BRIEF REPORT

Varicella-Zoster VirusSpecic
Antibody Responses in 5059-YearOld Recipients of Zoster Vaccine
Myron J. Levin,1 Kenneth E. Schmader,2 John W. Gnann,3
Shelly A. McNeil,7 Timo Vesikari,8 Robert F. Betts,4 Susan Keay,5
Jon E. Stek,6 Nickoya D. Bundick,6 Shu-Chih Su,6 Yanli Zhao,6
Xiaoming Li,6 Ivan S. F. Chan,6 Paula W. Annunziato,6 and Janie Parrino6
1

Prevaccination and 6-week postvaccination samples from the

immunogenicity substudy (n = 2269) of the zoster vaccine
(ZV) efcacy trial (N = 22 439) in 5059-year-old subjects
were examined for varicella-zoster virusspecic antibody
responses to vaccination. The varicella-zoster virus geometric mean titer (GMT) and geometric mean fold rise were
higher in ZV recipients than in placebo recipients (GMT,
660.0 vs 293.1 glycoprotein enzyme-linked immunosorbent
assay units/mL [P < .001], respectively; geometric mean fold
rise, 2.31 vs 1.00 [P < .025]). In each group there was a strong
inverse correlation between postvaccination GMT and risk of
subsequent herpes zoster. Although these data provide strong
evidence that relates ZV-induced antibody and the risk of
herpes zoster, a protective threshold was not determined.
Clinical Trials Registration. NCT00534248.
Keywords.

herpes zoster; zoster vaccine; immunogenicity.

The live attenuated herpes zoster (HZ) vaccine (zoster vaccine

[ZV]; ZostavaxTM; Merck & Co., Inc.) was recommended by
the Advisory Committee on Immunization Practices in the
United States in 2008 for immunocompetent individuals aged
60 years, based on a large randomized, placebo-controlled

METHODS
Study Design

The methods for this event-driven, randomized, double-blind,

placebo-controlled, multicenter study (NCT00534248) are published elsewhere [10]. Subjects were randomized (1:1 ratio) to
receive either ZV or placebo. To evaluate the correlation of
vaccine-induced VZV antibody responses and subsequent protection against HZ, serum samples were collected from study
subjects before and 6 weeks after vaccination, with VZV antibody
concentrations measured by gpELISA in (1) the immunology
subcohort population (10% protocol-prespecied, randomized
subcohort) and (2) the case-cohort population (immunology subcohort plus all subjects in whom suspected HZ developed).
Study Population

Received 17 December 2012; accepted 2 May 2013; electronically published 1 August 2013.
Presented in part: 48th Annual Meeting of the Infectious Diseases Society of America, 21
24 October 2010, Vancouver, British Columbia, Canada. Abstract 3363.
Correspondence: Janie Parrino, PhD, Merck & Co., Inc., PO Box 1000, UG3CD-28, North
Wales, PA 19454-1099 (janie_parrino@merck.com).
The Journal of Infectious Diseases 2013;208:138690
The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases
Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@
oup.com.
DOI: 10.1093/infdis/jit342

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Healthy subjects aged 5059 years with a history of varicella or

residence in a VZV-endemic area for 30 years, were enrolled.
Exclusion criteria have been described elsewhere and included
evidence of immunocompromise [9]. The protocol was conducted in accordance with principles of good clinical practice
and approved by the ethical review committee of each participating site; written informed consent was obtained from each
subject before study entry.

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University of Colorado Denver Anschutz Medical Campus, Aurora, 2Duke University,

Geriatric Research, Education and Clinical Center, Durham Veterans Affairs Medical
Center, North Carolina, 3Medical University of South Carolina, Charleston,
4
University of Rochester, New York, 5Veterans Affairs Maryland Health Care
System, Baltimore, Maryland, and 6Merck & Co., Inc., Whitehouse Station, New
Jersey; 7Dalhousie University, Halifax, Nova Scotia, Canada; and 8University of
Tampere, Finland

