S228 • JID 2008:197 (Suppl 2) • Oxman et al.
S U P P L E M E N T A R T I C L E
Vaccination against Herpes Zoster and Postherpetic
Michael N. Oxman,1,2Myron J. Levin,3and the Shingles Prevention Study Groupa
1VA San Diego Healthcare System, San Diego, and
2University of California, San Diego, California;
3University of Colorado Health Sciences
The incidence and severity of HZ and PHN increase with age in association with an age-related decline in varicella-
zoster virus (VZV)–specific cell-mediated immunity (VZV-CMI). VZV vaccines can boost VZV-CMI. Therefore,
we tested the hypothesis that VZV vaccination would protect older adults against HZ and PHN.
We enrolled 38,546 adults ?60 years of age in a randomized, double-blind, placebo-controlled trial
of an investigational HZ vaccine and actively followed subjects for the development of HZ. The primary end point
was the burden of illness due to HZ (HZ BOI), a composite measure of the incidence, severity, and duration of
pain and discomfort caused by HZ. The secondary end point was the incidence of PHN.
Subject retention was 195%. HZ vaccine reduced the HZ BOI by 61.1% (95% confidence interval
[CI], 51.1%–69.1%;) and reduced the incidence of PHN by 66.5% (95% CI, 47.5%–79.2%;P ! .001
incidence of HZ was also reduced by 51.3% (95% CI, 44.2%–57.6%;
injection site reactions were generally mild. HZ vaccine neither caused nor induced HZ.
The Shingles Prevention Study demonstrated that HZ vaccine significantly reduced the morbidity
due to HZ and PHN in older adults.
Herpes zoster (HZ) and postherpetic neuralgia (PHN) cause significant morbidity in olderadults.
P ! .001
). HZ vaccine was well tolerated;P ! .001
Herpes zoster (HZ), or shingles, is a disease of the
sensory ganglion, nerves, and skin that results from
reactivation of varicella-zoster virus (VZV) that has re-
mained latent within sensory neurons after primary
VZV infection (i.e., varicella, or chickenpox) [1–4]. HZ
is characterized clinically by unilateral radicular pain
and a vesicular rash that is generally limited to a single
Potential conflicts of interest: M.N.O. is Study Chairman of Department of
Veterans Affairs (VA) Cooperative Study #403, The Shingles Prevention Study, and
its substudies, which have been supported, in part, by grants from Merck to the
VA Cooperative Studies Program, The VA San Diego Medical Research Foundation,
and the VA Connecticut Research and Education Foundation. M.J.L. has received
lecture fees and honoraria, consultation fees, and research support from Merck;
holds a partial interest in a patent related to the herpes zoster vaccine; and is
on the Merck speakers’ bureau.
Financial support: The Shingles Prevention Study, VA Cooperative Study #403,
was conducted by the Cooperative Studies Program, Department of Veterans
Affairs, Office of Research and Development in collaboration with the National
Institute of Allergy and Infectious Diseases and Merck. Additional support was
provided by a grant from Merck to the VA Cooperative Studies Program and by
the James R. and Jesse V. Scott Fund for Shingles Research. Supplement
sponsorship is detailed in the Acknowledgments.
aMembers of the Shingles Prevention Study Group are listed after the text.
Reprints or correspondence: Dr. Michael N. Oxman, The Shingles Prevention
Study (111F-1), VA Medical Center, 3350 La Jolla Village Dr., San Diego, CA 92161
The Journal of Infectious Diseases
? 2008 by the Infectious Diseases Society of America. All rights reserved.
dermatome [1–6]. Neuropathic pain, likely due to neu-
ronal damage and inflammation resulting from the
multiplication and spread of the reactivated VZV, is a
major manifestation of HZ, especially in older persons
[1, 5–9]. The dermatomal HZ rash is frequently pre-
ceded by neuropathic pain; neuropathic pain usually
accompanies the rash; and neuropathic pain and dis-
comfort (e.g., allodyniaand severepruritus)maypersist
or develop after the dermatomal rash has healed—a
neuralgia” (PHN) [5–7, 9–15]. The pain and discom-
fort associated with HZ can be prolongedanddisabling,
severely compromising the patient’s quality of life and
capacity to carry out activities of daily living .
