Vaccine 33 (2015) 789–795

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Comparison of intramuscular and subcutaneous administration of a

herpes zoster live-attenuated vaccine in adults aged ≥50 years:
A randomised non-inferiority clinical trial
Javier Diez-Domingo a,b , Thomas Weinke c , Juan Garcia de Lomas d , Claudius U. Meyer e ,
Isabelle Bertrand f , Cécile Eymin f , Stéphane Thomas f , Christine Sadorge f,∗
a
FISABIO-Public Health, Avda Cataluna 21, 46020 Valencia, Spain
b
Universidad Católica de Valencia, ‘San Vicente Martir’, Valencia, Spain
c
Klinikum Ernst von Bergmann, Charlottenstr. 72, 14467 Potsdam, Germany
d
Department of Microbiology, University of Valencia, School of Medicine, Avda Blasco Ibañez 17, 46010 Valencia, Spain
e
Pediatric Immunlogy, University Medical Center of the Johannes Gutenberg University, Ober Zahlbacher Str. 63, 55128 Mainz, Germany
f
Sanofi Pasteur MSD, 162 avenue Jean Jaurès, CS 50712, 69367 Lyon Cedex 07, France

a r t i c l e i n f o a b s t r a c t

Article history: Zostavax® is a live, attenuated varicella zoster virus (VZV) vaccine developed specifically for the preven-
Received 24 September 2014 tion of HZ and PHN in individuals aged ≥50 years. During the clinical development of Zostavax, which was
Received in revised form mainly in the US, the vaccine was administrated by the subcutaneous (SC) route. In Europe, many health-
10 December 2014
care professionals prefer administering vaccines by the intramuscular (IM) route. This was an open-label,
Accepted 11 December 2014
randomised trial conducted in 354 subjects aged ≥50 years. The primary objectives were to demonstrate
Available online 30 December 2014
that IM administration is both non-inferior to SC administration in terms of 4-week post-vaccination geo-
metric mean titres (GMTs), and elicits an acceptable geometric mean fold-rise (GMFR) of antibody titres
Keywords:
Herpes zoster
measured by glycoprotein enzyme-linked immunosorbent assay. Pre-specified non-inferiority was set as
Shingles the lower bound of the 95% confidence interval (CI) of the GMT ratio (IM/SC) being >0.67. An acceptable
Varicella zoster virus vaccine GMFR for the IM route was pre-specified as the lower bound of its 95% CI being >1.4. Description of the
Intramuscular administration route VZV immune response using the interferon-gamma enzyme-linked immunospot (IFN-␥ ELISPOT) assay
Sub-cutaneous administration route and of the safety were secondary objectives.
Randomised controlled trial Participants were randomised to IM or SC administration (1:1). The baseline demographics were
comparable between groups; mean age: 62.6 years (range: 50.0–90.5). The primary immunogenicity
objectives were met (per protocol analysis): GMT ratio (IM/SC): 1.05 (95% CI: 0.93–1.18); GMFR: 2.7
(2.4–3.0). VZV immune response using IFN-␥ ELISPOT were comparable between groups. Frequencies
of systemic adverse events were comparable between groups. Injection-site reactions were less fre-
quent with IM than SC route: erythema (15.9% versus 52.5%), pain (25.6% versus 39.5%) and swelling
(13.6% versus 37.3%), respectively. In adults aged ≥50 years, IM administration of Zostavax elicited sim-
ilar immune responses to SC administration and was well tolerated, with fewer injection-site reactions
than with SC administration.
© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