trial, the Shingles Prevention Study (SPS) [1, 2]. There is strong
clinical evidence that varicella-zoster virus (VZV)specic cellmediated immunity (VZV CMI) is both necessary and sufcient
to prevent HZ and that ZV prevents HZ because it stimulates
VZV CMI [36]. It is believed that there is a causal inverse relationship between the loss of VZV CMI that occurs with aging
and the age-related increase in HZ. In contrast, VZV-specic
immunoglobulin G antibody (VZV antibody) does not decline
with age [3, 7]. Nevertheless, the SPS demonstrated that a measure of VZV antibody, in addition to 2 measures of VZV CMI,
correlated with protection against HZ, although no quantitative
measure of any of these responses reliably predicted the extent
of protection [8].
A subsequent efcacy trial of ZV in 22 439 subjects 5059
years old demonstrated an efcacy of 69.8% for preventing HZ
[9]. Ten percent of subjects were randomly assigned to an immunology substudy/subcohort that measured VZV antibody
response to ZV. The substudy objectives were to determine if
ZV in 5059-year-olds is immunogenic (as evaluated by glycoprotein enzyme-linked immunosorbent assay [gpELISA]) and
to assess the association between antibody response at week 6
after vaccination and the risk of HZ.

Intervention

Lyophilized ZV and placebo were supplied in 0.7-mL singledose vials and stored at 15C or colder. Placebo contained the
same stabilizers as ZV, but no live virus or virus components.
ZV and placebo were reconstituted with sterile water immediately before administration. All subjects received a single 0.65mL subcutaneous injection of either ZV or placebo in the
deltoid area.
Follow-up

Subjects were educated regarding the signs and symptoms of

HZ and instructed to call their study site if HZ symptoms occurred. Contact by an interactive voice response system was
undertaken monthly until study completion to ensure that suspected HZ was reported. Suspected HZ cases were evaluated by
a site investigator. Initiation of treatment with antiviral therapy
and pain medication was determined by the treating physician.

All HZ rash characteristics were recorded, and lesion swab

samples were submitted for detection of VZV, herpes simplex,
and human -globin DNA using a polymerase chain reaction
(PCR) assay ( performed at PPD Vaccines and Biologics) [10].

Statistics

The immunogenicity objectives were (1) to determine whether

administered ZV is immunogenic and (2) to assess the association between antibody response 6 weeks after vaccination and
the risk of HZ. To show a signicantly higher geometric mean
titer (GMT) in VZV antibody titers at 6 weeks after vaccination
in the ZV group compared with the placebo group, 2230 subjects for the 10% subcohort (1115 randomly selected in each
group) would provide an overall power of approximately 98%
at the .025 signicance level (1 sided; noninferiority criterion,
lower bound of 2-sided 95% condence interval for GMT ratio
[ZV/placebo] >1.4). This assumed that the true GMT ratio is
1.7 [12], the standard deviation of the natural-log-transformed
titers is 1.1, and there would be a 10% nonevaluable rate for immunogenicity measurements. The immunogenicity summaries
and analyses were based on a per-protocol approach. Subjects
and observations with protocol deviations that might invalidate
the evaluation of VZV-specic gpELISA antibody response
were excluded from the immunogenicity analyses.
RESULTS

Determination of Conrmed HZ Cases

Suspected HZ cases were dened as conrmed HZ if VZV

DNA was present in skin lesion samples. If the PCR assay was
positive for -globin or herpes simplex virus DNA, and negative for VZV DNA, then the case was dened as not HZ.
When there was no specimen or the specimen was inadequate, case determination was decided by a clinical evaluation
committee [9].
VZV-Specic Antibody Assay

The gpELISA for VZV-specic immunoglobulin G antibody

(performed at PPD Vaccines and Biologics) detects antibodies
to puried VZV glycoproteins from MRC-5 (normal human
lung broblasts, Medical Research Council 5 cell line) cells infected with VZV (KMcC strain), using methods described elsewhere [11]. First, VZV glycoproteins or uninfected MRC-5
lysates were adsorbed to polystyrene microtiter wells. Experimental, control, and standard curve serum samples were incubated in coated tissue culture wells in duplicate at 23C for
4080 minutes until the difference in optical density (OD)
between the VZV glycoproteincontaining ( positive) wells and
control (negative) wells was >0.700, as measured in the plate
reader at 405 nm approximately every 5 minutes after an initial
40-minute incubation. Color development was stopped with
50 L of 3N sodium hydroxide. Delta OD was calculated for
each serum sample as the difference between the average OD of
the 2 VZV antigen wells and that of the 2 MRC-5 control wells.
Quantitation was performed by comparing sample delta OD

