ORIGINAL CONTRIBUTION

Herpes Zoster Vaccine in Older Adults

and the Risk of Subsequent Herpes Zoster Disease
Hung Fu Tseng, PhD, MPH
Ning Smith, PhD
Rafael Harpaz, MD, MPH
Stephanie R. Bialek, MD, MPH
Lina S. Sy, MPH
Steven J. Jacobsen, MD, PhD

ERPES ZOSTER , COMMONLY

known as shingles, is a painful vesicular rash caused by
reactivation of varicella zoster virus, persisting latently in dorsal
root ganglia.1,2 The pain of herpes zoster is often disabling and can last for
months or even years, a complication
termed postherpetic neuralgia. Approximately 1 million episodes of herpes zoster occur in the United States annually,
but aside from age and immunosuppression, risk factors for this condition are not known.3,4
The Shingles Prevention Study (SPS)
is a clinical trial of a live-attenuated vaccine prepared from the Oka/Merck
strain of varicella zoster virus.5 The SPS
trial included 38 546 participants aged
60 years or older who had no history
of herpes zoster, immunosuppression, or conditions that could interfere with participation. In SPS, herpes
zoster vaccine reduced herpes zoster
and postherpetic neuralgia incidence by
51% (P.001) and 67% (P.001), respectively; laboratory markers indicating protection were not identified.6
Consequently, Zostavax (Merck & Co
Inc, Whitehouse Station, New Jersey)
was licensed by the US Food and Drug
Administration in 2006 and subsequently recommended by the Advi-

See also Patient Page.

160

Context Approximately 1 million episodes of herpes zoster occur annually in the United
States. Although prelicensure data provided evidence that herpes zoster vaccine works
in a select study population under idealized circumstances, the vaccine needs to be
evaluated in field conditions.
Objective To evaluate risk of herpes zoster after receipt of herpes zoster vaccine among
individuals in general practice settings.
Design, Setting, and Participants A retrospective cohort study from January 1,
2007, through December 31, 2009, of individuals enrolled in the Kaiser Permanente
Southern California health plan. Participants were immunocompetent communitydwelling adults aged 60 years or older. The 75 761 members in the vaccinated cohort
were age matched (1:3) to 227 283 unvaccinated members.
Main Outcome Measure Incidence of herpes zoster.
Results Herpes zoster vaccine recipients were more likely to be white, women, with
more outpatient visits, and fewer chronic diseases. The number of herpes zoster cases
among vaccinated individuals was 828 in 130 415 person-years (6.4 per 1000 personyears; 95% confidence interval [CI], 5.9-6.8), and for unvaccinated individuals it was
4606 in 355 659 person-years (13.0 per 1000 person-years; 95% CI, 12.6-13.3). In
adjusted analysis, vaccination was associated with a reduced risk of herpes zoster (hazard ratio [HR], 0.45; 95% CI, 0.42-0.48); this reduction occurred in all age strata and
among individuals with chronic diseases. Risk of herpes zoster differed by vaccination
status to a greater magnitude than the risk of unrelated acute medical conditions, suggesting results for herpes zoster were not due to bias. Ophthalmic herpes zoster (HR,
0.37; 95% CI, 0.23-0.61) and hospitalizations coded as herpes zoster (HR, 0.35; 95%
CI, 0.24-0.51) were less likely among vaccine recipients.
Conclusions Among immunocompetent community-dwelling adults aged 60 years
or older, receipt of the herpes zoster vaccine was associated with a lower incidence of
herpes zoster. The risk was reduced among all age strata and among individuals with
chronic diseases.
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JAMA. 2011;305(2):160-166

sory Committee for Immunization Practices for healthy individuals aged 60

years or older.7
Although the SPS provided evidence that herpes zoster vaccine works
under idealized conditions (ie, vaccine efficacy), confirmation of these results is needed in field conditions (ie,
vaccine effectiveness) to show whether
benefits of the vaccine can be generalized to conditions of clinical practice.8-10 This is particularly important
for herpes zoster vaccine, given the
medical and physiological diversity in

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the elderly population for whom the

vaccine is indicated1 and since there are
stringent storage and handling requirements for this live-attenuated vacAuthor Affiliations: Department of Research and Evaluation, Southern California Kaiser Permanente, Pasadena (Drs Tseng, Smith, and Jacobsen and Ms Sy); and
Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Harpaz and Bialek).
Corresponding Author: Hung Fu Tseng, PhD, MPH,
Department of Research and Evaluation, Kaiser
Permanente, Southern California Medical Group, 100
S Los Robles Ave, Second Floor, Pasadena, CA 91101
(Hung-Fu.x.Tseng@kp.org).

