Affairs Medical Center, One Veterans Drive (111-E), Minne-apolis, MN 55417.

Dr. Annunziato: Merck & Co., Inc., Mailstop Location UG3CD-28,

PO Box 1000, North Wales, PA 19454.

Author Contributions: Conception and design: R.D. Arbeit, G.R. John-

son, M.N. Oxman, M.J. Levin, K.E. Schmader, L.D. Gelb, L.E. Davis,

V.A. Morrison.

Analysis and interpretation of the data: M.S. Simberkoff, R.D. Arbeit,

G.R. Johnson, M.N. Oxman, M.J. Levin, K.E. Schmader, L.D. Gelb, S.

Keay, K. Neuzil, V.A. Morrison.

Drafting of the article: M.S. Simberkoff, R.D. Arbeit, G.R. Johnson,

M.N. Oxman, H.M. Williams, M.J. Levin, K.E. Schmader, L.D. Gelb,S. Keay, R.N. Greenberg, L.E. Davis, V.A. Morrison.

Critical revision of the article for important intellectual content: M.S.

Simberkoff, R.D. Arbeit, G.R. Johnson, M.N. Oxman, K.D. Boardman,

M.J. Levin, K.E. Schmader, K. Neuzil, R.N. Greenberg, M.R. Griffin,

V.A. Morrison, P.W. Annunziato.

Final approval of the article: M.S. Simberkoff, R.D. Arbeit, G.R. John-

son, M.N. Oxman, K.D. Boardman, H.M. Williams, M.J. Levin, K.E.

Schmader, L.D. Gelb, S. Keay, K. Neuzil, R.N. Greenberg, M.R. Grif-

fin, L.E. Davis, V.A. Morrison, P.W. Annunziato.

Provision of study materials or patients: M.S. Simberkoff, G.R. Johnson,

M.N. Oxman, M.J. Levin, K.E. Schmader, L.D. Gelb, S. Keay, K. Neu-

zil, R.N. Greenberg, M.R. Griffin, L.E. Davis, V.A. Morrison.

Statistical expertise: G.R. Johnson.

Obtaining of funding: G.R. Johnson, M.N. Oxman, K.E. Schmader.

Administrative, technical, or logistic support: R.D. Arbeit, G.R. John-

son, M.N. Oxman, K.D. Boardman, H.M. Williams, M.J. Levin, L.D.

Gelb, L.E. Davis, P.W. Annunziato.

Collection and assembly of data: M.S. Simberkoff, R.D. Arbeit, G.R.

Johnson, M.N. Oxman, K.D. Boardman, H.M. Williams, M.J. Levin,

K.E. Schmader, L.D. Gelb, S. Keay, K. Neuzil, M.R. Griffin, L.E. Davis,

V.A. Morrison.

Appendix Table 1. Physiologic Diagnostic Categories Used for Review of Serious Adverse Events

Category Description

Vascular (pathology) Cardiovascular events in which there was a priori or documented evidence of vascular abnormality not previouslyapparent. Included any cardiovascular events that were fatal, had documented tissue damage (for example,myocardial infarction, cerebrovascular accident, or transient ischemic attack), or resulted in vascular surgery(for example, stent or coronary artery bypass grafting).

Vascular (functional) Cardiovascular events that had no clear evidence of short-term abnormality; could be purely functional eventsoccurring in the absence of new or active vascular pathology (for example, arrhythmias, hypertension,syncope, congestive heart failure, or chest pain).

Autoimmune disorder Disorders observed were polymyalgia rheumatica, temporal arteritis, and Hashimoto thyroiditis.

Allergic react ion Acute a llergic events, including angioedema and drug react ions.

Infection Acute infections (for example, pneumonia, cellulitis, or urinary tract infection).

Cancer Newly diagnosed carcinomas, melanomas, lymphomas, leukemia.

Accident Restr icted to fa lls, motor vehicle accidents, and injury. Two persons had fal ls after syncope; syncope w ascoded separately in 1 person and not in the other.

