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Available online at

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www.sciencedirect.com

Review

Herpes zoster: Risk and prevention during immunomodulating

therapy
Cong Tri Tran a , Alexandra Ducancelle a , Charles Masson b,∗ , Françoise Lunel-Fabiani a
a
UPRES EA 3859, laboratoire de virologie, CHU d’Angers, 4, rue Larrey, 49933 Angers cedex 9, France
b
Service de rhumatologie, CHU Angers, 4, rue Larrey, 49933 Angers cedex 09, France

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

Article history: Herpes zoster can be serious or incapacitating, particularly in patients whose immune system is com-
Accepted 17 February 2016 promised by a disease or treatment. Immunomodulating drugs can increase the risk of infection.
Available online xxx Well-established risk factors include advanced age and glucocorticoid therapy. The data are somewhat
conflicting for medications such as methotrexate, tofacitinib, TNF␣ antagonists (infliximab, adalimumab,
Keywords: etanercept, certolizumab, and golimumab), abatacept, tocilizumab, and rituximab. Nevertheless, the risk
Varicella-zoster virus of herpes zoster is increased in patients taking biological agents, because of the underlying diseases
Immunomodulators
and/or effects of the drugs. A live attenuated herpes zoster vaccine has been proven effective and safe
Biotherapy
Vaccination
in immunocompetent individuals. At present, however, it is not recommended for patients with immu-
nodeficiencies, including those taking biological drugs, as no studies have assessed its risk/benefit ratio
in this population. This situation may change in the near future, as recent data support the effective-
ness and safety of the herpes zoster vaccine in patients who take biotherapies or have other causes of
immunodeficiency. Alternative approaches designed to protect these patients from herpes zoster and its
complications are also under evaluation. There is a need to define the indications of the herpes zoster
vaccine in terms of the target population, timing, modalities, and frequency, according to the underlying
chronic systemic disease, age group, varicella-zoster virus status, and exposure to therapeutic agents.
© 2016 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

1. Introduction
Herpes zoster is caused by reactivation of the varicella-zoster
virus (VZV) [1]. Cellular immunity is the main line of defense against
herpes zoster [2]. A decrease in the effectiveness of the cellular
immune responses due to age, disease, or treatments may explain
the increased risk of herpes zoster in populations exhibiting these
risk factors [2]. Asymptomatic episodes of VZV reactivation and
exposure to exogenous VZV may help to maintain immunity against
the virus [3].
The treatment of systemic inflammatory diseases has been radi-
cally transformed by the introduction of immunomodulating drugs
such as TNF␣ antagonists (infliximab, adalimumab, etanercept, cer-
tolizumab, and golimumab), abatacept, rituximab, tocilizumab, and
tofacitinib. However, these drugs affect the immune system and
are associated with an increased risk of infections due to bacteria
(e.g., tuberculosis) and viruses. The risk increase occurs not only
∗ Corresponding author.
E-mail address: ChMasson@chu-angers.fr (C. Masson).
for primary infections, but also for viral reactivation, for instance
of the hepatitis B virus [4] and herpes viruses such as the VZV. Rec-
ommendations about vaccinating patients on immunomodulating
drugs have therefore been issued, although they are fairly rarely
followed in everyday practice [5,6].
Here, we review the latest data on the risk of herpes zoster in
adults taking immunomodulating drugs, as well as on available pre-
ventive measures. Special emphasis is put on TNF␣ antagonists,
the most extensively studied immunomodulating drug class to
date.
2. Risk of herpes zoster during immunomodulating
treatment
2.1. Incidence with conventional immunomodulating drugs
Of the many risk factors associated with herpes zoster, the most
important are older age [7,8] and immunodeficiency [9,10]. The
incidence of herpes zoster increases from about 3/1000 person-
years before 30 years of age to 8/1000 person-years after 60 years
of age, with variations across studies and populations [7,8]. All types

http://dx.doi.org/10.1016/j.jbspin.2016.04.001
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Please cite this article in press as: Tran CT, et al. Herpes zoster: Risk and prevention during immunomodulating therapy. Joint Bone
Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.04.001
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Table 1
Immunomodulating drugs and herpes zoster.