2011 American Medical Association. All rights reserved.

EFFECTIVENESS OF HERPES ZOSTER VACCINE IN OLDER ADULTS

cine.7 Moreover, a large observational

study also allows for exploration of vaccine benefits among important patient
subgroups that would be unfeasible in
most randomized controlled trials. We
report the results of a large observational study among communitydwelling adults aged 60 years or older
evaluating the risk of herpes zoster after herpes zoster vaccination in a managed care organization.
METHODS
Setting

The study was conducted among members of Kaiser Permanente, Southern

California (KPSC), and the protocol was
reviewed and approved by the KPSC institutional review board, which waived
requirement for informed consent. KPSC
is an integrated health care system that
provides comprehensive prepaid health
services for its 3.2 million members.
Members are socioeconomically diverse and more than 99% are community dwelling. Patient data regarding demographics, services, and diagnoses are
tracked in the KPSC electronic health
record databases from the outpatient,
emergency department, and hospital settings. The databases provide a primary
diagnosis for hospitalizations; secondary hospital diagnoses, as well as diagnoses from outpatient and emergency
department visits, are not rank ordered. Data regarding care from nonKPSC providers are likely to be captured in KPSC databases because
documentation is required for reimbursement of such services. Vaccinations received by members are tracked
in the Kaiser Immunization Tracking
System,11 regardless of whether administered in or outside of KPSC. Herpes
zoster vaccine is provided to KPSC members at little or no charge.
Participants

This retrospective cohort study included data from January 1, 2007,

through December 31, 2009. The vaccinated cohort consisted of KPSC members who received herpes zoster vaccine at age 60 years or older, from
January 1, 2007, through June 30, 2009;

the date of vaccination was termed the

index date. The unvaccinated cohort
consisted of randomly sampled members who were matched 3:1 to the vaccinated cohort based on birth date (1
year). Unvaccinated individuals were
assigned the same index dates as the
matching vaccinated persons. Participants in both cohorts were limited to
individuals with continuous membership and drug benefits for the 1 year before their index date, and were observed for first occurrence of herpes
zoster, termination of KPSC membership, or study completion. Individuals
with herpes zoster codes during the
prior 6 months were excluded from
analysis.
Herpes zoster vaccine is not recommended for immunocompromised patients.7 The study therefore excluded
immunocompromised patients so that
the vaccinated and unvaccinated cohorts would be comparable in terms of
underlying herpes zoster risk and so
that the reduced risk associated with
herpes zoster vaccine could be interpreted in the context of national recommendations and the SPS.5,7 The study
defined immunocompromised individuals as those with human immunodeficiency virus, leukemia, or lymphoma diagnoses within 1 year before
the index date until the end of followup, or having immunosuppressing
agents dispensed within 1 year before
the index date (eBox, available at http:
//www.jama.com).

vaccine coverage and risk of herpes zoster both likely differ by race.7,12 Health
care utilization was defined as the number of hospitalizations or outpatient or
emergency department visits within 1
year before the index date, and chronic
diseases were defined as 1 or more diagnoses for diabetes or for heart, lung,
kidney, or liver disease within 1 year
before the index date. Patients could be
assigned multiple conditions.
Statistical Analysis

Incidence was calculated by dividing the

number of herpes zoster cases by the
total number of person-years. The 95%
confidence intervals (CIs) were estimated assuming occurrence of herpes
zoster follows a Poisson distribution.
Hazard ratios (HRs) and 95% CIs were
estimated for age, sex, race, and chronic
comorbid diseases using Cox proportional hazards regression models. These
models were also used to assess the association between vaccination and sex,
race, health care utilization, and chronic
comorbid diseases. Our sample size was
sufficient to detect a relative risk of herpes zoster incidence between the vaccinated and unvaccinated cohorts of
0.85 during the study interval, with
power of greater than 80% and type I
error rate of .05. Significance was set
at .05 based on a 2-sided test. We used
SAS Enterprise Guide 4.2 (SAS Institute Inc, Cary, North Carolina) for all
analyses.
Assessment of Bias

Outcomes, Subgroups, and

Covariates

Incident herpes zoster and ophthalmic herpes zoster were defined by International Classification of Diseases,
Ninth Revision (ICD-9) codes (053.XX
and 053.2X, respectively; in any position) from hospital, outpatient, and
emergency department settings during the study period. We categorized individuals to assess factors associated
with vaccination and risk of herpes zoster including sex, health care utilization, and comorbid chronic diseases.
Race (self-reported) was also included
in the analysis because herpes zoster

