Seminar

Varicella
Ulrich Heininger, Jane F Seward

Varicella-zoster virus, a herpesvirus, causes varicella (chickenpox) and, after endogenous reactivation, herpes zoster Lancet 2006; 368: 1365–76
(shingles). Varicella, which is recognised by a characteristic vesicular rash, arises mainly in young children, although Division of Paediatric
older individuals can be affected. In immunocompetent patients, symptoms are usually mild to moderate, but an Infectious Diseases and
Vaccinology, University
uncomplicated severe case can have more than 1000 lesions and severe constitutional symptoms. Serious Children’s Hospital, Basel,
complications—including central nervous system involvement, pneumonia, secondary bacterial infections, and Switzerland
death—are sometimes seen. Varicella can be prevented by vaccination. Vaccine is about 80–85% effective against all (Prof U Heininger MD); and Viral
disease and highly (more than 95%) effective in prevention of severe disease. In the USA, a routine childhood Vaccine Preventable Diseases
Branch, National
immunisation programme has reduced disease incidence, complications, hospital admissions, and deaths in children Immunization Program,
and in the general population, indicating strong herd immunity. Similar immunisation programmes have been Centers for Disease Control and
adopted by some other countries, including Uruguay, Germany, Taiwan, Canada, and Australia, and are expected to be Prevention, Atlanta, GA, USA
implemented more widely in future. (J F Seward MBBS)
Correspondence to:
Prof Ulrich Heininger, University
Varicella-zoster virus is the causal agent of varicella ment, pneumonia, secondary bacterial infections, and Children’s Hospital, PO Box
(chickenpox) and herpes zoster (shingles).1–3 Varicella, death) can arise.10–15 Varicella is highly infectious, with CH-4005, Basel, Switzerland
the primary varicella-zoster virus infection, is attack rates in susceptible contacts ranging from 61% to Ulrich.Heininger@unibas.ch
predominantly a childhood disease in non-vaccinated 100%.4,16–18 The disease occurs worldwide and is endemic
populations.4–9 It is characterised by a vesicular exanthem in most populations. The disease causes a sizeable
(figure 1), which is frequently accompanied by fever and societal burden for patients and their caregivers, and can
malaise. Although varicella usually results in mild to necessitate school absenteeism and work loss.19–22
moderate illness in immunocompetent patients, serious After primary infection, the virus persists in sensory
complications (such as central nervous system involve- nerve ganglia of the dorsal root and establishes latent
infection in neuronal cells.23 The virus can reactivate
years or decades later and spread unilaterally along a
dermatome to cause herpes zoster (shingles), a painful,
localised vesicular rash.24–26 Varicella can be prevented by
vaccination. A new vaccine to prevent or modify herpes
zoster and its complications in adults aged 60 years or
older was licensed in the USA in 2006.27,28 In this Seminar,
we focus on primary varicella infection.

Pathogenesis
Varicella-zoster virus is one of eight herpesviruses of the
Herpesviridae family that are known to cause disease in
people and some other primates.29 The virus is a DNA
α-herpesvirus with a genome of about 125 000 bp that
encode 70 genes.30 During primary lytic infection with
varicella virus, these genes are expressed sequentially, in
much the same way as they are in herpes simplex virus.31
Sequential expression leads to the production of groups of
immediate to early non-structural proteins, early non-
structural protein enzymes, and late structural proteins.31
The late structural proteins form a capsid surrounding the
DNA core, a tegument, and a lipid-containing envelope

Search strategy and selection criteria

We used the PUBMED database to search for publications with “varicella” and “VZV” as
keywords, plus additional terms including “vaccine”, “complications”, “hospitalization”,
“death”, “treatment”, and “side-effects”. Citations were selected from articles published in
English and German. For treatment and prophylaxis we focused on published randomised
controlled trials whenever available. Reference lists in key textbook chapters and review
articles were also checked for relevant publications and references.
Figure 1: Vesicular exanthem caused by varicella in an 8 month-old infant

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 Seminar
Lipid-containing
envelope
Capsid
Core with linear DNA
Figure 2: Structure of varicella zoster virus
(figure 2).32 The envelope of the virion is composed of
glycoproteins that also have important functions in
pathogenesis.33 After infection of a cell, varicella-zoster
virus replicates in the nucleus. There, DNA is incorporated
into preformed capsids, which leave the nucleus by a first
budding event at the inner nuclear membrane. Primary
enveloped virions are formed in the perinuclear space.