1. Introduction
Herpes zoster (HZ), commonly known as shingles, results from
the reactivation of varicella zoster virus (VZV), which remains
∗ Corresponding author. 69367 Lyon Cedex 07, France. Tel.: +33 (0)437 284 579;
fax: +33 (0)437 284 451.
E-mail addresses: diez jav@gva.es (J. Diez-Domingo), tweinke@klinikumevb.de
(T. Weinke), jglomas@gmail.com (J. Garcia de Lomas), meyer@uni-mainz.de
(C.U. Meyer), ibertrand@spmsd.com (I. Bertrand), ceymin@spmsd.com (C. Eymin),
sthomas@spmsd.com (S. Thomas), csadorge@spmsd.com (C. Sadorge).
latent in the spinal ganglia and cranial sensory ganglia after pri-
mary VZV infection. The primary infection is seen as varicella
or chickenpox [1–3]. HZ is characterised by a unilateral, painful,
vesicular rash that is usually limited to a single dermatome
[4].
In Europe, almost everybody is at risk of HZ, since more than 95%
of adults aged ≥40 years are VZV seropositive following varicella
and 90% of individuals become VZV seropositive before adolescence
[5,6]. There is a sharp increase in the incidence of HZ at the age of 50,
with 2/3 of HZ cases occurring in adults aged ≥50 [7]. The lifetime
risk of zoster is estimated to be 10–30% with incidence increasing