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Individuals who received herpes zoster

vaccine in the study population may
have differed from those who did not in
their underlying risk for herpes zoster
or in their ability and desire to access care
for herpes zoster. To assess whether our
results might have been distorted by
such confounders, rate ratios for 13 acute
symptomatic conditions in the vaccinated vs age-matched unvaccinated cohorts were estimated, as we did for herpes zoster (eTable 1). Because herpes
zoster vaccine should not protect against
these conditions, we reasoned that these
values should cluster around 1.0 and that
any deviation from 1.0 would alert us

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161

EFFECTIVENESS OF HERPES ZOSTER VACCINE IN OLDER ADULTS

to biases that might be confounding results regarding herpes zoster. This strategy is analogous to approaches used to
assess validity of estimates of vaccine effectiveness and other outcomes.13-18
To conduct this analysis, conditions
were selected that were likely to be comparable to herpes zoster in terms of access, health care seeking, and documen-

tation, but with no plausible association

with herpes zoster itself (eg, Bell palsy).
We identified conditions that were acute
and self-limited, with disturbing symptoms that would typically trigger efforts
to seek care in outpatient primary care
settings. We sought conditions with high
incidence among elderly individuals but
reasonably balanced across sex, race, and

Table 1. Baseline Characteristics of Study Cohorts by Herpes Zoster Vaccination Status a

No. (%) b
Characteristic
Age of participants, y

Vaccinated (n = 75 761)
23 195 (30.6)

Unvaccinated (n = 227 283)

69 585 (30.6)

60-64
65-69
70-74
75-79
80
Mean (SD)
Sex
Women
Men
Race
White
Black
Asian
Native American/multiple
Other
Unknown
No. of outpatient visits c
0
1-4
5-10

20 166 (26.6)
15 426 (20.4)
10 978 (14.5)
5966 (7.9)
0
69.6 (6.8)

60 498 (26.6)
46 278 (20.4)
32 934 (14.5)
17 988 (7.9)
0
69.6 (6.8)

42 822 (56.5)
32 939 (43.5)

118 506 (52.1)

108 771 (47.9)

45 435 (60.0)
4729 (6.2)
6599 (8.7)
87 (0.1)
2125 (2.8)
16 786 (22.2)

122 050 (53.7)

27 905 (12.3)
15 496 (6.8)
362 (0.2)
9176 (4.0)
52 294 (23.0)

1970 (2.60)
16 897 (22.3)
25 546 (33.7)

20 199 (8.89)
54 938 (24.2)
68 488 (30.1)

11
Mean (SD)
Median (25th-75th percentile)
No. of emergency visits c
0
1
2
Mean (SD)
No. of hospitalizations c
0
1
2
Mean (SD)
Chronic conditions/diseases
Diabetes
Kidney
Heart
Lung
Liver

31 348 (41.4)
11.8 (11.3)
9 (5-15)

83 658 (36.8)
10.8 (11.8)
7 (3-14)

61 139 (80.7)
10 064 (13.3)
4558 (6.0)
0.3 (0.8)

177 578 (78.1)

30 057 (13.2)
19 648 (8.6)
0.4 (1.1)

68 117 (89.9)
5684 (7.5)
1960 (2.6)
0.1 (0.5)

199 608 (87.8)

18 435 (8.1)
9240 (4.1)
0.2 (0.7)

14 720 (19.4)
9449 (12.5)
9266 (12.2)
1282 (1.7)
1030 (1.4)

50 212 (22.1)
31 873 (14.0)
31 238 (13.8)
4940 (2.2)
3417 (1.5)

a P.001 for all variables except age, which was the matching factor.
b Values are presented as No. (%) unless otherwise indicated.
c Data indicate 1 year prior to index date. Index date is the date of vaccination among vaccine recipients and their matched

unvaccinated group.

162

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socioeconomic status; they were conditions that are easily diagnosed and specifically coded with 1 or few categories
of ICD-9 codes. The conditions were selected without first estimating their incidence in the vaccinated and unvaccinated cohorts.
The incidence of the 13 indicator
conditions was ascertained using the
relevant ICD-9 codes (eTable 1) in any
diagnostic position of the outpatient
and emergency department files of the
KPSC databases, from the index date
through follow-up. Cases with codes for
indicator conditions during the prior 6
months were excluded from analysis.
RESULTS
Characteristics of Participants in
Vaccinated and Unvaccinated Cohorts

There were 75 761 vaccinated and

227 283 unvaccinated individuals included in the study. Compared with the
unvaccinated cohort, individuals in the
vaccinated cohort were more likely to
be white, women, and to have had a
larger number of outpatient visits, but
fewer emergency department visits and
hospitalizations in the 12 months prior
to the index date (TABLE 1). The vaccinated cohort had a lower prevalence
of chronic diseases.
Herpes Zoster Cases in Vaccinated
and Unvaccinated Cohorts