The frequency and severity of HZ and PHN increase
with increasing age; more than half of all recognized
cases of HZ and most cases of clinicallysignificantPHN
occur in immunocompetent persons ?60 years of age
[2–6, 9–15, 17]. Antiviral therapy reduces the duration
and severity of HZ, but it does not prevent PHN [4,
9, 14, 15, 18–20]. PHN may persist for months or even
years, and it is often refractory to treatment . Thus,
some means of preventing HZ and PHN is needed to
reduce the burden of these painful conditions on older
Vaccination for Herpes Zoster and PHN • JID 2008:197 (Suppl 2) • S229
persons, who constitute a growing proportion of the popula-
tions of most developed countries [21–23].
In 1965, after 16 years of careful surveillance for varicella
and HZ among the patients in his medical practice, Edgar
Hope-Simpson published his seminal observations and a re-
markably prescient hypothesis . He observed that the inci-
dence and severity of HZ increased with increasing age and
hypothesized that this was due to an age-related decline in
immunity to VZV. Hope-Simpson also observed that recur-
rences of HZ were relatively uncommon among immunocom-
petent persons (incontrasttothefrequentrecurrencesofherpes
simplex), and he hypothesized that this was because an episode
of HZ induced an increase in immunity to VZV sufficient to
“immunize” against a subsequent episode [3, 21]. Observations
during the past 4 decades have supported the thesis that T cell–
mediated immunity to VZV (VZV-CMI) is the major deter-
minant of the risk and severity of HZ [2, 9, 21, 24–32]. The
increased incidence and severity of HZ and PHN observed in
older adults are closely correlated with a progressiveage-related
decline in VZV-CMI, whereas levels of antibody to VZVremain
relatively constant with increasing age [2, 9, 21, 24, 27–32].
The development by Takahashi and his colleagues of the live
to immunize VZV-naive children and adults against varicella
[33–36] and to explore the possibility of boosting VZV-CMI
in older adults [21, 31]. Subsequent studies have demonstrated
that Oka-derived VZV vaccines can elicit a significant increase
in VZV-CMI in immunocompetent older adults [32, 37–39]
and can reduce the incidence and severity of HZ in recipients
of bone marrow allografts [40, 41]. These observations led us
to hypothesize that immunization of older adults with live at-
tenuated Oka VZV vaccine would boost their waning VZV-
CMI and thereby provide protection against HZ and PHN [21,
31, 42, 43]. The Shingles Prevention Study (SPS), Department
of Veterans Affairs Cooperative Study #403, was initiated to
test this hypothesis by determining whether vaccination with
an investigational live attenuated Oka/Merck VZV vaccine
would decrease the incidence and/or severity of HZ and PHN
in immunocompetent adults ?60 years of age. The results of
the SPS presented here have been published elsewhere .
STUDY DESIGN AND METHODS
The SPS was a placebo-controlled, double-blind, multicenter
trial in which adults ?60 years of age were randomized to
receive either VZV vaccine or placebo in a 1:1 ratio at 22 study
sites across the United States. Randomization was stratified by
study site and age group, 60–69 and ?70 years of age. The SPS
was approved by a Department of Veterans Affairs Cooperative
Studies Program Human Rights Committee and all local in-
stitutional review boards. All subjects provided written in-
The design and execution of the SPS presented several major
challenges (listed in the Appendix). Enrollment of a large num-
ber of subjects proved to be more difficult than anticipated.
However, with the aid of local outreach, media coverage, ad-
vertising, and letters to households with ?1 members ?60
years of age in zip codes around each study site, 38,546 subjects
were enrolled in the SPS between November 1998 and Septem-
ber 2001. Eligible subjects were required to have a history of
varicella or at least 30 years of residence in the continental
United States, to be ?60 years of age, and to give written
informed consent. Exclusion criteria included immunosup-
pression resulting from diseases or their treatment, prior HZ
or varicella vaccination, hypersensitivity to components of the
investigational vaccine/placebo, receipt of blood products
within 3 months before or planned during the study period,
receipt of live vaccines within 1 month or inactivated vaccines
within 2 weeks before randomization,concurrentantiviralther-
apy, or any condition that the investigator believed might in-
terfere with the trial. Subjects who developed HZ were offered
famciclovir without cost in accordance with the protocol-spec-
ified HZ follow-up procedure and received treatment for pain
prescribed by SPS physicians.