Authors Populations Treatments Sample size Design Results 95%CI

Wolfe et al., 2006 [17] RA TNF␣A (I, A, E) 6167 Prospective I: HR = 1.2 (1.0–1.5)
DMARD Multivariate A: HR = 0.4 (0.2–0.9)
analysis E: HR = 0.9 (0.7–1.2)
MTX: HR = 1.0 (0.8–1.3)
Leflu: HR = 1.4 (1.1–1.8)
Aza: HR = 2.0 (1.2–3.3)
GC: HR = 1.5 (1.2–1.8)
Smitten et al., 2007 [13] RA Biologics (I, E, AN) 32 Case-control aOR = 1.54 (1.04–2.29)
or DMARD 306 aOR = 1.37 (1.18–1.59)
or GC 166 aOR = 2.51 (2.05–3.06)
vs. no GC or DMARDs 877 Reference
Strangfeld et al., 2009 [19] RA TNF␣A (I, A, E) 3266 Prospective aHR = 1.63 (0.97–2.74)
vs. DMARD 1774 Reference
McDonald et al., 2009 [22] RA TNF␣A (I, A, E) 3661 Retrospective I: HR = 1.32 (0.85–2.03)
A: HR = 0.53 (0.31–0.91)
E: HR = 0.62 (0.40–0.95)
DMARD MTX: HR = 1.13 (0.75–1.70)
Leflu: HR = 0.95 (0.58–1.56)
Aza: HR = 1.06 (0.46–2.40)
GC GC: HR = 1.08 (0.69–1.70)
Galloway et al., 2013 [20] RA TNF␣A (I, A, E) 1,1881 Prospective aHR = 1.7 (1.1–2.7)
vs. DMARD 3673 Reference
Veetil et al., 2013 [14] RA TNF␣A 137 Retrospective HR = 1.24 (0.56–2.74)
DMARD MTX: HR = 1.34 (0.85–2.10)
GC GC: HR = 1.72 (1.03–2.87)
Winthrop et al., 2013 [15] RA, CIBD, Pso, PsA, TNF␣A 33,324 Retrospective aHR = 1.09 (0.88–1.36)
SpA (initiation of I, A, E)
vs. DMARD 25,742 Reference
Che et al., 2014 [21] RA TNF␣A Equivalent to Metaanalysis Pooled risk ratio = 1.61 (1.16–2.23)
vs. DMARD 163,077 Reference
patient-years
Pappas et al., 2015 [7] RA TNF␣A 4321 Retrospective Reference
(CORONA registry) vs. other biologics (rituximab, 2170
abatacept, and tocilizumab)
aHR = 0.834 (0.51–1.37)
vs. DMARD 1505 aHR = 1.359 (0.82–2.25)

95%CI: 95% confidence interval; RA: rheumatoid arthritis; TNF␣A: TNF␣ antagonist; I: infliximab; A: adalimumab; E: etanercept; AN: anakinra; DMARD: synthetic disease-
modifying antirheumatic drug; GC: glucocorticoid; CIBD: chronic inflammatory bowel disease; Pso: cutaneous psoriasis; PsA: psoriatic arthritis; SpA: spondyloarthritis;
MTX: methotrexate; Leflu: leflunomide; Aza: azathioprine; aOR: adjusted odds ratio; aHR: adjusted hazard ratio.