http://dx.doi.org/10.1016/j.vaccine.2014.12.024
0264-410X/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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 790 J. Diez-Domingo et al. / Vaccine 33 (2015) 789–795
with age, affecting up to 50% of people who live up to 85 years
[7–10].
The most frequent and debilitating complication of HZ is post-
herpetic neuralgia (PHN), a neuropathic pain syndrome that can
persist for months, years or even decades after the HZ rash has
gone [11,12]. The frequency and severity of PHN increases with
age, occurring in between 25% and 50% of patients with HZ aged
≥50 years old [13–16]. Although the mechanisms responsible for
maintaining VZV in its latent state and for its reactivation are not
fully understood, evidence suggests that cell-mediated immunity
(CMI) is critical [17–19]. The age-related decline in VZV-specific
CMI has been shown to have temporal association with an increase
in the incidence and severity of HZ and its complications in older
adults [20–25].
HZ and particularly PHN are debilitating and have a damaging
impact on multiple aspects of patients’ lives. They also have an
impact on their physical functionality by interfering with activities
of daily living [26–32].
Zostavax® (commercialised in Europe by Sanofi Pasteur MSD,
manufactured by Merck Sharpe and Dohme) is a live, attenuated
VZV vaccine developed specifically for the prevention of HZ and
PHN in individuals aged ≥50 years [33]. The vaccine boosts VZV-
specific cell-mediated immunity (CMI); this boosted CMI controls
reactivation of the latent VZV and/or replication and, therefore,
prevents herpes zoster or attenuates its severity [17,34–39].
In the large-scale Shingles Prevention Study (SPS) involving
more than 38,000 subjects aged ≥60 years, vaccine efficacy for
the prevention of HZ was 63.9% (95% confidence interval (CI):
55.5–70.9) in individuals aged 60–69 years, and 37.6% (95% CI:
25.0–48.1) in those aged ≥70 years [40,41]. The vaccine efficacy for
the reduction in PHN was 65.7% (95% CI: 20.4–86.7) in those aged
60–69 years and 66.8% (95% CI: 43.3–81.3) for those aged ≥70 years.
Zostavax has also been shown to reduce the burden of HZ-related
interference with daily living activities and the impact on health-
related quality of life [42]. In the Zostavax Efficacy and Safety Trial
(ZEST), involving more than 20,000 subjects aged 50–59 years, the
vaccine significantly reduced the risk of developing HZ by 69.8%
(95% CI: 54.1–80.6) [43]. In Europe, Zostavax is indicated for the
prevention of HZ and PHN in adults aged ≥50 years [44].
During clinical development, which was mainly done in the
US, the vaccine was administered by the subcutaneous (SC) route.
The preference for the administration route can vary between
healthcare professionals and between countries; in some European
countries the preferred administration route is intramuscular (IM).
The objectives of this trial were to compare the immunogenic-
ity, safety and tolerability of Zostavax when administered by the
IM route versus the SC route, to support and facilitate the use of
the vaccine in Europe by offering the choice for the administration
route.
2. Methods
2.1. Study population
Healthy adults aged ≥50 years with a history of varicella or res-
ident for >30 years in a country with endemic VZV infection were
eligible. Subjects were excluded if they had previously been vac-
cinated with any VZV-containing vaccine or had previously been
diagnosed with HZ. In addition, were excluded: any subjects with a
history of a febrile episode (≥38.3 ◦ C) in the 72 h prior to study vac-
cination, those who had received any live vaccine within 28 days
of study vaccination or inactivated vaccine within 14 days of study
vaccination or immunoglobulins or other blood products within 5
months before vaccination and those who were taking systemic
antiviral therapy or had an immune deficiency associated with
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disease (e.g. human immunodeficiency virus, cancer) or medical
treatment (e.g. chemotherapy, transplant recipients).
The study was carried out in accordance with the principles of
Good Clinical Practice and the ethical principles of the Declaration
of Helsinki. The study protocol was approved by the appropri-
ate institutional review boards and regulatory agencies. Written,
informed consent was obtained from all subjects before study
entry.
ClinicalTrials.gov identifier: NCT01391546 and EudraCT identi-
fier: 2009-012458-19.
2.2. Study design
This was an open-label, randomised, comparative, study con-
ducted in seven centres in Germany and three in Spain from June
2011 to September 2012 to compare IM and SC administration of
one dose of Zostavax in adults aged ≥50 years. The subjects were
randomised using an electronic case report form (e-CRF). Alloca-
tion schedules were generated using a 1:1 ratio with permuted
blocks of 4–6. The randomisation was stratified by ‘ELISPOT’ site
(see below) or not and by age with three strata: 50–59, 60–69 and
≥70 years (because the immune response has been shown to be
age-dependent) [34,45,46]. There were no protocol amendments
after the start of subject recruitment.
Blood samples were taken at visit 1, before vaccination, and at
visit 2, 4 weeks after vaccination (between 28 and 35 days). The
humoral immune response was assessed using the glycoprotein
enzyme-linked immunosorbent assay (gpELISA) assay to measure
the VZV antibody titre in all subjects and the CMI response was
assessed for a sub-set of subjects enrolled at designated sites,
the ‘ELISPOT’ sites, using the interferon-gamma (IFN-␥)-enzyme-
linked immunospot (ELISPOT) assay [47,48].
Between visit 1 and 2, the participants were given a diary card
to record their temperature if they were febrile (oral tempera-
ture ≥38.3 ◦ C), occurrence of any solicited injection-site (erythema,
swelling and pain) adverse reactions (Days 0–4) and any unsolicited
injection-site adverse reactions, varicella, varicella-like rashes, HZ
and zoster-like rashes and other systemic adverse events (AEs)
(Days 0–28). They were also asked to report any serious AEs (SAEs)
that occurred at any time during the study.
2.3. Study vaccine
The study vaccine, Zostavax, was administered in the deltoid
region of the upper arm, by IM (needle: 25 mm, 23 gauge) or
SC (needle: 16 mm, 25 gauge) according to the randomisation.
Use of an anaesthetic cream or patch was not allowed. Each
dose of 0.65 mL contained ≥19,400 PFU of varicella-zoster virus,
Oka/Merck strain (live, attenuated) (Lot Numbers: WL00040507;
WL00046785).
2.4. Objectives
2.4.1. Co-primary objectives
The two co-primary objectives were to demonstrate that IM
administration of Zostavax in healthy adults aged ≥50 years is
non-inferior to SC administration in terms of the 4-week post-
vaccination VZV antibody geometric mean titre (GMT) measured
with gpELISA and that it induces an acceptable geometric mean
fold rise [GMFR] of VZV antibody titres (gpELISA) from pre- to 4-
week post-vaccination. Non-inferiority was defined as the lower
bound of the two-sided 95% confidence interval (CI) around the
post-vaccination GMT ratio (IM group/SC group) being greater than
2/3 (i.e. ruling out a decrease of ≥1.5-fold). An acceptable GMFR
was defined as the lower bound of the two-sided 95% CI around
the GMFR being greater than 1.4 in the IM group based on a
 J. Diez-Domingo et al. / Vaccine 33 (2015) 789–795 791

Screened
N=359
(ELISPOT: N=228)
Screen failures, n=5
Met exclusion criteria (4) lost
to follow-up (1)
Randomised
N=354
(ELISPOT: N=228)