At enrollment, subjects were educated about the signs and
symptoms of HZ and instructed to contact their study site
immediately for evaluation by a SPS physician if they devel-
oped a new rash or unilateral pain syndrome. To ensure cap-
ture of mild or vaccine-modified cases of HZ, study personnel
maintained a low threshold for evaluating subjects with new
rashes and for classifying subjects as “suspected cases of HZ.”
Active follow-up and case ascertainment were ensured by an
interactive automated telephone response system (ATRS) de-
veloped and validated for the SPS. Subjects were instructed
to call the toll-free ATRS number on a specific day each
month. If their responses to a standardized set of questions
suggested possible HZ, they were instructed to immediately
contact their local study site, and a fax containing their re-
sponses was sent to the site. The ATRS also reminded subjects
to report HZ-like rashes to the study site as soon as they
occurred. Subjects who did not call the ATRS within a pre-
established time interval were called by the ATRS. If thisfailed,
the ATRS transmitted a fax prompting the local study site to
contact the subject directly. The ATRS handled 86% of subject
follow-up, permitting SPS personnel to focus on retention of
subjects at risk of being lost to follow-up. This resulted in
retention and follow-up of 195% of the enrolled subjects
through the end of the study. Closeout interviews with each
subject did not reveal any missed cases of HZ.
Development of a quantitative measure of severity for cases
of HZ was problematic because pain and discomfort are the
major cause of morbidity in older persons with HZ, and these
symptoms are subjective. Accordingly, we developed and val-
S230 • JID 2008:197 (Suppl 2) • Oxman et al.
ample of the HZ Severity-of-Illness Score for a hypothetical subject with
HZ. The HZ Severity-of-Illness Score is defined as the area under the
curve of Zoster Brief Pain Inventory (ZBPI) “worst pain in the last 24 h”
scores over time during the 182-day period after HZ rash onset.
Herpes Zoster (HZ) Severity-of-Illness Score. This is an ex-
idated an HZ-specific assessment tool, the Zoster Brief Pain
Inventory (ZBPI), that captured HZ pain and discomfort, in-
cluding unpleasant sensations, such as allodynia and pruritus,
that are not always characterized as pain by persons with HZ
. The ZBPI, administered to subjects at specified intervals
over a 182-day observation period, asked subjects to rate their
level of HZ-associated pain and discomfort at its “worst,” “av-
erage,” and “least” in the past 24 h and “right now” on a 0–
10 rating scale. The “worst pain in the last 24 h” score was
chosen as the end point measurement because it had the
greatest reliability and was highly correlated with the ZBPI
average pain score and other validated pain measures [44, 45].
For each evaluable case of HZ, the ZBPI data were used to
calculate an “HZ Severity-of-Illness Score,” defined as the area
under the ZBPI “worst pain” response–versus–time curve dur-
ing this 182-day period(figure1).IncreasingmeanHZSeverity-
of-Illness Scores have been shown to be highly correlated with
decreasing health-related quality of life and functional status
in older adults . The HZ Severity-of-Illness Score was de-
fined as 0 for subjects who did not develop HZ during the
The primary SPS end point was the burden of illness caused
by HZ (HZ BOI), a severity-by-durationmeasurerepresenting
the total HZ-associated pain and discomfort in a population
of study subjects [16, 44, 46]. The HZ BOI is the sum of the
HZ Severity-of-Illness Scores of all members of the group
(vaccine recipients or placebo recipients). This end pointmea-
sures any effect of the HZ vaccine on the incidence of HZ
and/or the severity and/or duration of HZ pain and discom-
fort (figure 2).
The secondary SPS end point was the incidence of clinically
significant PHN, defined as HZ-associated pain or discomfort
rated as ?3 (on a 0–10 scale) persisting or appearing 190 days
after HZ rash onset.Scores !3arenotassociatedwithsignificant
decrements in quality of life or ability to carry out activities of
daily living and, thus, were notconsideredtorepresentclinically
significant PHN [10, 44].