There were 5434 herpes zoster cases

identified in the study: 4593 (84.5%) in
outpatient settings, 574 (10.6%) in emergency departments, and 267 (4.9%) hospitalized. Among the unvaccinated and
vaccinated cohorts, follow-up averaged
1.56 and 1.72 years, yielding herpes zoster incidence of 13.0 (95% CI, 12.613.3) and 6.4 (95% CI, 5.9-6.8) per 1000
person-years, respectively, in univariate analysis (TABLE 2).
Among unvaccinated individuals, herpes zoster incidence varied by several factors. It increased with age (80 years vs
60-64years:HR,1.45;95%CI,1.30-1.63),
waslowerinmen(HR,0.75;95%CI,0.700.79), and was also lower in black individuals (HR, 0.69; 95% CI, 0.62-0.76).
It varied by chronic disease, being higher
inindividualswithlungdisease(HR,1.34;

2011 American Medical Association. All rights reserved.

EFFECTIVENESS OF HERPES ZOSTER VACCINE IN OLDER ADULTS

Table 2. Comparison of Herpes Zoster Incidence in Study Cohorts by Herpes Zoster Vaccination Status
Unvaccinated (n = 227 283)

Vaccinated (n = 75 761)

Characteristic
Age of participants, y
60-64

No. of
No. of Total No. of
Participants Cases Person-years

Incidence/1000
Incidence/1000
Person-years
No. of
No. of Total No. of
Person-years
(95% CI)
Participants Cases Person-years
(95% CI)

P
Value

0.55 (0.47-0.64) .001

23 195

204

38 405

5.3 (4.6-6.1)

69 585

1027

105 700

65-69

20 166

197

34 975

5.6 (4.9-6.5)

60 498

1206

94 835

12.7 (12.0-13.5) 0.44 (0.38-0.52) .001

70-74

15 426

202

27 635

7.3 (6.3-8.4)

46 278

1090

74 532

14.6 (13.8-15.5) 0.50 (0.43-0.58) .001

75-79

10 978

146

19 894

7.3 (6.2-8.6)

32 934

824

54 074

15.2 (14.2-16.3) 0.48 (0.40-0.58) .001

5996

79

9506

8.3 (6.6-10.4)

17 988

459

26 518

17.3 (15.8-19.0) 0.48 (0.38-0.61) .001

Women

42 822

518

73 713

7.0 (6.4-7.7)

118 506

2770

186 096

14.9 (14.3-15.5) 0.47 (0.43-0.52) .001

Men

32 939

310

56 703

5.5 (4.9-6.1)

108 771

1836

169 552

10.8 (10.3-11.3) 0.50 (0.45-0.57) .001

Race a
White

45 435

597

80 358

7.4 (6.9-8.1)

122 050

2887

193 202

Black

4729

25

7200

3.5 (2.3-5.1)

27 905

452

44 983

10.1 (9.1-11.0)

Asian

6599

61

11 093

5.5 (4.2-7.1)

15 496

351

24 812

14.2 (12.7-15.7) 0.39 (0.30-0.51) .001

87

146

362

585

80

9.7 (9.1-10.3)

Rate Ratio
(95% CI)

Sex

Native American/
multiple
Other
Unknown
Chronic conditions/
diseases
Diabetes

Overall

6.9 (0.2-38.3)

2125

19

3571

5.3 (3.2-8.3)

9176

198

14 199

16 786

125

28 047

4.5 (3.7-5.3)

52 294

713

77 879

14.9 (14.4-15.5) 0.50 (0.46-0.54) .001

8.5 (2.8-19.9)

0.34 (0.23-0.51) .001

0.79 (0.09-6.78)

.84

13.9 (12.1-16.0) 0.38 (0.24-0.61) .001

9.2 (8.5-9.9)

0.49 (0.40-0.59) .001

14 720

174

25 490

6.8 (5.9-7.9)

50 212

1052

77 523

13.6 (12.8-14.4) 0.50 (0.43-0.59) .001

Kidney

9449

117

16 060

7.3 (6.0-8.7)

31 873

758

48 177

15.7 (14.6-16.9) 0.46 (0.38-0.56) .001

Heart

9266

116

16 143

7.2 (5.9-8.6)

31 283

754

47 323

15.9 (14.8-17.1) 0.45 (0.37-0.55) .001

Lung

1282

20

2205

9.1 (5.5-14.0)

4940

145

6808

21.3 (18.0-25.1) 0.43 (0.27-0.69) .001

Liver

1030

12

1634

7.3 (3.8-12.8)

3417

59

4673

12.6 (9.6-16.3)

75 761

828

130 415

227 283

4606

355 659

6.4 (5.9-6.8)

0.58 (0.31-1.08)

.09

13.0 (12.6-13.3) 0.49 (0.46-0.53) .001

Abbreviation: CI, confidence interval.

a Individuals were self-identified.