Then the primary envelope fuses with the outer leaflet of
the nuclear membrane and the nucleocapsids are released
into the cytoplasm. Subsequently virions are re-enveloped
at the transGolgi network, and mature virions are released
to the environment after fusion of the vesicle membrane
with the cell’s plasma membrane.34 Varicella-zoster virus
has little molecular variability.35 So far, three major
genotypes of wild-type varicella-zoster virus have been
described.36,37 The European Dumas strain and both the
Japanese Oka vaccine strain and its parental virus have
been completely sequenced.30,38
Infection 1st viraemia 2nd viraemia
Virus droplets,
aerosols
Exanthem*
0 5 10 20
Figure 3: Schematic representation of pathogenesis of varicella zoster virus infection
*Onset varies between 10 and 21 days after exposure.
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The incubation period of varicella is usually 14–15 days
Glycoprotein spikes
(range 10–21 days). Varicella-zoster virus spreads by
droplets and aerosols from the nasopharynx 1–2 days
before onset of a rash, and from skin lesions during the
first 5–7 days after appearance of rash.39–42 This contagious
period lasts up to several weeks in immunocompromised
hosts.3 The virus is thought to enter a susceptible host via
the mucosal surfaces of the respiratory tract, although it is
difficult to detect by culture or RT-PCR in this location.3,38,40
Several viral glycoproteins act in concert to adhere to
mucosal cells, and allow the virus to enter and spread
from cell to cell.43 These glycoproteins also stimulate the
host’s immune response.44–46 Varicella zoster virus is
thought to multiply in regional lymph nodes before the
first subclinical viraemia after about 4–6 days. During
viraemia the virus disseminates to the viscera, as has been
shown in animals and in fetal varicella syndrome.41,46–48
Virus then multiplies further in reticuloendothelial
tissues. A second viraemic phase occurs about 14 days
after infection (between 10 and 21 days; figure 3). The
Tegument second viraemic phase promotes viral spread to the
nasopharyngeal surfaces and the skin, causing the typical
maculopapular–vesicular rash. The vesicles contain large
amounts of virus, and might be the most important route
of viral transmission.40,49,50 The period of contagiousness
ends when all lesions have crusted.
The precise roles of humoral and cellular immunity in
protection against varicella-zoster virus infection are not
entirely understood. However, cell-mediated immunity
seems to be more important than humoral immunity,
probably because the spread of virus within the body is
exclusively via the intracellular route.2,3 Antibody res-
ponses against glycoproteins and other varicella-zoster
virus structures have been detected by serological
methods.3,51–53 Cell-mediated immunity is measurable by
in-vitro stimulation of lymphocytes with specific varicella-
zoster virus antigens or, more conveniently, by an ELISA
spot-forming cell assay.54 Furthermore, both antibody-
dependent cellular cytotoxicity and natural-killer cell
cytotoxicity are important in the host’s ability to clear
infection.55 The importance of cell-mediated immunity
for clearance of primary infection, prevention of recurrent
infections, and reactivation of infection has been shown
indirectly by (1) increased severity of disease in children
with cellular immunodeficiencies,56 (2) absence of serious
disease in individuals with hypogammaglobulinaemia,3
Anti-varicella-zoster (3) increasing risk for herpes zoster associated with
virus lgM cellular immune dysfunction and with waning cellular
immunity in elderly people,24 and (4) enhanced risk of
herpes zoster in children infected with varicella-zoster
virus in utero or shortly after birth.57–59 However, humoral
Anti-varicella-zoster immunity does seem to supplement protection by cell-
virus lgG and T-cell
response mediated immunity, as shown by the success of passive
immunisation with specific immune globulin.60 Recur-
Days
rent symptomatic varicella infections have been reported,
but are rare in otherwise healthy individuals; subclinical
infection can occur more commonly.2,61,62
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Epidemiology
The epidemiology of varicella differs in temperate and
tropical climates.5,63,64 In most temperate climates more
than 90% of people are infected before adolescence,8,9,65,66
whereas in many tropical climates the disease is acquired
later in life and adults are more susceptible than are
children.63,64,67,68 Epidemiological variation might relate to
differences in population density and risk of exposure,
differences in transmissibility of the heat-labile varicella-
zoster virus in hot, humid conditions, environmental
and social factors, or a combination of all these factors.