The incidence of HZ was also determined in vaccine and
To determine “evaluable cases of HZ” for the analysis of
vaccine efficacy, each suspected case of HZ was classified as an
“evaluable case of HZ” or “not a case of HZ” beforeunblinding,
by use of a hierarchical algorithm that incorporated the results
of a central polymerase chain reaction (PCR) assay, local virus
culture, and the final clinical diagnosis established by a clinical
evaluation committee (CEC) .
A real-time PCR assay, developed and validated for the SPS,
employed 2 sets of primers and a probe from VZV gene 62 to
detect and discriminate between DNA from wild-type and Oka
vaccine strains of VZV on the basis of a single-base-pair dif-
ference and the preferential amplification of the target by ho-
mologous primers. Another set of primers and probe was used
to detect herpes simplex virus (HSV) DNA. Each primer pair
and its probe was run in individualPCRs, togetherwithpositive
and negative controls and viral and human b-globinDNAstan-
dards. Assay sensitivity was sufficient to detect ∼13 copies of
wild-type or vaccine-strain VZV DNA. Every PCR for viral
DNA detection was multiplexed with primers and a probe for
the human b-globin gene to demonstrate adequacy of the spec-
imen by detecting cellular DNA (R. Harbecke, P. M. Keller, and
M.N.O., unpublished data).
Although not required by the SPS protocol, viral culture was
performed by local laboratories at some study sites.
The CEC, a group of 5 study physicians with HZ expertise,
evaluated all suspected cases of HZ identified during thestudy.
Each CEC member provided a clinical diagnosis for each sus-
pected case of HZ after independently reviewing a summary
of the rash and pain evaluations, digital photographs of the
subject’s rash, and progress notes documenting the course of
illness. CEC members were blinded to treatment assignment
and laboratory results. A unanimous diagnosis of “HZ” or
“not HZ” by the CEC members constituted a final clinical
diagnosis. CEC members discussed each nonunanimous case
and determined the final clinical diagnosis by majority vote.
Individual CEC members did not evaluate cases from their
respective study sites.
If the PCR assay revealed VZV DNA, the case was classified
as an “evaluable case of HZ”; if the PCR assay was negative
for VZV DNA but positive for b-globin or HSV DNA, the case
was classified as “not a case of HZ.” If the PCR specimen was
“inadequate” (i.e., negative for both virus and b-globin DNA)
or missing, isolation and confirmation of VZV or HSV in the
local virology laboratory, if available, was used to establish the
Behavior of the HZ BOI if the HZ vaccine were to reduce the incidence but not the severity of HZ, in which case there would be fewer cases of HZ
in the vaccine recipients than in the placebo recipients, but the cases of HZ in the vaccine recipients would have, on average, HZ Severity-of-Illness
Scores comparable to those of the cases in placebo recipients. B, Behavior of the HZ BOI if the HZ vaccine were to reduce the severity but not the
incidence of HZ, in which case there would be just as many cases of HZ in the vaccine recipients as in the placebo recipients, but the cases of HZ
in the vaccine recipients would have, on average, lower HZ Severity-of-Illness Scores than those in the placebo recipients. C, Behavior of the HZ BOI
if the HZ vaccine were to reduce both the incidence and the severity of HZ, in which case there would be fewer cases of HZ in the vaccine recipients
then in the placebo recipients, and the cases of HZ in the vaccine recipients would have, on average, lower HZ Severity-of-Illness Scores than those
in the placebo recipients. In all 3 situations, the HZ BOI would be lower in the vaccine recipients than in the placebo recipients. The figures shown
for the HZ Severity-of-Illness Scores and for the HZ BOI are for purposes of illustration only.
Diagrams illustrating the behavior of the herpes zoster (HZ) Burden of Illness (HZ BOI) under 3 different theoretical circumstances. A,
S232 • JID 2008:197 (Suppl 2) • Oxman et al.
Illness (HZ BOI). The primary end point of the Shingles Prevention Study
was the HZ BOI, a severity-by-duration measure of the total pain and
discomfort associated with HZ in the population of study subjects. For
each confirmed case of HZ, responses to the “worst pain in the last 24
h” question in the Zoster Brief Pain Inventory were used to calculate an
HZ Severity-of-Illness Score, defined as the area under the curve of HZ
pain and discomfort plotted against time during the 182-day period after
the onset of HZ rash. Subjects with HZ had HZ Severity-of-Illness Scores
ranging from 0 to 1813. Increasing HZ Severity-of-IllnessScoresarehighly
correlated with a decrease in the health-related quality of life and in
functional status of older adults . An HZ Severity-of-Illness Score of
0 was recorded for subjects in whom HZ did not develop during the study
period. The HZ BOI Score represents the average HZ Severity-of-Illness
Score among all subjects in the vaccine or placebo groups; it was cal-
culated as the sum of the HZ Severity-of-Illness Scores of all members
of a group divided by the total no. of subjects in the group. The figure
is based on data published in .