There were 22 439 subjects randomly assigned to receive ZV or

placebo (Supplementary Figure 1 - CONSORT diagram). Serum
samples were obtained in all subjects before and 6 weeks after vaccination; VZV antibody was measured in the 10% immunology
subcohort and in patients with suspected HZ. The ZV and placebo
recipients in the immunology subcohort were well matched by sex,
age, race, and study completion. Most subjects (94%) were white,
and 62% were female (Supplementary Table 1 - demographics);
>94% of subjects completed the study.
At baseline (day 1), 5 subjects (3 ZV and 2 placebo recipients)
did not have VZV-specic antibody measured by gpELISA. The
2 treatment arms were well matched before vaccination in the
distribution of high and low antibody titers (P = .84; 2 test
for homogeneity) (Table 1). Six weeks after vaccination the
GMT was 660 gpELISA units/mL in ZV recipients, versus 293
gpELISA units/mL in placebo recipients, for an estimated GMT
ratio (ZV/placebo) of 2.3 (95% condence interval, 2.22.4;
P < .001), which met the prespecied statistical criterion. Half
of the ZV recipients had at least a doubling of VZV antibody
titer. The geometric mean fold rise (GMFR) in titer in ZV
recipients was 2.31, compared with no fold rise in placebo
recipients (P < .025).
During the study, 30 ZV and 99 placebo recipients developed
HZ; 6 ZV and 10 placebo recipients developed HZ before collection of their postvaccination blood sample and thus were excluded from the immunogenicity analyses (Table 2). For the
subjects included in the immunogenicity analyses, HZ was
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Assessment of Suspected HZ Cases

with a standard curve, with results reported as concentrations

of antibody in gpELISA units per milliliter.

Table 1.

VZV-Specic gpELISA Titers in ZV and Placebo Recipientsa

ZV Recipients (n = 1136)
No. (%)b

Immunogenicity End Point

Placebo Recipients (n = 1133)

No. (%)b

95% CI

95% CI

c,d

Titer at day 1, gpELISA units/mL

<1.25

3 (0.3)

0.10.8

2 (0.2)

0.00.6

1.25 to 100

161 (14.3)

12.316.5

157 (14.0)

12.016.1

>100 to 300
>300 to 500

469 (41.8)
174 (15.5)

38.944.7
13.417.7

453 (40.3)
192 (17.1)

37.443.2
14.919.4

>500

316 (28.1)

25.530.9

320 (28.5)

GMT, gpELISA units/mL

Titer at week 6, gpELISA units/mLe,f

283.6

<1.25

265.7302.8

292.8

25.831.2
274.4312.3

0 (0.0)

0.00.3

2 (0.2)

0.00.7

23 (2.1)
201 (18.5)

1.33.2
16.220.9

141 (13.0)
443 (40.8)

11.015.1
37.843.7

>300500

197 (18.1)

15.920.5

188 (17.3)

15.119.7

>500
GMT, gpELISA units/mL

667 (61.3)
660.0

58.364.2
624.7697.2

313 (28.8)
293.1

26.131.6
274.7312.6

2
3

541 (49.8)
330 (30.4)

46.852.8
27.633.2

36 (3.3)
4 (0.4)

2.34.6
0.10.9

221 (20.3)

18.022.8

3 (0.3)

0.10.8

5
GMFRg

166 (15.3)
2.31

13.217.5
2.202.43

3 (0.3)
1.00

0.10.8
0.981.02

1.25 to 100
>100300

Fold rise from day 1g

Immunogenicity subcohort population; does not include all subjects who developed suspected HZ.

Values represent No. (%) of subjects except in rows for GMT and GMFR.

Prevaccination: 1123 ZV and 1124 placebo subjects contributed to this analysis.

P = .84 (2 test for homogeneity in distributions of baseline titers between vaccine and placebo arms).

Week 6: 1088 ZV and 1087 placebo recipients contributed to this analysis.

P < .025 (2 test for homogeneity in distributions of week 6 titers between vaccine and placebo arms).

Fold rise: 1087 ZV and 1086 placebo subjects contributed to this analysis.

identied by PCR in 19 of 24 ZV and 78 of 89 placebo recipients; for the rest, HZ cases were conrmed by the clinical evaluation committee assessment.

Table 2.