Varicella shows pronounced seasonality in temperate
climates and most tropical climates, with peak incidence
in the cooler, drier months during winter or spring.63,69–72
In temperate climates studies have shown that disease
incidence in the total population is in the range of
13–16 cases per 1000 people per year,3,83,96 with substantial
year-to-year variation.5,7,69 Epidemics tend to arise at
intervals of 2–5 years.69,70,72
Varicella is a childhood disease, with the highest
incidence in children aged 1–9 years.4,5,64,69,73–79 Over the
last decade, a shift to younger age at infection (below
5 years) has been observed, probably because of
attendance at child-care centres.5,77,80 Investigators have
also examined sex (most report no differences in sero-
prevalence between male and female individuals);
number of siblings (reduced susceptibility in children
with more siblings); and race (black adolescents were
reported to be more susceptible than white adolescents
in the USA).8,65,81
Older age and a compromised immune system are the
most important risk factors associated with severity of
varicella disease and death. Anecdotal evidence from
case reports and case series suggests that varicella in
pregnant women is more severe than in non-pregnant
women. Population-based prospective studies are needed
to investigate this possibility.82 In developed countries,
average crude varicella mortality rates range from 0·3 to
0·5 per million population, and overall case fatality rates
are about 2–4 per 100 000 cases.7,13,69,74,83–85 The risk of dying
from varicella is highest at the extremes of age: in adults,
the risk of death was 23–29 times higher, and in infants
four times higher, than that in children, in whom case
fatality rates were about one per 100 000.7,13,74,83
Crude rates of admission to hospital with varicella in
developed countries range from about two to six per
100 000 population.69,74,83,84,86,87 Most of these admissions
(56–67%) were children, which is consistent with the
fact that 90% of varicella cases happen in this age
group.3,5,69 For all ages combined, rates of hospital
admission per 1000 cases of varicella have ranged from
2·2 to 4·7 in national studies, mainly in France, USA,
and UK7,83,86,87 Variability in surveillance, health-care
systems, and completeness of ascertainment could
account for these reported differences. As with the risk
of dying from varicella, risk of hospital admission is
higher for infants and adults than for children.5,73,74,83,86
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Although varicella infection is more severe in
immunocompromised people (mortality was about 7% in
children with acute lymphocytic leukaemia before the
availability of varicella zoster immunoglobulin and
effective antiviral agents),56 most cases of severe morbidity
and mortality are seen in healthy people.13 For example,
70% of all varicella deaths in France (1990–97) took place
in people with no underlying high-risk medical disorders
(including HIV/AIDS, leukaemia and other malignant
diseases, other forms of blood dyscrasia, and immune
deficiencies).83 Similarly, in the USA (1970– 94), 89% and
75% of varicella deaths in children and adults, respectively,
occurred in otherwise healthy people.13 Almost 90% of
people admitted to hospital with varicella are described
as healthy or immunocompetent.14,86
Population-based data for mortality and hospital
admissions from developing countries and from those
with tropical climates are sparse. The high age of infection
and severe disease in adults in tropical countries might
account for the increased morbidity and mortality from
varicella and its complications, such as congenital
varicella syndrome, in such countries.62,88,89 We need more
population-based studies to investigate varicella morbidity
and mortality in countries with high HIV transmission
and prevalence of AIDS.62,88
Clinical features
Clinical illness is characterised by onset of fever, which is
usually concurrent with appearance of the self-limited,
pruritic, vesicular rash; various mucosal sites (ie,
conjunctivae, oropharynx, and introitus of the genito–
urinary tract) can also be affected. The rash starts as
macules, and progresses rapidly through papular and
vesicular stages, before beginning to crust within a short
period (24–48 h). The vesicles appear in crops, so that on
any one part of the body the rash can be in different
stages of development. Lesions have a central distribution,
and are more concentrated on the face and trunk than on
the limbs. Varicella lesions are superficial and crusts fall
off after 1–2 weeks, frequently leaving spots of
hypopigmentation that can remain for several months or
leave persistent scars.90
Varicella commonly causes systemic signs and
symptoms including fever, headache, malaise, and loss
of appetite or feeding difficulties. Secondary cases in
household contacts tend to be more severe than primary
cases.16 Varicella in previously immunised individuals
(known as “breakthrough varicella”) is usually mild, with
less than 50 skin vesicles compared with 200–400 lesions
in immunologically naive patients; breakthrough varicella
also carries a reduced risk of complications.91–93 Break-
through varicella can present diagnostic challenges.