Herpes zoster (HZ) vaccine efficacy for the HZ Burden of
diagnosis. In the absence of a valid laboratory diagnosis, the
case was classified on the basis of the final clinical diagnosis
by the CEC.
All serious adverse events (SAEs) were actively ascertained
during the first 42 days after vaccination and passively ascer-
tained thereafter. Deaths were identified by reports from the
families of subjects and during follow-up of missed ATRS calls.
Approximately 6600 subjects (∼300 per study site) were en-
rolled in an Adverse Events (AE) Substudy. These subjects
maintained a daily log of body temperature and a report card
of clinical complaints during the first 42 days after vaccination.
During the remainder of the study, subjects in the AE Substudy
were actively followed to identify all hospitalizations.
tween November 1998 and September 2001; 19,270 received
HZ vaccine, and 19,276 received placebo. The median age in
both groups was 69 years; 6.6% of the vaccine recipients and
6.9% of the placebo recipients were ?80 years of age. Forty-
one percent of the subjects in the vaccine and placebo groups
were female. At enrollment, most subjects had no (51.3%) or
mild (38.6%) health limitations on their activities. The mean
duration of HZ surveillance was 3.13years(median,3.12years),
with no difference between the vaccine and placebo groups.
More than 95% of enrolled subjects were actively followed to
the end of the study and completed a closeout interview. Only
0.6% withdrew or were lost to follow-up; 4.1% died before the
study ended .
Evaluable cases of HZ.
A total of 1308 suspected cases of
HZ were evaluated; 317 subjects with rashes (156 in the vaccine
group; 161 in the placebo group) were determined not to have
HZ. Except for 49 of these that were caused by HSV (24 in
vaccine recipients and 25 in placebo recipients), no specific
alternative diagnosis was established for suspicious rashes de-
termined not to be HZ. Study closeout interviews did not iden-
tify any missed cases of HZ. The final diagnosis in 1156(88.4%)
of the 1308 suspected cases of HZ (417 in vaccine recipients;
739 in placebo recipients) was based on the results of the PCR
assay. Of the 1308 suspected cases, 984 (75.2%) were deter-
mined to be evaluable cases of HZ. Of these, 24 were excluded
from the primary efficacy analysis per protocol because they
occurred within 30 days of vaccination (6 in vaccine recipients
and 18 in placebo recipients), and 3 were excluded because
they represented a subject’s second case of HZ (1 in a vaccine
recipient and 2 in placebo recipients). The remaining 957 ev-
aluable cases of HZ (315 in vaccine recipients; 642 in placebo
recipients) constituted the end points for the efficacy analysis.
In each group, 193% of the subjects with HZ were positive for
wild-type VZV DNA by PCR assay. Vaccine virus was never
A total of 38,546 subjects were enrolled be-
HZ burden of illness.
the HZ BOI Score (average HZ Severity-of-Illness Scoreamong
all vaccine versus placebo recipients)(
all, vaccine efficacy for the HZ BOI (VEBOI) was 61.1% (95%
confidence interval [CI], 51.1%–69.1%), which met the pre-
specified criteria for success. There were no significant differ-
ences in VEBOIby sex or by age stratum, although VEBOIap-
peared to be slightly lower in the older subjects (figure 3).
Moreover, the mean HZ Severity-of-Illness Score among ev-
aluable cases of HZ was significantly lower among vaccine re-
cipients than among placebo recipients (141.2 vs. 180.5; P p
). For virtually every level of HZ Severity-of-Illness Score, .008
fewer cases were seen in the vaccine group than in the placebo
group; this was especially notable for cases with higherscores—
that is, cases with more painful and protracted disease .
For example, HZ Severity-of-Illness Scores 1600, equivalent to
160 days of “the worst pain imaginable,” were observed in only
11 vaccine recipients, compared with 40 placebo recipients,
which represents a 79% reduction in the HZ vaccine recipients
(data not shown).