Other Al l events not assigned to one of the previous categories, including musculoskeletal chest pain, gastrointest inal or endocrine disorders, mental status changes, behavioral changes, and seizures.

Annals of Internal Medicine

W-184 4 May 2010 Annals of Internal Medicine Volume 152 Number 9 www.annals.org

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Appendix Table 2. Duration of Adverse Events at the Inoculation Site in Substudy Participants

AdverseEvent

Herpes Zoster Vaccine Group Placebo Group PValue*

Patients,n

MeanDuration(SD), d

MedianDuration,d

Percentile Patients,n

MeanDuration(SD), d

MedianDuration,d

Percentile

25th 75th 90th 25th 75th 90th

Erythema 1191 5.0 (7.0) 3 2 5 9 221 2.6 (5.6) 1 1 2 4 0.001Swelling 887 3.8 (3.3) 3 2 5 7 144 1.9 (3.1) 1 1 2 3 0.001

Pain 1157 3.7 (8.0) 3 2 4 6 279 2.7 (8.5) 1 1 2 3 0.001

Rash 19 4.3 (4.4) 3 2 5 9 7 20.9 (22.9) 11 3 33 66 0.033

Pruritus 239 4.3 (4.7) 3 2 5 9 32 1.9 (2.6) 1 1 2 3 0.001

Hematoma 53 9.7 (8.9) 8 3 13 18 45 10.2 (15.1) 4 2 10 26 0.099

Mass 30 4.6 (3.0) 4 2 6 8 1 1.0 (0.0) 1 1 1 1 0.059

Warmth 57 3.9 (3.0) 3 2 5 6 11 1.0 (0.0) 1 1 1 1 0.001

* For testing differences in duration of adverse events between treatment groups by nonparametric Wilcoxon rank-sum test. Erythema was the only local adverse event to last longer in younger vaccine recipients than in older recipients (data not shown). Rash at the inoculation site was the only adverse event that lasted longer in placebo recipients.

Appendix Figure 1. Cumulative mortality rates for the total

study population, by age stratum and treatment group.

CumulativeMortalityR

ate,%

Years of Follow-up

Years of Follow-up

Placebo, 6069 y


Placebo, 70 y


Aged 6069 yPlacebo 10 223 10 323 10 245 7231 2081

Herpes zoster

vaccine 10 281 10 331 10 239 7223 2034

Aged 70 y

Placebo 8692 8775 8621 6337 1942

Herpes zoster

vaccine 8713 8815 8646 6415 1948

0 1 2 3 4

0 1 2 3 4At risk, n

0

6

4

2

8

10

Cumulative mortality rate is shown for the time to death in all studyparticipants. There is no significant treatment difference within agestrata: For persons aged 60 to 69 years, log-rankP 0.20; for persons70 years or older, log-rank P 0.37. Overall treatment comparison:log-rankP 0.95. Comparison of age strata 60 to 69 years versus 70years or older: log-rank P 0.001.

Appendix Figure 2. Time to first hospitalization for

participants in the adverse events substudy, by age stratum

and treatment group.

CumulativeHospitalizationRate,%

Years of Follow-up

Years of Follow-up

Placebo, 6069 y


Placebo, 70 y


Aged 6069 yPlacebo 1729 1548 1410 1276 656

Herpes zoster

vaccine 1724 1584 1438 1284 683

Aged 70 y

Placebo 1541 1349 1177 973 513

Herpes zoster

vaccine 1612 1387 1189 1006 489

0 1 2 3 4

0 1 2 3 4At risk, n

0

15

10

5

20

25

30

35

40

45

Cumulative hospitalization rate is shown for the first hospital admissionoccurring for participants in the adverse events substudy. There is nosignificant treatment difference within age strata: For persons aged 60 to69 years, log-rankP 0.77; for persons 70 years or older, log-rankP0.55. Overall treatment comparison: log-rankP 0.80. Comparison ofage strata 60 to 69 years versus 70 years or older: log-rank P 0.001.

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