In each treatment arm after vaccination, the GMT for subjects who did not develop HZ was signicantly higher than for
subjects who developed HZ, although the GMT for the placebo

Relationship of HZ to gpELISA Titers 6 Weeks After Vaccination

ZV Recipients (n=1164)a
No.b

Immunogenicity End Point

Observed Response (95% CI)

Placebo Recipients (n=1223)a

No.b

Observed Response (95% CI)

GMT
Developed HZ

24

Did not develop HZ

GMFR from d 1

1086

Developed HZ
Did not develop HZ

454.1 (300.2687.0)c
659.3 (624.1696.6)

89
1079

178.3 (140.0227.1)c
294.2 (275.7313.9)

24

1.6 (1.21.9)

89

1.0 (0.91.0)

1085

2.3 (2.22.4)

1078

1.0 (1.01.0)

Abbreviations: CI, confidence interval; GMFR, geometric mean fold rise; GMT, geometric mean titer; gpELISA, glycoprotein enzyme-linked immunosorbent assay;
HZ, herpes zoster; ZV, zoster vaccine.
a

Case-cohort population, which includes the 10% immunogenicity subcohort plus all subjects who developed suspected HZ.

Number of subjects contributing to the immunogenicity analysis; subjects who developed HZ before the 6-week date were excluded from this analysis.

In both arms, GMT differed significantly between subjects who developed HZ and those who did not (ZV group, P = .02; placebo group, P < .01; 1-sided 2 sample t test).

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Abbreviations: GMFR, geometric mean fold rise; GMT, geometric mean titer; gpELISA, glycoprotein enzyme-linked immunosorbent assay; VZV, varicella-zoster
virus; ZV, zoster vaccine.

recipients who did not develop HZ was much lower than the
GMT for the ZV recipients who did develop HZ. The GMFR
was also signicantly lower for the ZV recipients who developed HZ than for those who did not. In the placebo recipients,
VZV-antibody did not increase.
DISCUSSION

Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases
online (http://jid.oxfordjournals.org). Supplementary materials consist of
data provided by the author that are published to benet the reader. The
posted materials are not copyedited. The contents of all supplementary data
are the sole responsibility of the authors. Questions or messages regarding
errors should be addressed to the author.

Notes
Acknowledgments. The authors thank all the subjects who participated
in this study. The Zostavax Protocol 022 Study Group included the following members, by country: Belgium: G. Leroux-Roels, P. Van Damme.
Canada: R. Girard, J. McElhaney, and S. McNeil. Finland: T. Haapaniemi,
J. Immonen, K. Ivanitskiy, T. Karppa, A. Karvonen, S. Kokko, T. Korhonen,
K. Kuismanen, P. Lagerstrom-Tirri, I. Seppa, and M. Virta. Germany:
B. Bergtholdt, P. Kindermann, C. Klein, A. Labitzke, R. Schaetzl, I. Schenkenberger, H. Stahl, and V. von Behren. United States: M. Adams,
R. Baxter, H. Bays, M. Berger, B. Berwald, S. Block, D. Bolshoun, B.
Bowling, D. Brandon, D. Classen, L. Cohen, M. Cooperman, Cuevas, D.
DeSantis, F. Dunlap, J. Earl, W. Ellison, R. Feldman, T. Fiel, C. Fisher,
N. Fraser, H. Geisberg, J. Geohas, G. Gerhard, L. Gilderman, H. Gillum,
R. Haselby, J. Hoeksrta, W. Jennings, G. Juriansz, S. Keay, K. Kempf,
J. Kirstein, J. Lawless, M. Levin, T. Littlejohn, F. McCarty, D. McCluskey,
J. McGettigan, R. Mills, W. Miser, N. Misra, A. Murray, L. Murray,
M. Noss, J. Pappas, C. Petit, S. Powell, A. Pragalos, A. Puopolo, G. Raad,
K. Reisinger, M. Reynolds, E. Riffer, G. Risi, S. Rodstein, P. Rogge, Rosen,