The use of antiviral medications in evaluable cases of HZ
The HZ vaccine significantlyreduced
)(figure3).Over-P ! .001
Vaccination for Herpes Zoster and PHN • JID 2008:197 (Suppl 2) • S233
herpetic neuralgia (PHN). HZ vaccine significantly reduced the incidence
of PHN, by approximately two-thirds, in all subjects and in both age
strata. It is important to note that this reduction is among all subjects
and not just those with HZ. The figure is based on data published
Herpes zoster (HZ) vaccine efficacy for the incidence of post-
HZ vaccine significantly reduced the overall incidence of HZ, by 51.3%,
although vaccine efficacy for the incidence of HZ was reduced substan-
tially in subjects ?70 years of age. The figure is based on data published
Herpes zoster (HZ) vaccine efficacy for the incidence of HZ.
was comparable in vaccine and placebo recipients (87% and
86%, respectively) and was initiated within 72 h of HZ rash
onset in 64% of vaccine recipients and 66% of placebo recip-
ients . The frequency of pain medication use was com-
parable in the vaccine and placebo recipients who developed
HZ (acetaminophen, 44% and 46%, respectively; anticonvul-
sants, 9% and 12%; corticosteroids, 3% and 3%; nonsteroidal
anti-inflammatory drugs,41% and 42%;opiates,44%and42%;
tricyclic antidepressants, 5% and 6%), whereas the average du-
ration and quantity of opiate usage were lower by 38% and
42%, respectively, in the vaccine recipients who developed HZ.
Incidence of PHN.
There were107 cases ofPHN;27among
vaccine recipients and 80 among placebo recipients (0.46 vs.
1.38 cases/1000 person-years, respectively;
Overall, vaccine efficacy for PHN (VEPHN) was 66.5% (95% CI,
47.5%–79.2%), which met the prespecified criteria for success.
There were no significant differences in VEPHNby sex or by age
stratum (figure 4). In fact, there was no decrease in VEPHNin
the older subjects. The VEPHNdid not change appreciably when
PHN was defined using alternate cutoff times for duration of
pain (from 11 month to 16 months after rash onset) .
Incidence of HZ.
Although not a primary or secondaryend
point, the incidence of HZ per 1000 person-years was signif-
icantly reduced by the HZ vaccine, from 11.1 in placebo re-
cipients to 5.4 in vaccine recipients(
efficacy for the incidence of HZ (VEHZ) was 51.3% (95% CI,
44.2%–57.6%); VEHZwas significantly higher in the younger
age stratum than in the older age stratum (figure 5) .
In the total SPS population,deathratesover
the entire study period were comparable in the vaccine and
placebo recipients (4.1% in each group). During the first 42
days after vaccination, the proportion of vaccine and placebo
) (figure 4).P ! .001
)(figure5).VaccineP ! .001
subjects with ?1 SAE was also similar (1.4% in each group),
as was the distribution of SAEs by organ system (data not
shown). During this period, injection-site rashes were signifi-
cantly more frequent in the vaccine group than in the placebo
group, but rashes at other locations occurred at similar rates
in each group. During the first 42 days after vaccination, there
were 7 evaluable cases of HZ in vaccine recipients and 24 in
placebo recipients. During the entire study, 5 subjects experi-
enced SAEs that were assessed by the study site investigators
as being “possibly vaccine-related.” Two had received vaccine:
a 64-year-old woman with exacerbation of asthma on day 2
after vaccination and an 80-year-old man with a diagnosis of
polymyalgia rheumatica on day 3 after vaccination. Three had
received placebo: a 65-year-old man with an anaphylactoid re-
action 90 min after vaccination (and 30 min after eating pea-
nuts), a 69-year-old man with a diagnosis of polymyalgia rheu-
matica on day 15 after vaccination, and a 78-year-old man with
a diagnosis of Goodpasture syndrome on day 52 after vacci-
In the AE substudy, significantly more subjects in the vaccine
group had ?1 AE of any type than in the placebo group,
reflecting a greater frequency of injection-site AEs in vaccine
recipients. The most frequent injection-site AEs reported by
vaccine recipients were erythema (36%), pain or tenderness
(35%), swelling (26%), and pruritus (7%). In contrast, the
proportion of subjects with ?1 systemic AE was similar in the
vaccine and placebo recipients. During the postvaccination pe-
riod, significantly more AE Substudy subjects in the vaccine
group than in the placebo group experienced ?1 SAE (1.9%
vs. 1.3%, respectively;P p .034
ferences in the distribution of SAEs by body system or event
(data not shown). A post hoc, subject-by-subject review re-
); there were no significant dif-
S234 • JID 2008:197 (Suppl 2) • Oxman et al.