IM group SC group
N=177 N=177
(ELISPOT: N=115) (ELISPOT: N=113)

Past history of HZ, not vaccinated and no

blood drawn, n=1 No pre- or post-vaccination
ELISPOT results, n=2

No pre- or post-vaccination
ELISPOT results, n=1

ELISPOT FAS n=113 FAS and Safety Set FAS and Safety Set ELISPOT FAS n=111
n=176 n=177

Protocol deviation * which Immunosuppressive treatment

invalidated ELISPOT results, n=2 before & during the trial, n=1

ELISPOT PPS n=111 PPS n=175 PPS n=177 ELISPOT PPS n=111

* one subject exposed to VZV and one subject with a rash of interest following vaccination

Fig. 1. Disposition of study participants. IM: intramuscular; SC: subcutaneous; BS: blood sample; PPS: per protocol set; FAS: full analysis set.

minimum increase that was established using the results from
the SPS trial [41]. Success of the trial required that both of the
co-primary objectives were satisfied.
2.4.2. Secondary objectives
The secondary immunological objectives were to describe the
gpELISA GMT and GMFR in both groups and the IFN-␥ ELISPOT GMC
and GMFR in both groups in the ELISPOT sub-set at 4-weeks post-
vaccination. The secondary safety objectives were to describe and
compare the safety profiles of Zostavax administered by the IM and
SC routes.
2.5. Sample size calculation
It was planned to randomise 177 subjects to each group
(N = 354). Assuming that 90% of the participants would be evaluable,
this sample size would give 159 evaluable subjects per group for
the main analysis (per protocol). If the true GMT ratio (IM group/SC
group) was 1.0 (with a standard deviation of 1.1 on a natural log
scale) and the true GMFR was 2.0 (with a standard deviation of 1.0
on a natural log scale), the study would have an overall power of
90% based on a 2.5% one-sided alpha-error rate.
Descriptive analyses were performed for the ELISPOT subgroup.
The number of the subjects to be enrolled in the subgroup was
decided, based on previous experience, so that it would be possi-
ble to provide a reliable estimate of the post-vaccination ELISPOT
GMC [49]. The planned sample size was 80 evaluable subjects per
group, giving 114 randomised subjects per group, assuming that
70% of the subjects would be evaluable for the ELISPOT per protocol
analysis.
2.6. Statistics
SAS® (V9.1.3; SAS Institute Inc., Cary, North Carolina, USA) was
used to perform the statistical analyses. The immunogenicity anal-
yses were performed on the per protocol set (PPS) that included all
randomised participants who received the study vaccine and had
at least one valid (either pre- or post-vaccination) immunogenicity
evaluation for VZV antibody (PPS) or VZV ELISPOT count (ELISPOT
PPS). The gpELISA GMT ratio (IM group/SC group) and the corre-
sponding 95% CI were calculated using a longitudinal data analysis
model including pre- and post-vaccination log-transformed titres
as response variables and age at vaccination, group and visit (pre-
and post-vaccination) as covariates [50]. This model handles miss-
ing data and provides the same results as an ANCOVA model when
there are no subjects with missing data. The CI around the GMFR
in the IM group was calculated using Student’s t distribution for
paired samples on log-transformed data.
The safety analyses were performed on all participants who
received the study vaccine and who had safety follow-up (safety
analysis set). Data were analysed according to the administration
route actually used for the vaccine. Descriptive statistics and risk
differences between the IM and SC groups for the comparison of
the safety data are provided.
3. Results
3.1. Subject disposition and baseline characteristics
A total of 354 of the 359 screened subjects were randomised
to receive ZOSTAVAX by the IM route (N = 177; ELISPOT sub-
set N = 115) or SC route (N = 177; ELISPOT sub-set N = 113); 353

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 792 J. Diez-Domingo et al. / Vaccine 33 (2015) 789–795

Table 1
Demographic characteristics of subjects in the randomised set.