of immunodeficiency increase the risk, particularly those affecting
the cellular immune system [9,10]. The risk of herpes zoster is also
elevated in patients with chronic autoimmune or inflammatory
diseases such as rheumatoid arthritis (RA), systemic lupus ery-
thematosus (SLE), and chronic inflammatory bowel disease (IBD)
[10–14]. In these patients, the risk increase occurs earlier than
usual: thus, in populations with RA, the risk at 40–50 years of age
is similar to that seen after 60 years of age in the general popula-
tion, and a risk increase is already apparent at 21–30 years of age in
patients with SLE [8]. The excess risk may stem not only from the
disease, but also from the drugs used to treat it. No data are avail-
able on the incidence of herpes zoster in patients with polymyalgia
rheumatica or giant cell arteritis.
Glucocorticoid therapy increases the risk of herpes zoster, 1.5-
to 2.5-fold [7,11,13–16]. Although the risk increases with the dose,
even low doses are associated with an excess risk [16]. The data
on conventional disease-modifying antirheumatic drugs (DMARDs)
are more controversial. Some of these drugs may be associated with
the occurrence of herpes zoster [13]. Thus, one study showed rel-
ative risks of 1.4 with leflunomide, 2.0 with azathioprine, and 4.2
with cyclophosphamide [17]. Others do not seem to have this effect.
An example is methotrexate: although several case-reports of her-
pes zoster during methotrexate therapy have been published, this
drug does not seem to be associated with a significant increase in
susceptibility to herpes zoster [14,18].
2.2. Incidence during biological therapy
Data on biological drugs are somewhat conflicting (Table 1). Sev-
eral studies showed an increased risk of herpes zoster in patients
taking TNF␣ antagonists to treat RA [13,19–21]. In a metaanalysis
of studies in patients with RA [21], the pooled risk ratio of her-
pes zoster during TNF␣ antagonist therapy compared to synthetic
DMARD therapy was 1.61 (95%CI, 1.16–2.23). Other investigations,
however, produced different findings [7,14,15,17,22,23]. A retro-
spective cohort study [15] assessed the incidence of herpes zoster in
patients with various inflammatory diseases, with special attention
to the potential effect of TNF␣ antagonists. There were 310 cases
of herpes zoster among 33,324 patients taking TNF␣ antagonists.
The risk of herpes zoster was not higher with TNF␣ antagonists
than with conventional treatments. In contrast, an excess risk of
herpes zoster was demonstrated with other biological drugs such
as tofacitinib [24], and this risk was further increased by the con-
comitant use of conventional DMARDs or glucocorticoids [25]. The
risk of herpes zoster may vary across biologics. Among TNF␣ antag-
onists, infliximab seems to carry the greatest risk of herpes zoster
[19,20,22,26,27]. However, discrepancies also exist among data on
this point. Thus, in a retrospective cohort study of 29,129 patients
who had recently started a TNF␣ antagonist, abatacept, rituximab,
or tocilizumab, no significant differences were found across these
drugs [16] (Table 2).

Please cite this article in press as: Tran CT, et al. Herpes zoster: Risk and prevention during immunomodulating therapy. Joint Bone
Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.04.001
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Table 2
Risk of herpes zoster with different immunomodulating agents.

Authors Populations Treatments Sample size Design Comparison of 95%CI

biologics

Strangfeld et al., 2009 [19] RA TNF␣A (I, A, E) 3266 Prospective aHR = 1.63 (0.97–2.74)
I, A I, A: aHR = 1.82 (1.05–3.15)
E E: aHR = 1.36 (0.73–2.55)
vs. DMARD 1774 Reference
McDonald et al., 2009 [22] RA TNF␣A (I, A, E) 3661 Retrospective I: HR = 1.32 (0.85–2.03)
A: HR = 0.53 (0.31–0.91)
E: HR = 0.62 (0.40–0.95)
Serac et al., 2012 [26] RA, CIBD, SpA TNF␣A (I, A, E): 24 cases Case-control I and A: OR = 3.49 (1.12–10.90)
monoclonal antibodies 9 (I) + 10 (A) Multivariate
(I, A) analysis
vs. soluble receptor (E) 5 E as the reference
Galloway et al., 2013 [20] RA TNF␣A (I, A, E) 11,881 Prospective aHR = 1.7 (1.1–2.7)
vs. DMARD 3673 I: aHR = 2.2 (1.4–3.4)
A: aHR = 1.82 (0.9–2.4)
E: aHR = 1.7 (1.0–2.7)
Reference
Winthrop RA, TNF␣A 33,324 Retrospective
et al., CIBD, I 6300 I as the reference
2013 Pso, A 14,553 A: aHR = 0.82 (0.55–1.22)
[15] PsA, E 12,470 E: aHR = 1.09 (0.82–1.45)
SpA vs. DMARD 25,742
Yun et al., 2015 [16] RA Immuno-modulators 29,129: Retrospective
Abatacept 8389 Abatacept as the
reference
Infliximab 3612 aHR = 0.98 (0.69–1.39)
Adalimumab 4486 aHR = 1.04 (0.72–1.51)
Etanercept 3554 aHR = 1.26 (0.87–1.81)
Certolizumab 1689 aHR = 1.30 (0.77–2.23)
Golimumab 1282 aHR = 0.91 (0.47–1.76)
Rituximab 4311 aHR = 1.20 (0.88–1.63)
Tocilizumab 1777 aHR = 1.05 (0.60–1.84)