Complications of varicella illness can be mediated by
either viruses or bacteria. The most frequent comp-
lications are secondary bacterial infections, mainly
caused by group A β-haemolytic streptococci or Staphy-
lococcus aureus.14,73 Such infections usually affect the
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skin and underlying soft tissue. Invasive infections (eg,
pneumonia, arthritis, osteomyelitis, necrotising
fasciitis, and sepsis) can be life threatening.14,73,86,94
Complications of the central nervous system range
from benign cerebellar ataxia (one in about 4000 cases)73
to serious manifestations such as meningoencephalitis,
meningitis, and vasculitis affecting small or large
vessels. Intracranial vasculitis causes strokes, most
frequently in children.95 Such strokes often happen
several months after varicella, and might not be
recognised as a complication of the disease. Other
serious complications include pneumonia and
haemorrhages—both can be fatal.13,73,96 Dehydration and
feeding difficulties caused by varicella disease also
frequently require hospital treatment.14 Varicella is
especially severe in immunocompromised hosts, for
whom there is an increased risk that the virus will
disseminate throughout their organs; that new skin
lesions will continue to appear for several weeks; that
vesicles will become large and haemorrhagic; that
varicella pneumonia will develop; and that the patient
will have disseminated intravascular coagulation.56
Congenital varicella syndrome occurs in 0·4–2·0% of
children born to mothers with primary varicella-zoster
virus infection during the first 20 weeks of gestation.97,98
However, cases have been reported as late as the 28th
week of gestation.99 This disabling syndrome consists of
a characteristic sequence of abnormalities, including
large areas of scarring on the skin, hypoplastic limbs,
chorioretinitis, cataracts and other eye malformations,
and brain abnormalities.100 Affected infants are
developmentally retarded and their outlook is poor. The
incidence of varicella during pregnancy varies according
to the susceptibility of women of childbearing age and
the rate of their exposure to the virus. Extrapolation from
consultation rates for varicella in adults aged 15–44 years
in the UK74 suggests an incidence of 2–3 cases per
1000 pregnancies.82
Intrauterine varicella infection in infants whose
mothers do not have antibodies can cause severe disease.
These newborn infants are at greatest risk of severe or
fatal illness if the mother’s rash appears between 5 days
before and 2 days after delivery. For infants given varicella
zoster immune globulin at birth, the clinical attack rate is
about 50% but death is rare101 compared with 30 years
ago.102
Diagnosis
In most cases, the characteristic features of the vesicular
varicella rash establish the clinical diagnosis. If doubt
remains, a recent history of exposure to varicella (or
herpes zoster) or the occurrence of secondary cases in
close contacts can help diagnosis. The differential
diagnosis consists mainly of allergic reactions (especially
Stevens-Johnson syndrome), generalised herpes zoster
or herpes simplex infections, enterovirus infections,
pityriasis lichenoides et varioliformis acuta (PLEVA), and
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guttate psoriasis—and in newborn babies, syphilis and
incontinentia pigmenti.3,103 Before eradication of smallpox
and in posteradication surveillance, varicella was the
disease most commonly confused with smallpox.104–106
Also, congenital histiocytosis can mimic congenital
varicella syndrome.107
The most common application of laboratory testing for
varicella is to confirm fatal, severe, or atypical illness. In
countries with varicella vaccination programmes,
laboratory testing is also needed to distinguish infection
with wild-type varicella-zoster virus from vaccine strain
infections (by use of restriction enzyme analyses or
sequencing of amplified genomic material).108–110
Additionally, as the disease is controlled or eliminated,
such testing is needed to confirm varicella cases,
especially in vaccinated people.108–110 Varicella-zoster virus
can be identified in clinical materials by culture (which
requires 3–5 days), or indirectly by PCR or rapid antigen
tests based on immunofluorescence techniques.39–41,108,111
Skin scrapings are the preferred specimens for these
methods; they should include cells from the base of the
lesion. Crusts are useful specimens for PCR analysis,
whereas varicella-zoster virus is more difficult to isolate
from the nasopharynx. Other specimen sites, such as
cerebrospinal fluid, lungs, liver, and brain, are more
likely to be tested at autopsy. Electronmicroscopy can be
used to identify individual herpesviruses in situations in
which rapid diagnosis is needed (eg, to rule out suspected
smallpox), and when antigen detection methods are not
available. The Tzanck smear, available in many pathology
departments, is a rapid and useful test for confirmation
of an α-herpesvirus infection, but is not specific for
varicella-zoster virus.