IM group (N = 177) SC group (N = 177) Total (N = 354)

Age at vaccination (years)a

Mean (±SD) 62.6 (±8.3) 62.6 (±8.5) 62.6 (±8.4)
Median (min; max) 61.1 (50.0; 90.5) 61.1 (50.1; 86.1) 61.1 (50.0; 90.5)

Age group (years) n (%)

50–59 81 (45.8) 82 (46.3) 163 (46.0)
60–69 56 (31.6) 55 (31.1) 111 (31.4)
≥70 40 (22.6) 40 (22.6) 80 (22.6)

Gender n (%)
Male 79 (44.6) 80 (45.2) 159 (44.9)
Female 98 (55.4) 97 (54.8) 195 (55.1)
a
Data missing for one subject in the IM group.

Table 2
Pre- and 4-week post-vaccination GMTs and GMFRs of VZV antibody titres (gpELISA units/mL; per protocol seta ).

IM route group (N = 175) SC route group (N = 177)

n GMT (95% CI) n GMT (95% CI)

Pre-vaccination 175 144.6 (125.3–166.9) 176 158.9 (137.9–183.1)

Post-vaccination 168 395.3 (350.6–445.6) 173 391.7 (348.9–439.7)

IM route group (N = 175) SC route group (N = 177)

n GMFR (95% CI) n GMFR (95% CI)

Post-/pre-vaccination 168 2.7 (2.4–3.0) 172 2.5 (2.2–2.8)

CI, confidence interval; GMFR, geometric mean fold-rise; GMT, geometric mean titre; gpELISA, glycoprotein enzyme-linked immunosorbent assay; IM, intramuscular; N,
number of subjects; n, number of subjects with available data; SC, subcutaneous; VZV, varicella-zoster virus.
a
The per protocol analysis set for the primary outcome included all subjects with at least one valid for pre- or post-vaccination immunogenicity evaluation.

subjects received the study vaccine (Fig. 1). One randomised subject 100
in the IM group belonging to the ELISPOT subset was not vaccinated 90
due to past history of herpes zoster, which was an exclusion criteria,
80
and no blood sample was provided, thus the full analysis set (FAS)
and the safety analysis set included 353 subjects (IM: n = 176; SC: 70

n = 177). In addition, in the IM group, one subject received immuno- 60

suppressive therapy prior to vaccination and during the trial. Thus
Subjects (%)

50
352 subjects (IM: n = 175; SC: n = 177) were included in the per
40
protocol set (PPS). Four subjects were excluded from the ELISPOT
randomised sub-set: the subject with a past history of herpes zoster 30
and three other subjects because there were no pre- and post- 20
vaccination ELISPOT results (due to loss of sample during transfer to
10
the laboratory for testing; IM: n = 1; SC: n = 2); thus the ELISPOT FAS
included 224 subjects (IM: n = 113; SC: n = 111). Two additional sub- 0
1 10 100 1,000 10,000
jects were excluded from the IM ELISPOT sub-set due to exposure
Log anti VZV titre (units/mL)
to VZV and rash of interest following vaccination; these protocol
deviations invalidated their post-vaccination ELISPOT results; thus Fig. 2. Reverse cumulative distribution curve of VZV antibody titres pre-vaccination
the ELISPOT PPS included 222 subjects (IM: n = 111; SC: n = 111). and 4-week post vaccination with ZOSTAVAX (IM or SC route) measured by gpELISA
The two groups were comparable in terms of age and gender (per-protocol set). The solid lines show the results for the subjects in the IM group
and the dashed lines show those for subjects in the SC group. IM: intramuscular; SC:
(Table 1). The baseline characteristics for the ELISPOT randomised
subcutaneous; VZV: varicella-zoster virus.
subset were comparable to those of the overall randomised
set.
3.2.2. Secondary immunogenicity objectives
The pre-vaccination and 4-week post-vaccination VZV antibody
3.2. Immunogenicity GMTs and GMFRs were comparable between groups (Table 2 and
Fig. 2). There was a trend for these values to decrease with increas-
3.2.1. Primary immunogenicity objectives ing age (Table 3). The pre-vaccination and 4-week post-vaccination
Both primary immunogenicity objectives were met. The 4-week ELISPOT GMCs and the ELISPOT GMFR were comparable between
post-vaccination VZV antibody GMT in the IM group was non- groups (Table 4).
inferior to that in the SC group (lower bound of the 95% CI of
the GMT ratio (IM/SC) >0.67). The estimated GMT ratio (IM/SC) 3.3. Safety
was 1.05 (95% CI: 0.93–1.18) (p < 0.001). In the IM group, the esti-
mated GMFR of the VZV antibody titres from pre-vaccination to Fewer participants in the IM group experienced at least one
4-week post-vaccination was 2.7 (95% CI: 2.4–3.0) which allowed AE compared with those in the SC group (47.2% versus 69.5%,
to conclude that it was acceptable (lower bound of the 95% CI >1.4) respectively; Table 5). The rates of systemic AEs were compara-
(Table 2). ble between the administration routes (23.3% versus 22.6% for IM