95%CI: 95% confidence interval; RA: rheumatoid arthritis; TNF␣A: TNF␣ antagonist; I: infliximab; A: adalimumab; E: etanercept; AN: anakinra; DMARD: synthetic disease-
modifying antirheumatic drug; GC: glucocorticoid; CIBD: chronic inflammatory bowel disease; Pso: cutaneous psoriasis; PsA: psoriatic arthritis; SpA: spondyloarthritis; OR:
odds ratio; aHR: adjusted hazard ratio

The reasons for these discrepancies are unclear. The risk of
herpes zoster associated with immunomodulating agents seems
moderate, and failure to detect an excess risk may therefore be
ascribable to insufficient statistical power. The nature of the group
against which biologics are compared may also deserve criticism.
None of the studies compared biologics to a placebo and few com-
pared them to absence of glucocorticoid therapy [13]. In most
studies, conventional DMARDs were compared to biologics, which
would induce at least the same level of risk. Finally, discrepan-
cies may originate in part from confounding factors, such as age,
despite the use of statistical adjustment methods. Glucocorticoid
treatment and the severity of the underlying disease may also
act as confounders [14,16]. For instance, in patients at the severe
end of the spectrum, greater frequency and higher doses of gluco-
corticoid therapy may be involved as well as the administration
of immunomodulators. Immunomodulators may induce a small
risk increase that becomes statistically or clinically significant only
when combined with other factors, even those with similarly small
effects.
2.3. Severity of herpes zoster
In most studies, the frequency of severe herpes zoster was
increased in patients taking immunomodulating agents [5]. In a
metaanalysis, herpes zoster was severe in 4.9 to 20.9% of patients
taking TNF␣ antagonists compared with 2 to 5.5% of patients
taking conventional drugs [21]. Admissions for herpes zoster were
increased 9-fold among patients with RA treated with TNF␣ antag-
onists [28]. Combined immunomodulatory and glucocorticoid
therapy may increase the risk of complications [29]. In a study of
patients taking various biologics to treat RA, the risk of admission
for infection was higher with etanercept, infliximab, and rituximab
than with abatacept [30].
In sum, immunomodulating drug therapy is associated with an
excess risk of herpes zoster, which becomes at least as high as that
seen in the overall population older than 60 years of age, in which
prevention is recommended.
3. Prevention of zona and immunomodulating drugs
3.1. Live attenuated vaccine against herpes zoster
3.1.1. Recommendations
A live attenuated vaccine against herpes zoster is now available.
Since 2008, the Advisory Committee on Immunization Practices has
recommended the administration of this vaccine to adults older
than 60 years of age [31]. In 2011, the Food and Drug Adminis-
tration in the US approved herpes zoster vaccination starting at
50 years of age, but no corresponding recommendation has been
issued. As the vaccine contains the live virus, it has been contraindi-
cated in patients with immunodeficiencies and in those taking
immunosuppressants, including high-dose glucocorticoid therapy
(≥ 20 mg/d prednisone-equivalent) for more than 2 weeks and bio-
logical agents [31,32]. High-dose glucocorticoid therapy must be
stopped at least 1 month before considering administration of the
vaccine. Vaccination may be considered either 14 days before the