Figure 1. Kaplan-Meier Estimates of the Cumulative Risk of Herpes Zoster by Herpes Zoster
Vaccination Status
4
Unvaccinated

Herpes Zoster Incidence, %

95% CI, 1.13-1.59) compared with those

without. An increase in incidence among
individualswithkidneydisease(HR,1.04;
95%CI,0.95-1.13)andheartdisease(HR,
1.06; 95% CI, 0.97-1.16) was not significantly significant. Differences in herpes
zoster incidence remained when we adjusted for sex, race, chronic diseases, and
health care utilization. In addition, the
risk of herpes zoster was associated with
number of outpatient visits during the
year before the index dates, an indicator
of health careseeking behavior. The adjustedHRswere1.94(95%CI,1.62-2.31)
for 1 to 4 outpatient visits, 2.44 (95% CI,
2.05-2.91)for5to10visits,and3.03(95%
CI, 2.55-3.61) for 11 or more outpatient
visits. There was no association between
hospitalizationsoremergencydepartment
visits and herpes zoster.
The Kaplan-Meier plot showing cumulative risk of herpes zoster in the vaccinated and unvaccinated cohorts is
shown in FIGURE 1. In the fully adjusted analysis, vaccination was asso-

Vaccinated
2

0.5

1.0

1.5

2.0

2.5

77 367
30 574

29 226
12 527

3.0

Follow-up, y
No. at risk
Unvaccinated 227 283
Vaccinated
75 761

208 374
73 722

158 887
58 425

ciated with reduced risk of herpes zoster (HR, 0.45; 95% CI, 0.42-0.48); the
reduction in risk did not vary by age at
vaccination (TABLE 3), sex, race, or with
presence of chronic diseases. Herpes
zoster vaccine recipients had reduced

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128 920
48 658

risks of ophthalmic herpes zoster

(HR, 0.37; 95% CI, 0.23-0.61) and
hospitalizations coded as herpes
zoster (HR, 0.35; 95% CI, 0.24-0.51).
In a secondary analysis, definition
of immunocompetent was further

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EFFECTIVENESS OF HERPES ZOSTER VACCINE IN OLDER ADULTS

restricted by excluding individuals

having documentation of at least 1 corticosteroid dispensed within 1 year before the index date, including those

taken by mouth, injection, nasal spray,

or inhalation. The HR in this fully
adjusted analysis was 0.46 (95% CI,
0.43-0.49).

Table 3. Hazard Ratio of Herpes Zoster in Study Cohorts

Hazard Ratio (95% Confidence Interval)
Unadjusted

Adjusted a

0.49 (0.46-0.53)

0.45 (0.42-0.48)

Subgroups
All
Age at vaccination, y
60-64

0.55 (0.47-0.64)

0.50 (0.43-0.58)

65-69

0.44 (0.38-0.52)

0.40 (0.34-0.47)

70-74

0.50 (0.43-0.58)

0.46 (0.39-0.53)

75-79

0.48 (0.40-0.58)

0.45 (0.38-0.54)

80

0.48 (0.38-0.61)

0.44 (0.35-0.56)

Sex
Men

0.50 (0.45-0.57)

0.47 (0.42-0.53)

0.47 (0.43-0.52)

0.44 (0.40-0.48)

Race b
White

0.50 (0.46-0.54)

0.48 (0.44-0.52)

Black

0.34 (0.23-0.51)

0.33 (0.22-0.49)

Asian

0.39 (0.30-0.51)

0.37 (0.29-0.49)

Native American/multiple

0.79 (0.09-6.78)

0.61 (0.05-6.96)

Other

0.38 (0.24-0.61)

0.36 (0.23-0.58)

Unknown

0.49 (0.40-0.59)

0.42 (0.35-0.51)

Women

Chronic conditions/diseases
Diabetes

0.50 (0.43-0.59)

0.49 (0.42-0.57)

Kidney

0.46 (0.38-0.56)

0.45 (0.37-0.54)

Heart

0.45 (0.37-0.55)

0.44 (0.36-0.53)

Lung

0.43 (0.27-0.69)

0.39 (0.25-0.63)

Liver

0.58 (0.31-1.08)

0.56 (0.30-1.05)

The incidence of 13 acute symptomatic indicator conditions was compared in the vaccinated and agematched unvaccinated cohorts (FIGURE 2
and eTable 2). The adjusted rate ratios for the 13 conditions ranged from
0.76 to 1.38 (mean, 1.05; SD, 0.19),
being 1.0 or greater for 7 of the 13 conditions. None of the conditions had adjusted rate ratios as low as 0.45, the rate
ratio for herpes zoster.
COMMENT
Our data complement the results of the
original clinical trial of herpes zoster vaccine,5 indicating that the vaccine was associated with a reduced risk of herpes
zoster in a community setting with its
mixed population and routine clinical
practices. In addition, our data indicate
that the vaccine was associated with reduced risks of ophthalmic herpes zoster and hospitalizations potentially attributable to herpes zoster. The results
also suggest that these potential benefits extended to individuals of all ages
for whom herpes zoster vaccine is recommended, and to individuals with
chronic diseases.
Overall, we found that herpes zoster
vaccine was associated with a 55% reduction in incidence of herpes zoster,

a Adjusted for age, sex, race, health care utilization, and chronic disease in the model.
b Individuals were self-identified.