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 J. Diez-Domingo et al. / Vaccine 33 (2015) 789–795 793

Table 3
Pre- and 4-week post-vaccination geometric mean titres (GMTs) and geometric mean fold-rises (GMFR; post/pre-vaccination) of VZV antibody titres (gpELISA units/mL) by
age group – per protocol set.

IM group (N = 175) SC group (N = 177)

Pre-vaccination Post-vaccination Pre-vaccination Post-vaccination

50–59 years old

n 79 74 82 79
GMT [95% CI] 133.9 [108.9;164.7] 446.1 [368.1;540.6] 164.8 [134.3;202.3] 454.1 [390.1;528.5]
GMFR [95% CI] 3.2 [2.7;3.9] 2.8 [2.3;3.4]

60–69 years old

n 56 55 54 54
GMT [95% CI] 154.5 [117.4;203.3] 394.7 [321.1;485.2] 158.7 [121.4;207.4] 338.6 [273.1;419.8]
GMFR [95% CI] 2.5 [2.0;3.1] 2.2a [1.8;2.6]

≥70 years old

n 40 39 40 40
GMT [95% CI] 153.4 [112.8;208.5] 314.8 [250.7;395.3] 147.7 [108.1;201.9] 356.3 [268.9;471.9]
GMFR [95% CI] 2.1 [1.8;2.5] 2.4 [1.9;3.0]
a
Data for one subject missing: n = 53; CI, confidence interval; VZV, varicella-zoster virus.

Table 4
Pre- and 4-week post-vaccination GMC and GMFR of VZV INF-γ ELISPOT counts (ELISPOT per protocol set).

IM route group (N = 111) SC route group (N = 111)

a
n GMC (95% CI) na GMC (95% CI)

Pre-vaccination 101 64.3 (49.6–83.4) 96 58.4 (42.6–80.2)

Post-vaccination 103 209.8 (175.2–251.3) 105 195.7 (161.9–236.6)

IM route group (N = 111) SC route group (N = 111)

na GMFR (95% CI) na GMFR (95% CI)

Post-/pre-vaccination 93 3.3 (2.8–3.9) 90 3.4 (2.7–4.3)

CI, confidence interval; GMC, geometric mean count; GMFR, geometric mean fold-rise; IM, intramuscular; INF, interferon; N, number of participants; n, number of participants
with available data; SC, subcutaneous; VZV, varicella-zoster virus.
a
Missing data for pre-vaccination time points are due to non-evaluable samples. Missing data for post-vaccination time points are due to protocol deviations and thus
results were excluded from the per protocol analyses.

Table 5 70
-36.6
Summary of safety (safety analysis set). (-45.4; -27.2)
p<0.001
IM group (N = 176) SC group (N = 177) 60

n (%) n (%) -14.0

(-23.5; -4.2) -23.7
50 p=0.005 (-32.3; -14.8)
AE (Days 0–28) 83 (47.2) 123 (69.5) p<0.001
Vaccine-related AE (Days 0–28) 68 (38.6) 118 (66.7)
% of subjects