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initiation of biological therapy or 1 month after discontinuation of
biological therapy (expert opinion) [31].
3.1.2. Efficacy
The efficacy of the herpes zoster vaccine has been convinc-
ingly demonstrated in immunocompetent individuals older than
60 years. Thus, in the pivotal Shingles Prevention Study [33], the
incidence of herpes zoster diminished by 51.3%, the pain severity
score by 61.1%, and the incidence of postherpetic neuralgia by 66.5%
(Table 3). Nevertheless, efficacy decreased with advancing age and
time since vaccination, particularly regarding the incidence of her-
pes zoster [34]. The decline in efficacy over time may be related
to age-related impairments in cellular immunity [35]. Therefore,
whether the vaccine can protect patients with immunodeficien-
cies and those taking immunosuppressants deserves discussion. No
such patients were included in the studies of vaccine efficacy. A
faster decline in efficacy, starting as early as the 5th year, has been
reported in patients with inflammatory or autoimmune diseases
[36].
Markers for specific anti-VZV immunity consist of the anti-VZV
antibody titer and, more importantly, the specific cellular response
to the virus, evaluated by ELISPOT IFN- or the responder cell fre-
quency (RCF) [37,38]. Correlations seem weak between antibody
titers and the ELISPOT response. The vaccine induces both antibody
and cellular responses, which are not potentiated by a second dose
[39]. As the vaccine contains live virus, it has rarely been studied
in patients taking biological agents. An ongoing pilot randomized
placebo-controlled trial (VERVE) is assessing the immunological
response to the vaccine in patients taking TNF␣ antagonists, with
the primary objective of measuring vaccine immunogenicity after
6 weeks [40]. Another randomized placebo-controlled trial focused
on patients taking methotrexate therapy then started on tofacitinib
or a placebo 2–3 weeks after administration of the vaccine [41].
Both the humoral response and the cellular response were similar
in the tofacitinib and placebo groups [41].
The efficacy of the herpes zoster vaccine in immunocompro-
mised individuals has also been evaluated based on clinical data
such as the incidence and severity of the disease. According to rec-
ommendations, vaccination can be considered before the period
of immunosuppression or initiation of biological therapy [32].
Whether it is effective in these situations needs to be assessed.
Among individuals given the vaccine, 42% (95%CI, 27–53%)
remained protected during subsequent cancer chemotherapy [42].
However, in 77% of patients, a full year elapsed between vacci-
nation and chemotherapy initiation. This interval was 60 days in
TRAN 152 (3.2%) patients, in whom the vaccine failed to provide
significant protection. Another issue is whether the vaccine is effec-
tive when given during the period of immunosuppression. In a vast
study [11], overall vaccine effectiveness was 37% (95%CI, 6–58%)
in immunocompromised patients (n = 4469) compared to 51% in
immunocompetent individuals (95%CI, 41–59%).
The efficacy of the herpes zoster vaccine in patients taking bio-
logics was evaluated based on the association between herpes
zoster vaccination and the incidence of herpes zoster in patients
older than 60 years who had RA, psoriasis, psoriatic arthritis, or
chronic IBD [43]. Median follow-up was 2 years. Of 18,931 patients
given the vaccine, 633 took biologics at the time of vaccination or
within the next 42 days. Of these 633 patients, 14 developed herpes
zoster, yielding an incidence rate of 8.5/1000 patient-years, com-
pared to 16.0/1000 patient-years in patients who took biologics
but did not receive the vaccine. Vaccine efficacy was estimated at
47% in the group taking biologics and 42% in the overall popula-
tion. However, the study design leaves unclear the proportion of
patients given the vaccine before versus during biological therapy.
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3.1.3. Safety
The potential benefits of herpes zoster vaccination must be
weighed against the possible risks associated with giving a very
high titer, live, attenuated vaccine to patients at high risk for infec-
tion. In the immunocompetent individuals enrolled in the Shingles
Prevention Study [33], the safety profile was satisfactory, even in
older individuals who probably had some degree of cellular immu-
nity impairment [44,45]. Cases of herpes zoster or skin infection
related to the vaccine strain were very rare. One occurred in an
immunocompetent women without detectable risk factors [46]
and another in a patient taking methotrexate for RA and given
tofacitinib after administration of the vaccine [41]. This patient
had no previous immunity against the VZV. Routine serological
testing for anti-VZV antibodies may therefore be in order before
administering the live attenuated vaccine and perhaps also in the
small minority of individuals who have no known history of vari-
cella and who may require biological therapy at some point [47].
In sum, in patients with previous immunity against the VZV, the
risk of vaccine-induced herpes zoster seems very low. This situ-
ation is not comparable to the introduction of a live attenuated
virus into a previously unexposed population, and a better safety
profile can therefore be expected, even in immunocompromised
individuals.
Few studies have assessed the risks associated with the herpes
zoster vaccine in immunocompromised patients, since live attenu-
ated vaccines are theoretically contraindicated in this population.
In a study of 62 patients with hematological malignancies who were
selected by their physicians to receive the herpes zoster vaccine
based on the risk/benefit ratio, there were no documented serious
adverse events related to the vaccine [48]. Thus, the vaccine seems
relatively safe in selected patients without major immunodeficien-
cies.
The vaccine has been tested in patients on biological drug
therapy. In one study, the vaccine was given instead of the next
scheduled biological drug dose, and 2 weeks were then allowed
to elapse before the biological treatment was resumed [49], and
in another tofacitinib was given 2–3 weeks after the vaccine [41].
These protocols were associated with a satisfactory safety profile.
In a retrospective cohort study of 633 patients given a dose of a bio-
logical drug (TNF␣ antagonist in 551), there were no instances of
herpes zoster, varicella, or admission for meningitis or encephali-
tis [43]. Preliminary data from the ongoing pilot VERVE trial show
no evidence of serious adverse events in patients taking TNF␣
antagonists and given the vaccine [40]. It would be of interest to
obtain data on patients with polymyalgia rheumatica or giant-
cell arteritis, who are often elderly or very elderly and treated
with glucocorticoids and, in some cases, immunomodulating drugs.
Although encouraging, these data are insufficient to conclude that
the vaccine is safe in patients with immunodeficiency and in those
taking biological drugs. Strategies other than a live attenuated vac-
cine are being evaluated [50].
3.2. Alternatives and future prospects
3.2.1. Inactivated vaccine
The heat-inactivated Oka/Merck varicella vaccine has been eval-
uated in hematopoietic stem cell transplant recipients. It proved
relatively safe and was effective in stimulating anti-VZV T-cell
immunity and in decreasing the morbidity due to VZV reactivation
[51]. A multicenter randomized double-blind placebo-controlled
trial has been conducted in 341 immunocompromised patients
(solid or hematological malignancies or HIV infection with a
CD4+ T-cell count ≤ 200/␮L) [52]. Overall, the incidence of all
adverse events was similar in the active-treatment and placebo
groups. Cellular immunity as measured by the ELISPOT IFN-␥
was significantly stronger in the vaccinated group. Finally, in
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Table 3
Efficacy of herpes zoster vaccines in different populations.