Figure 2. Comparison of Adjusted Hazard Ratios of 13 Indicator Conditions and Herpes Zoster in Study Cohorts by Herpes Zoster Vaccination
Status
Vaccinated Group
(n = 75 761)

Indicator Conditions
Herpes zoster

No. of
Cases
828

Total No. of
Person-Years
130 415

Unvaccinated Group
(n = 227 283)
No. of
Cases
4606

Total No. of
Person-Years
355 659

Adjusted
Hazard Ratio
0.45

Hip fracture

237

130 938

811

359 676

0.76

Thrombosis

171

131 015

623

359 851

0.80

1947

128 919

6886

352 565

0.82

Cholelithiasis and cholecystitis

401

130 731

1114

359 268

0.95

Wrist fracture

471

130 667

1172

359 223

0.97

Renal stone

1213

129 863

3349

356 847

0.98

Epistaxis

1025

130 155

2513

357 889

1.08

Lipomas

1066

130 105

2457

357 925

1.14

Eyelid disorders

3744

127 224

7895

352 454

1.16

19 730

108 180

46 609

309 964

1.17

2133

128 849

4716

355 579

1.22

806

130 360

1759

358 635

1.23

6790

123 826

13 184

347 299

1.38

Gout

Cataracts
Ingrown nail
Wound of hand or finger
Hemorrhoids

0.40

0.55

0.75

1.00

1.25

1.60

Adjusted Hazard Ratio (95% CI)

CI indicates confidence interval.

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EFFECTIVENESS OF HERPES ZOSTER VACCINE IN OLDER ADULTS

which is consistent with the 51% vaccineefficacyreportedfromtheSPS.These

results would be consistent with an absolute reduction in herpes zoster risk of
1.4% at 30 months of follow-up; alternatively,1episodeofherpeszosterwould
be averted for every 71 individuals receivingthevaccine.IncontrasttotheSPS,
however, we found that the lower herpes zoster risk associated with the vaccine was retained across all age strata
(P=.62).5,19 Thus,ourresultssupportrecommendations to offer herpes zoster vaccine to eligible patients of all ages including the oldest population. Not only might
these patients experience a reduction in
their relative risk of herpes zoster, but
for the oldest group, this could translate
into a very large absolute reduction in
disease because they bear the greatest
burden of herpes zoster and postherpetic
neuralgia and are also especially vulnerable to these disabling conditions.1,20,21
The efficacy of herpes zoster vaccine
at preventing ophthalmic herpes zoster
was not assessed in the SPS. Our finding that the vaccine recipients had a reduced risk of these episodes was therefore particularly important. Ophthalmic
involvement is a common manifestation of herpes zoster and it can lead to
serious vision-threatening sequelae.2,4,22-24
Our study provides new information
regarding the risk of herpes zoster in key
vaccinated and unvaccinated subgroups.
Herpeszostervaccinewasassociatedwith
a similar reduction across sexes and racial groups. Although we confirm results
of other studies showing that black personsareatlowerriskofherpeszosterthan
whitepersons,3,25,26 incidenceamongblack
individualsremainsconsiderableandprevention in this population is important
because racial disparities in access to care
mayhinderthecomplicatedmanagement
of herpes zoster and postherpetic neuralgia. Our data demonstrating disparities
in herpes zoster vaccine uptake, consistent with other national data,12,27,28 highlight the need to offer this vaccine to all
racial and ethnic groups. We also found
that individuals with certain chronic diseases were at increased underlying risk of
herpes zoster, but that herpes zoster vaccine was associated with a reduced risk

in these individuals too. This is reassuring information because it was plausible