vealed no clinically meaningful differences between treatment
groups in the pathophysiology, nature, timing, intensity, or
outcome of these events . Subjects in the AE Substudy were
monitored for hospitalizations from the day of vaccination to
the end of study. The number of subjects with ?1 hospitali-
zations was similar for the vaccine and placebo groups (0.2%
in each). No hospitalization in either group was assessed as
being vaccine related .
HZ and PHN cause significant morbidity in older adults [14–
17, 19,44].It is estimated,onthebasisofcurrentUSpopulation
figures and data on the age-specific incidence, that there are a
million or more new cases of HZ each year in the United States,
a number that is likely to increase as the population ages. An-
tiviral therapy does not eliminate the morbidity of HZ and
PHN [4, 9, 15, 19, 20], and the neuropathic pain of PHN is
often refractory to treatment . Thus, a means of prevention
would offer significant medical and economic benefit.
The SPS demonstrated that an investigational HZ vaccine
reduced the HZ BOI in people ?60 years of age by 160% .
The HZ BOI was chosen as the primary SPS end point because
it is sensitive to changes in the incidence, severity, and duration
of HZ pain and discomfort [16, 44, 46]. The HZ vaccine also
reduced the incidence of PHN, the most common debilitating
complication of HZ, by 66.5% . Comparable efficacy with
respect to PHN was demonstrated in both age strata, with a
trend toward greater efficacy for PHN of longer duration. The
vaccine showed significant efficacy for both end points in both
age strata and in both sexes . Further analysis of the vac-
cine’s effect on the components of the HZ BOI showed that it
reduced the overall incidence of HZ by 51.3% and significantly
reduced the average severity of illness among subjects who
developed HZ . The comparable usage of antivirals by vac-
cine and placebo recipients who developed HZ and the lower
average usage of opiates by the vaccine recipients indicate that
the treatment administered to subjects who developed HZ did
not bias the study results in favor of HZ vaccine.
The SPS confirmed the increased incidence and severity of
HZ in older individuals, which is associated with a progressive
age-related decline in VZV-CMI [3, 18, 21, 26–32]. Because
recent studies, as well as data from individuals in the SPS,
indicate that VZV vaccines can boost VZV-CMI in older in-
dividuals [21, 32, 37–39], we believe that the observed efficacy
of the investigational HZ vaccine reflects its ability to boost
VZV-CMI in vaccinated subjects. The investigational HZ vac-
cine was well tolerated. In the entire study population, rates of
SAEs, systemic AEs, hospitalizations, and deaths were low and
comparable in the vaccine and placebo groups, and local re-
actions at the vaccination site were generally mild.
The capacity of the HZ vaccine to protect against HZ may
have added significance if, as has been hypothesized by some
vaccination results in an accelerated loss of VZV-CMI in adults
no longer exposed to children with varicella and a correspond-
ing increase in the age-specific incidence of HZ [47, 48].
Several features of the SPS are noteworthy. Monthly contact
with subjects, facilitated by the ATRS, permitted active sur-
veillance for HZ, helped to retain 195% of the 38,546 enrolled
subjects in the SPS, ensured the identification and evaluation
of all cases of HZ that occurred (including mild and atypical
cases), and supported the evaluation of vaccine safety. The
sensitive and specific PCR assay for VZV and HSV DNA, de-
veloped and validated for the SPS, established the diagnosis in
88.4% of the suspected cases of HZ and in 93.4% of the ev-
aluable cases of HZ in the study.