Authors Populations Sample size Design Reduction Efficacy (%) 95%CI

Live attenuated vaccine

Oxman et al., 2005 [33] Immunocompetent 38,546 Randomized Incidence of HZ 51.30 (44.2–57.6)
> 60 years 19,270 (active) Double-blind Severity 61.10 (51.1–69.1)
19,276 (placebo) vs. placebo PHN 66.50 (47.5–79.2)
Schmader et al., 2012 [45] Immunocompetent 22,439 Randomized Incidence Z 69.80 (54.1–80.6)
50–59 years 11,211 (active) Double-blind Severity 73.00 (52.7–84.6)
11,228 (placebo) vs. placebo
Morrison et al., 2015 [34] Immunocompetent 6867 Models based on the Incidence of HZ 21.10 (10.9–30.4)
> 60 years placebo groups in the Severity 37.30 (26.7–46.4)
7–11 years SPS and STPS trials PHN 35.40 (8.8–55.8)
post-vaccination
Tseng et al., 2014 [42] Before starting cancer 4710 vaccinated Prospective cohort Incidence of HZ 42 (27–53)
chemotherapy
vs. 16,766 not
vaccinated
Langan et al., 2013 [11] > 65 years 4469 immuno- Retrospective cohort Incidence of HZ 37 (6–58)
General population compromised (immunocompromised)
(including vaccinated vs. Incidence of HZ 51 (41–59)
immune-compromised 140,925 not (immunocompetent)
individuals) vaccinated PHN (total) 59 (21–79)

Zhang et al., 2012 [43] RA, CIBD, Pso, PsA, SPA 633 vaccinated during Retrospective cohort Incidence of HZ (biologics) 47
(> 60 years) biotherapy (within Incidence of HZ (total) 42
42 days after
vaccination)
Subunit vaccine
Lal et al., 2015 [56] Immunocompetent 15,411 Multicenter Incidence of HZ 97.20 (93.7–99.0)
> 50 years 7698 (active) 7713 Randomized
(placebo) Double-blind
vs. placebo

95%CI: 95% confidence interval; RA: rheumatoid arthritis; CIBD: chronic inflammatory bowel disease; Pso: cutaneous psoriasis; PsA: psoriatic arthritis; SpA: spondyloarthritis;
HZ: herpes zoster; PHN: postherpetic neuralgia; SPS: Shingles Prevention Study; STPS: Short-Term Persistence Substudy.

patients given biological drugs to treat autoimmune diseases, immunocompromised patients, in whom it is effective in boost-
the vaccine proved safe and the humoral and cellular immune ing the humoral and cellular immune responses against the virus.
responses were significantly increased 28 days post-vaccination These preliminary data need to be confirmed in larger studies of
[53]. various immunocompromised populations.