that these diseases might have interfered
with functional immunity and vaccine effectiveness.29 Control of pain from herpes zoster and postherpetic neuralgia is
complicated in these patients because of
theirunderlyingconditionsandthemedicationstheymusttake.Herpeszostervaccine provides an opportunity to prevent
herpes zoster and the clinical challenge
of managing its symptoms.
Observational studies can be subject
to biases because patients who seek the
vaccinemaydifferintheirunderlyingrisk
of disease or in their ability and desire to
access care for the condition. Such biases
have, for instance, confounded interpretation of results from studies of influenza
vaccine in elderly individuals because
those at greatest risk of hospitalization
ordeathfrominfluenzamaybeleastlikely
to be offered the vaccine.8-10 The potential for bias in studies of herpes zoster
vaccine is particularly large because the
riskfactorsthatdistinguishimmunocompetent individuals who develop herpes
zoster and who receive herpes zoster
vaccine are not known.3 The marked
heterogeneity in physiology, fitness, and
health care seeking that exists in elderly individuals targeted for herpes zoster
vaccine could potentially hide these important yet unrecognized risk factors. We
assessed the association between vaccination and 13 indicator conditions in the
vaccinated and unvaccinated study cohorts,justaswehadforherpeszoster.The
adjusted rate ratios for all 13 conditions
were considerably greater than that for
herpes zoster; in fact, 7 adjusted rate ratios were significantly greater than 1.0.
A possible explanation for this excess risk
is that individuals receiving herpes zoster vaccine are generally more inclined
or better able to obtain medical care for
acute conditions. This interpretation is
consistent with our observation that herpes zoster vaccine recipients had more
outpatient encounters. If correct, herpes
zoster vaccine recipients might be more
likely to seek care for episodes of herpes
zoster as well, making our estimates of
reduced risk associated with herpes zoster vaccine conservative.

2011 American Medical Association. All rights reserved.

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Our study had limitations. It included

a fully insured population in 1 region of
the country; therefore, the results need to
be generalized carefully. It was not designed to assess severity or duration of
symptoms among herpes zoster cases or
to assess the effectiveness of herpes zostervaccineatpreventingpostherpeticneuralgia. In the SPS, herpes zoster vaccine
was associated with less pain and discomfort among individuals in whom herpes
zoster developed and reduced the incidenceofpostherpeticneuralgiaby66.5%.5
Average length of follow-up in our study
was short and it was not designed to captureanydeclineinprotectionthatislikely
tooccurwithtime.30 Misclassificationwas
possiblebecauseweascertainedstudyoutcomes and variables using passive followup through health care encounters and
using electronic health records. Such data
have proven fairly reliable for detecting
herpes zoster, although their role in detecting ophthalmic involvement has not
been adequately explored.4,31-33 It would,
however, seem that misclassification of
vaccinationorherpeszosterstatusismost
likely to result in an underestimate of the
reduction in risk associated with herpes
zoster vaccine. The prevalence of chronic
diseases and number of hospitalizations
prior to the index date were higher in the
unvaccinatedcohort;weadjustedforthese
factors and the magnitude of the difference was small, so they should not affect
our conclusions substantially.
Regarding chronic disease status, our
results were unchanged when we expanded our definition to include individuals with at least 1 relevant diagnosis at any time during follow-up (data not
shown). Although our conclusion that
herpes zoster vaccine was associated with
fewer herpes zostercoded hospitalizations is important, it should be interpreted cautiously because herpes zoster
is often incidental to herpes zoster
coded hospitalization rather than its
cause.7,34 Furthermore, although we controlled for age and excluded immunosuppressed individuals from our study,
the risk of hospitalization due to herpes
zoster is so strongly associated with these
factors that residual confounding is possible.4,7,20 A source of potential confound-

(Reprinted) JAMA, January 12, 2011Vol 305, No. 2

165

EFFECTIVENESS OF HERPES ZOSTER VACCINE IN OLDER ADULTS

ing we could not address in this study

was family history of herpes zoster,
which could predispose family members to herpes zoster, encourage them to
seek vaccination, or both.35 Such a bias
would result in an underestimate of reduced risk associated with the vaccine.
In conclusion, we found that individuals aged 60 years or older who received herpes zoster vaccine had a reduced risk of herpes zoster regardless of
age, race, and presence of chronic diseases. Herpes zoster vaccine was licensed recently, which means the durability of its protection needs to be
assessed in future studies. Meanwhile,
however, this vaccine has the potential

Author Contributions: Dr Tseng had full access to all

of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Tseng, Smith, Harpaz,
Bialek, Jacobsen.
Acquisition of data: Tseng, Smith.