Injection site reaction (Days 0–28) 60 (34.1) 114 (64.4) 40

Solicited injection site reaction 58 (33.0) 110 (62.1)
(Days 0–4)
30
Unsolicited injection site 9 (5.1) 14 (7.9)
reaction (Days 0–28)
20
Systemic AE (Days 0–28) 41 (23.3) 40 (22.6)
-4.5
Vaccine-related systemic AE 12 (6.8) 13 (7.3) (-9.3; -0.5)
(Days 0–28) 10

Injection site rash (Days 0–28) 0 0

Non-injection site rash (Days 0–28) 1 (0.6) 0 0
SAE 1 (0.6) 2 (1.1)
Vaccine-related SAE 0 0
Withdrawal due to an AE 0 0
AE, adverse event; IM, intramuscular; N, number of participants; n (%), number (per-
centage) of participants presenting the AE at least once; SAE, serious adverse event;
SC, subcutaneous.
and SC groups, respectively; Table 5). Injection-site reactions were
significantly less frequent in the IM group than in the SC group
for: erythema (15.9% versus 52.5%; p < 0.001), pain (25.6% versus
39.5%; p = 0.005), swelling (13.6% versus 37.3%; p < 0.001) and pru-
ritus (1.7% versus 6.2%), respectively (Fig. 3). One subject in the
IM group reported a zoster-like rash (right thoracic dermatome) of
mild intensity that occurred 12 days post vaccination and lasted
6 days. Although no specimen was obtained for VZV confirmation
Erythema Pain Swelling Pruritus
Fig. 3. Percentage of subjects (and 95% CI) with injection site adverse reactions from
Days 0 to 28 (safety analysis set) for the IM group (N = 176; grey bars) and the SC
group (N = 177; white bars). The numbers above the bars are the percentage risk
differences between the IM and SC groups with their 95% confidence intervals. p
values were calculated for the solicited adverse reactions only, in compliance with
the protocol; pruritus was an unsolicited adverse reaction and therefore no p value
was calculated.
by PCR testing, the investigator considered the event to be possi-
bly related to the study vaccine. Three subjects experienced SAEs
(IM Group: obstructive hernia (n = 1); SC Group: humerus fracture
(n = 1), deep venous thrombosis (n = 1)), none of which were con-
sidered to be vaccine-related by the investigators (Table 5). None
of the subjects withdrew from the trial because of an AE.