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This trial conrms that persons who indicate that they had
prior varicella and/or had resided in the United States for 30
years have serologic evidence of prior varicella infection (only 5
of 2369 individuals lacked antibody at baseline by gpELISA). In
the previous trial of subjects 60 years old, this was true of all
1395 samples tested with gpELISA [8]. The 3 subjects in the
current trial who were seronegative at the time of ZV administration did not develop any serious adverse events or VZV-like
rashes, thereby adding to the safety data available from seronegative ZV recipients [13].
In subjects 5059 years old, ZV was immunogenic, as measured by a signicant rise in VZV antibody titer. The postvaccination GMT was 660 gpELISA units/mL versus 293 gpELISA
units/mL in the control group, and the 6-week GMFR was 2.3.
This response was greater than that observed in the trial of
older subjects [12], in whom the postvaccination GMT and
GMFR were 478.4 and 1.7, respectively. These results indicate a
more robust VZV antibody response to ZV in younger vaccinees (5059-year-olds) and is consistent with greater efcacy
for HZ prevention (69.8%) in 5059-year-olds than in older
subjects (64% and 38% for the 6069- and 70-year age
groups, respectively) in the SPS [1, 9].
The VZV antibody response 6 weeks after vaccination in this
younger group was strongly inversely correlated (P < .001) with
the likelihood of developing HZ, as demonstrated elsewhere in
the ZV trial in older subjects, but neither trial established a titer
of VZV antibody that would serve as a surrogate of protection
[8]. The lack of a quantitative surrogate of protection is demonstrated in the current ndings; VZV antibody titers measured
in the placebo recipients who did not develop HZ were lower
than those achieved by ZV recipients who did develop HZ.
This conrms that VZV antibody should not be considered
directly responsible for the efcacy of ZV against HZ; rather,
VZV CMI is necessary and sufcient for preventing HZ. This
essential role of VZV CMI has previously been established by
(1) substantial clinical observations indicating that HZ occurs
in immunocompromised patients with high levels of VZV antibody [46] and (2) the relationship between the increasing incidence of HZ with increasing age and the decline in VZV CMI
[14], whereas there is no such relationship with VZV antibody
[7]. In addition, the trial in older subjects did not demonstrate
any correlation between VZV antibody and VZV CMI. This
lack of correlation between these 2 classes of immune

responses, which has been conrmed [15], may represent the

detection of different VZV epitopes unique to each class of
immune response.
The absence of paired VZV CMI and VZV antibody data is a
limitation of our study. Another limitation is the lack of data
on chronic pain, which may have been related to the magnitude
of the immune response. Postherpetic neuralgia greatly affects
quality of life and is the most common complication of HZ but
the role of the immune response to HZ and the subsequent
development of postherpetic neuralgia are poorly understood.
In addition, the study was performed almost entirely in white
subjects; immune response to HZ may differ by racial origin, just
as the incidence of HZ is lower in blacks than in whites [16].
The practical implication of the study data is that although
this specic antibody measure is predictive of a ZV response and
is a suitable immunogenicity marker for comparative studies of
ZV, it does not provide a precise threshold for protection. Given
that protection from HZ depends on VZV-specic CMI, gpELISA
may be inadequate for assessments among individuals with
altered immune function, in whom there may be a lack of correlation between cellular and humoral responses. Also important when considering comparative immunogenicity studies is
the relationship between gpELISA GMT and GMFR and clinical efcacy, which may be specic to ZV, a vaccine that
contains the entire Oka strain virus. These immunogenicity
measures may not be correlated with the efcacy of alternative
HZ vaccines based on different formulations (such as subunit
or recombinant vaccines) that may be developed in the future.

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J. Rubino, K. Schmader, D. Schumacher, B. Seidman, J. Seiler, R. Severance,

S. Sharp, G. Shockey, J. Stringer, C. Strout, M. Throne, K. Tyring, M. van
Cleeff, and C. Woodruff. The Data Monitoring Committee included
C. Crumpacker, S. Gravenstein, J. Neaton, H. Tilson, and J. Zaia, and the
Clinical Evaluation Committee, R. Betts, J. Gnann, M. Levin, V. Morrison,
K. Schmader, and D. Weber.
Author contributions. M. J. L., K. E. S., J. W G., S. A. M., T. V., R. F. B.,
and S. K. were responsible for subject enrollment, data collection, and data
interpretation. X. L., Y. Z., I. S. F. C., P. W. A., and J. P. were responsible for
study concept/design and data analysis/interpretation. J. E. S., N. D. B., and
S. C. S. were responsible for data analysis/interpretation. All authors were
responsible for manuscript preparation.
Sponsors role. This study was funded by Merck & Co., Inc. (sponsor).
In conjunction with the external investigators, this study was designed, executed, and analyzed by the sponsor. Although the sponsor formally reviewed a penultimate draft, the opinions expressed are those of the authors
and may not necessarily reect those of the sponsor. All coauthors approved the nal version of the manuscript.
Financial support. This work was supported by Merck & Co., Inc.
Potential conicts of interest. Other than employees of Merck & Co.,
Inc., all authors have been investigators for the sponsor. Employees may
hold stock and/or stock options in the company. M. J. L. is a consultant to
the sponsor and shares intellectual property rights for ZostavaxTM. All
other authors report no potential conicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.