Analysis and interpretation of data: Smith, Harpaz,

Bialek, Sy, Jacobsen.
Drafting of the manuscript: Tseng, Harpaz, Bialek.
Critical revision of the manuscript for important intellectual content: Smith, Harpaz, Bialek, Sy, Jacobsen.
Statistical analysis: Tseng, Smith, Harpaz.
Obtained funding: Jacobsen.
Administrative, technical, or material support: Tseng,
Bialek, Jacobsen.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure
of Potential Conflicts of Interest. Drs Tseng, Smith, and
Jacobsen and Ms Sy report having received research
funding from Merck for other vaccine studies. Dr Jacobsen reports having served as an unpaid consultant for Merck Research Laboratories. Drs Harpaz and
Bialek report no disclosures.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily
represent the views of the Centers for Disease Control and Prevention, US Department of Health and Human Services.
Online-Only Material: An eBox and eTables 1 and 2
are available at http://www.jama.com.

coccal disease after pneumococcal vaccination: an alternative method to estimate the efficacy of pneumococcal vaccine. N Engl J Med. 1980;303(10):
549-552.
14. Eurich DT, Marrie TJ, Johnstone J, Majumdar SR.
Mortality reduction with influenza vaccine in patients with pneumonia outside flu season: pleiotropic benefits or residual confounding? Am J Respir Crit
Care Med. 2008;178(5):527-533.
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Weiss NS. Evidence of bias in estimates of influenza
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16. Leung J, Harpaz R, Molinari NM, Jumaan A. Herpes zoster incidence among insured persons in the
United States, 1993-2006. Ann Intern Med. In Press.
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strategies are needed to improve the accuracy of influenza vaccine effectiveness estimates among seniors.
J Clin Epidemiol. 2009;62(7):687-694.
18. Tate JE, Curns AT, Cortese MM, et al. Burden of
acute gastroenteritis hospitalizations and emergency
department visits in US children that is potentially preventable by rotavirus vaccination: a probe study using
the now-withdrawn rotashield vaccine. Pediatrics.
2009;123(3):744-749.
19. Merck & Co. ZOSTAVAX (Zoster vaccine live): important information regarding storage and handling
[package insert]. http://www.merck.com/product
/usa/pi_circulars/z/zostavax/zostavax_pi.pdf. Accessed June 15, 2010.
20. Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster hospitalizations: the prevaricella vaccine era. J Infect Dis. 2000;181(6):
1897-1905.
21. Schmader K. Herpes zoster in the elderly: issues
related to geriatrics. Clin Infect Dis. 1999;28(4):
736-739.
22. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and
morbidity. Ophthalmology. 2008;115(2)(suppl):
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23. Severson EA, Baratz KH, Hodge DO, Burke JP. Herpes zoster ophthalmicus in Olmsted county, Minnesota: have systemic antivirals made a difference? Arch
Ophthalmol. 2003;121(3):386-390.
24. Shaikh S, Ta CN. Evaluation and management of
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25. Schmader K, George LK, Burchett BM, Pieper CF.

Racial and psychosocial risk factors for herpes zoster

in the elderly. J Infect Dis. 1998;178(suppl 1):S67S70.
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Jacobsen SJ. Risk factors of herpes zoster among children immunized with varicella vaccine: results from a
nested case-control study. Pediatr Infect Dis J. 2010;
29(3):205-208.
27. Lindley M. Zoster vaccine for adults 60 or older:
do they know about it and do they want it? Paper presented at: 44th National Immunization Conference;
April 19-22, 2010; Atlanta, GA.
28. Lu PJ, Euler GL, Jumaan AO, Harpaz R. Herpes
zoster vaccination among adults aged 60 years or older
in the United States, 2007: uptake of the first new vaccine to target seniors. Vaccine. 2009;27(6):882887.
29. Okamoto S, Hata A, Sadaoka K, Yamanishi K, Mori
Y. Comparison of varicella-zoster virus-specific immunity of patients with diabetes mellitus and healthy
individuals. J Infect Dis. 2009;200(10):1606-1610.
30. Merck Research Laboratories. ZOSTAVAXZoster
vaccine live (Oka/Merck): presented by Merck Research Laboratories at the Vaccines and Releated Biological Products Advisory Committee meeting of the
Food and Drug Administration, December 15, 2005.
http://www.fda.gov/ohrms/dockets/ac/05/slides
/5-4198S2_2.ppt. Accessed July 28, 2010.
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incidence of herpes zoster. Arch Intern Med. 1995;
155(15):1605-1609.
32. Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil
K, Seward JF. Incidence of herpes zoster, before and
after varicella-vaccination-associated decreases in the
incidence of varicella, 1992-2002. J Infect Dis. 2005;
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Houston H. Incidence of herpes zoster, 1997-2002.
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to annually prevent tens of thousands of

cases of herpes zoster and postherpetic
neuralgia nationally.7 To date, herpes
zoster vaccine uptake has been poor due
to weaknesses in the adult vaccine infrastructure and also due to serious barriers to the vaccine among clinicians and
patients.12,36 Solutions to these challenges need to be found so that individuals seeking to receive herpes zoster vaccine will be able to reduce their risk of
experiencing this serious condition.

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