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 794 J. Diez-Domingo et al. / Vaccine 33 (2015) 789–795
4. Discussion
This study was designed to assess the immunogenicity and
safety of IM administration of Zostavax compared with SC adminis-
tration. The results show that the immune response to IM Zostavax
is similar to that to SC Zostavax. In addition, IM administration
results in significantly fewer injection-site reactions with a compa-
rable rate of systemic AEs, as has been described for other vaccines
[51,52].
The estimated GMFR, obtained using the gpELISA assay, was
comparable to those observed in previous studies that evaluated
immune response at 4-week post-vaccination in adults aged ≥50
years [34,45,46]. Unlike our trial, these three trials had only two
age groups: 50–59 years and >60 years, therefore we could only
compare the 50–59 age groups in which the values ranged from
2.4 to 3.9. As expected and as already reported in other stud-
ies, the estimated GMFRs were numerically higher in those aged
50–59 years (3.2 in the IM group and 2.8 in the SC group) com-
pared with those who were older (60–69 years: 2.5 and 2.2; ≥70
years: 2.1 and 2.4, in the IM and SC groups, respectively). The
lower immunological response observed with age is due to the phe-
nomenon of immunosenescence, or ageing of the immune system
[53,54].
The estimated GMFRs obtained using the IFN-␥ ELISPOT assay
in a subset of subjects (N = 228) enrolled at 4 of the 10 study sites
were comparable between the two groups: 3.3 in IM group and 3.4
in SC group. The IFN-␥ ELISPOT was used in two previous studies in
older populations (≥60 years) [49,55]. In one of these studies, the
estimated GMFR was 2.1 at 6-weeks post-vaccination and 2.7 and
2.1 at 2 and 6-weeks post-vaccination, respectively, in the other
study [49,55].
The safety profile of Zostavax in the SC group was compara-
ble to the known safety profile of the product [56]. In the IM
group, there were fewer injection-site reactions than in the SC
group. Lower rates of injection-site reactions were also reported
in two studies in healthy children that compared the IM and
SC administration of varicella vaccine, Varivax® and a combina-
tion paediatric vaccine, ProQuad® , which contain the same VZV
strain [57,58]. A literature review of clinical trials reported that in
two trials comparing immunogenicity or safety of pneumococcal
vaccines in adults and in four trials comparing immunogenic-
ity or safety of influenza vaccines administered via IM or SC
routes in adults, the immunogenicity and systemic safety were
at least as good by IM administration compared with SC, and
that reactogenicity was generally better with IM administration
[51].
One possible limitation of this study was the open-label design
for the routes of administration. However, randomisation was per-
formed using an eCRF thus minimising any subject selection bias.
In addition, the immunogenicity assays were performed on blinded
samples so that the laboratory staff who performed the immuno-
genicity assays (including primary criteria) were unaware of the
vaccination administration route. The present study had an excel-
lent completion rate, with only two randomised subjects (2/354;
0.6%) not completing the trial.
5. Conclusion
In adults aged ≥50 years, IM administration of Zostavax elicited
similar immune responses to SC administration and was well
tolerated with fewer injection-site reactions than with SC admin-
istration. These data support the administration of vaccine using
either SC or IM and thus could allow healthcare professionals the
flexibility to choose their preferred administration route in routine
clinical practice.
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Authors’ contributions
All authors participated in the implementation and/or conduct
of the study including substantial contributions to conception and
design, the gathering of the data, or analysis and interpretation of
the data. All the authors revised the manuscript critically for impor-
tant intellectual content and approved the final version before
submission.
Financial disclosure
Sanofi Pasteur MSD funded this clinical trial and was involved
in all stages of the study conduct and analysis. Sanofi Pasteur MSD
also funded the development and publication costs for the present
manuscript. All authors had full access to the data and the cor-
responding author had final responsibility for submission of the
manuscript.
Conflicts of interest
JDD has been and is the principal investigator in trials sponsored
by Sanofi Pasteur MSD, GSK, Merck, Baxter, Novartis and Pfizer. His
institutions have received research grants from Sanofi Pasteur MSD,
Pfizer and Baxter. He has received grants for attending meeting and
has been a member of advisory boards for GSK, Pfizer and Sanofi
Pasteur MSD.
TW has received honoraria for lecturing and consulting activities
from Novartis Vaccines and Sanofi Pasteur MSD.
JGDL and CUM have no potential conflicts of interest to declare.
IB, CE, ST and CS are employed by Sanofi Pasteur MSD, the com-
pany that commercialises the herpes zoster live-attenuated vaccine
(Zostavax® ) in Europe.
Acknowledgements
The authors would like to thank the subjects who participated in
the trial, as well as the following investigators for their contribution
to the study: Rolf Dominicus (Dülmen, Germany); Christine Gri-
gat, Martina Lilie (Hamburg, Germany); Dorothee Kieninger-Baum
(Mainz, Germany); Wiefried Steinborn (Straubing, Germany); Peter
Kindermann (Riesa, Germany); Enrique Guinot, Vincenta Pineda
(Valencia, Spain).
They also would like to thank Xavier Cornen, Sylvie Dard, Nicolas
Goulleret and Elodie Turpaud (Sanofi Pasteur MSD), Martina König
(THEOREM Clinical Research GmbH & Co. KG) for their contribu-
tion to the conduct of the study; Janie Parino and Paula Annunziato
(Merck & Co., Inc.) for their input during the study design and for
their critical review of the study results and Laura Malette and Bar-
bara E. Meyer (PPD Vaccine and Biologics, LLC, Wayne, PA, USA)
for overseeing the gpELISA assays and Julie Bowman (ViraCor-IBT
Laboratories Inc, Lenexa, KS, USA) for overseeing the IFN-␥ ELISPOT
assay.
The authors take full responsibility for the content of this
manuscript and thank Margaret Haugh from MediCom Consult,
Villeurbanne, France (funded by Sanofi Pasteur MSD) for providing
medical writing and editorial assistance.
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