3.2.2. Subunit vaccines

Another approach consists in using subunit vaccines, which
are composed of one or more viral proteins. The VZV glycopro-
tein E (gE) is a key target of the cellular and immune responses
against the VZV. Preliminary studies assessed a herpes zoster sub-
unit vaccine (HZ/su) composed of 50 ␮g of gE combined with a
liposome-based adjuvant system (AS01B ). The safety profile was
satisfactory in healthy elderly individuals and the cellular and
humoral responses were both strong and sustained [54,55]. The
trials are still underway, but their preliminary results seem highly
promising. A Phase III, multicenter, randomized placebo-controlled
trial of the HZ/su vaccine in 15,411 participants older than 50 years
was reported in 2015 [56]. Vaccine efficacy was estimated at 97.2%
(95%CI, 93.7–99.0%), with no differences across age groups. Serious
adverse events were similar in the two groups. A Phase II ran-
domized trial indicated that the humoral and cellular responses in
individuals older than 60 years persisted for at least 6 years after
two doses of the HZ/su vaccine [57]. Trials in immunocompro-
mised patients are beginning to become available. They include a
study in adults who had had autologous bone marrow transplan-
tation within the past 50–70 days [58] and patients infected with
the HIV [59]. These randomized placebo-controlled trials indicate
good safety and efficacy. Thus, the immune response was signifi-
cantly stronger in the active-vaccine groups and comparable to that
seen in immunocompetent adults older than 50 years of age [58].
These promising findings indicate that the subunit vaccine
against the VZV has a rather favorable safety profile even in
4. Conclusion
In sum, patients taking immunomodulating agents are at
increased risk for herpes zoster, particularly in its severe forms.
This excess risk may be ascribable to the drugs themselves, the
underlying disease and its severity, and/or concomitant medica-
tions. Glucocorticoid therapy, in particular, is a major risk factor
that increases both the incidence and the severity of herpes zoster
and potentiates the effects of immunomodulating drugs. Their use
should be as economical as possible. Methods are available for
preventing herpes zoster in these patients, who are at risk far
before 60 years of age. Whenever possible, herpes zoster vaccina-
tion should be considered before initiating the immunomodulating
treatment or during a temporary treatment discontinuation, whose
optimal duration remains to be defined.
The few studies that evaluated the live attenuated herpes
zoster vaccine in patients with immunodeficiency or immunomod-
ulating treatments showed a fairly good safety profile, with no
increase in the risk of severe varicella or herpes zoster, provided
immunity against the VZV had developed before administration
of the vaccine. The vaccine also exhibited some measure of effi-
cacy in diminishing the incidence of herpes zoster and the burden
associated with the infection, which may include a short-term
risk of cerebrovascular events in patients with systemic diseases
[60].

Please cite this article in press as: Tran CT, et al. Herpes zoster: Risk and prevention during immunomodulating therapy. Joint Bone
Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.04.001
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A booster injection or repeat vaccination will probably be
required in this high-risk population. However, no recommenda-
tions on this point have been issued.
Alternatives to the live attenuated vaccine consist of a heat-
inactivated vaccine and a subunit vaccine, which have been proven
safe and effective in preventing herpes zoster in immunocompe-
tent patients. Studies in immunocompetent patients have yielded
promising results. Nevertheless, to determine the exact role for
herpes zoster vaccination in recipients of immunomodulating
treatments, particularly those with inflammatory joint diseases
or other systemic conditions, large-scale multicenter trials are
needed. Appropriate pharmacotherapy should be given immedi-
ately to patients who develop herpes zoster. This treatment is
particularly urgent in immunocompromised patients.
Disclosure of interest
The authors declare that they have no competing interest.
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