THE SHINGLES PREVENTION STUDY GROUP
The Shingles Prevention Study was planned and/or adminis-
tered by a Planning/Executive Committee: Michael N. Oxman
(Chair), Robert D. Arbeit, Patricia Barry, Chris Beisel, Kathy
D. Boardman, Cindy L. Colling, Larry E. Davis, Lawrence D.
Gelb, Anne A. Gershon, Anthony R. Hayward, Michael R. Ir-
win, Gary R. Johnson, Myron J. Levin, Peter N. Peduzzi, Ken-
neth E. Schmader, Michael S. Simberkoff, Stephen E. Straus,
Adriana Weinberg, Heather M. Williams, Paula Annunziato,
Christina Y. Chan, Ivan S. F. Chan, and Jeffrey L. Silber
The VA Cooperative Studies Program Shingles Prevention
Study Investigators include the following individuals: L. E. Da-
vis (Albuquerque, NM); C. A. Kauffman (Ann Arbor, MI); S.
K. Keay (Baltimore, MD); A. R. Marques, N. E. Soto, and P.
Brunell (Bethesda, MD); J. W. Gnann (Birmingham, AL); R.
Serrao, D. J. Cotton, R. P. Goodman, and R. D. Arbeit (Boston,
MA); C. T. Pachucki (Hines, IL); M. J. Levin (Denver, CO); K.
E. Schmader (Durham, NC); W. A. Keitel (Houston, TX); R.
N. Greenberg (Lexington, KY); V. A. Morrison (Minneapolis,
MN); P. F. Wright and M. R. Griffin (Nashville, TN); M. S.
Simberkoff (New York, NY); S. S. Yeh and Z. Lobo (Northport,
NY); M. Holodniy and J. Loutit (Palo Alto, CA); R. F. Betts
(Rochester, NY); L. D. Gelb (St. Louis, MO); G. E. Crawford
(San Antonio, TX); J. Guatelli and P. A. Brooks (San Diego,
CA); K. M. Neuzil (Seattle, WA); and J. F. Toney (Tampa, FL).
Administrative and statistical support was provided by the
VA Cooperative Studies Program Coordinating Center, West
Haven, Connecticut: P. Antonelli, B. Huff, J. H. Zhang, T. C.
Kyriakides, K. Newvine, R. Concepcion, K. DiBenedetto, S.
O’Neil, and P. O’Brien.
Clinical research pharmacy management was provided by
the VA Cooperative Studies Program Clinical Research Phar-
macy Coordinating Center, Albuquerque, New Mexico: K. D.
Boardman, J. Peterson, and B. Del Curto.
Central Laboratory services were provided by the Denver
Vaccination for Herpes Zoster and PHN • JID 2008:197 (Suppl 2) • S235
Central Cell-Mediated Immunity Laboratory, Denver, Colo-
rado: D. Elizabeth, L. Enomoto, and M. Jones; by the SanDiego
Central Cell-Mediated Immunity Laboratory: H. A. Stanleyand
P. Jordan; and by the San Diego Central DiagnosticLaboratory:
R. Harbecke, Y. Naidu, and L. J. Wopschall.
Statistical assistance at Merck was provided by I. S. F. Chan,
W. W. B. Wang, J. Xu, J. Heyse, and H. Matthews. Clinical
administration at Merck was provided by J. Ryan, J. Eiden, F.
Scho ¨del, J. Sadoff, S. Manoff, C. J. White, R. Vessey, D. Stinson,
M. E. Thompson, K. Adair, P. Brownell, K. Perrrin, S. Senior,
R. Rutledge, and N. Bundick.
plement entitled “Varicella Vaccine in the United States: A Decade of Pre-
vention and the Way Forward,” sponsored by the Research Foundation for
Microbial Diseases of Osaka University, GlaxoSmithKline Biologicals, the
Sabin Vaccine Institute, the Centers for Disease Control and Prevention,
and the March of Dimes.
This article was published as part of a sup-
THE SHINGLES PREVENTION STUDY: MAJOR
Enrollment of a large number of subjects at increased
risk for herpes zoster (HZ) and postherpetic neuralgia
(i.e., persons ?60 years of age)
Active follow-up of all subjects to identify and evaluate
every case of HZ occurring in the study population as
soon as possible after rash onset
Development of a quantitative measure of HZ severity
Selection of a primary end point that would measure the
impact of the HZ vaccine on the incidence, severity, and/
or duration of HZ
Determination of evaluable cases of HZ for the analysis
of HZ vaccine efficacy
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