Serological tests are less useful than rapid antigen-
detection methods for the diagnosis of acute varicella in
clinical practice. Serum can test positively for IgM and
IgA antibodies against varicella-zoster virus as early as
1 or 2 days after appearance of the varicella or herpes
zoster rash. However, the absence of antibodies does not
rule out the diagnosis. The time course of the IgM
response in varicella infections has not been well
described. IgG antibodies appear shortly after IgM and
IgA responses, and persist throughout the patient’s
lifetime. There is known to be some cross-reactivity
between varicella-zoster virus and herpes simplex virus
type 1 (HSV-1), which is generally thought to indicate
aminoacid sequence homology between glycoprotein B
in varicella-zoster virus and in HSV-1.112–114
The fluorescent antibody to membrane antigen (FAMA)
test is regarded as the gold standard for identification of
varicella-zoster virus antibodies.115 The FAMA test is the
most reliable serological correlate of protection in non-
immunised individuals. However, the method is
demanding and time-consuming, and is not available in
most laboratories. Second episodes of varicella have been
documented in people with previous laboratory-
confirmed disease, and with demonstrable IgG antibody
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responses.116,117 But for practical purposes and sero-
surveillance studies, ELISA tests have proven sufficiently
sensitive and specific for measurement of immunity
after natural varicella infection. By contrast, antibody
values are about ten-fold lower in vaccinated people than
in non-vaccinated people, so commercially available tests
might not be sufficiently sensitive to assess vaccine-
induced immunity. Moreover, the presence of antibodies
is an imperfect predictor of protection in immunised
people. However, the presence of antibodies 6 weeks after
vaccination, as measured by both FAMA and by a
specially developed ELISA test against varicella-zoster
virus glycoproteins (gpEIA), are reported to relate
reasonably well to protection.112,118–22 Additional methods
for measuring IgG antibodies that are used by some
laboratories include latex agglutination, neutralising
antibody tests, complement fixation tests, radio-
immunofluorescence assays, and immunofluorescence
assays.3,8,52,53,112,123
Treatment
In almost all cases, varicella is a self-limited disease, and
symptomatic treatment (with acetaminophen to control
fever, lotions for pruritus, and fluid substitution to
maintain hydration) is sufficient. Treatment with acetyl
salicylic acid is strongly discouraged in children because
of its association with Reye’s syndrome.124 Moreover, the
use of non-steroidal anti-inflammatory drugs in children
with varicella might increase the risk of necrotising soft
tissue infections and invasive group A β-haemolytic
streptococci infections: several prospective multicentre
case-control studies produced conflicting results, so that
this association cannot be ruled out with certainty.125,126
Secondary bacterial infections require rapid adminis-
tration of antibiotics. Treatment with antivirals is
mandatory for patients at risk for severe disease (such as
immunocompromised hosts and newborns whose
mothers acquired infection around the time of delivery)
and for any people with varicella-zoster virus infection
with virally mediated complications (such as ocular
involvement, pneumonia, or encephalitis). Acyclovir is
most effective if given intravenously within 72 h of onset
of disease.127 The recommended daily dosage for children
is 1500 mg/m² per day; for adolescents and adults it is
30 mg/kg per day in three divided doses. Since the drug
is excreted via the kidneys, enough fluids need to be
given at the same time as the drug to avoid renal damage,
and dosage should be reduced appropriately in patients
with renal dysfunction.
In healthy children with varicella, treatment with oral
acyclovir within 24 h of onset of illness resulted in a 1-day
reduction of fever and a 15–30% reduction in the severity
of cutaneous and systemic signs and symptoms.128
Acyclovir treatment did not seem to reduce the rate of
complications; however, the number of complications
was small and most were bacterially mediated.128 The
recommended dosage is 80 mg/kg per day divided into
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four doses for children and 4 g per day divided into five
doses for adults for 5 days. Some authorities do not
recommend routine use of oral antivirals in uncom-
plicated cases of varicella in healthy children, but endorse
their use (if initiated within 24 h of rash onset) for groups
of people at higher risk of severe diseases, including
otherwise-healthy non-pregnant individuals 13 years of
age or older, children older than 12 months with a chronic
cutaneous or pulmonary disorder, and those receiving
long-term salicylate therapy.129 Famciclovir and valacyclovir
are currently licensed for treatment of herpes zoster but
not for varicella. Varicella-zoster virus resistance to
acyclovir is not a common problem and has so far been
reported mainly in patients with underlying HIV
infection. Resistance should be suspected in patients
failing to respond to treatment, and intravenous foscarnet
(up to 200 mg/kg per day in two or three divided doses)
could be used if appropriate.130
Prevention
The available varicella vaccines are a single antigen
vaccine and a combination vaccine against measles,
mumps, rubella, and varicella (MMRV). The live,
attenuated varicella vaccine is available worldwide as
Varivax (Merck, NJ, USA), Varilrix (GlaxoSmithKline,
Rixensart, Belgium), and Okavax (Biken, Osaka Japan).
The vaccine was developed in Japan.131 All vaccines use
the Oka strain of varicella-zoster virus, which was isolated
from a healthy child with varicella and attenuated by
sequential passage in cell culture.3
The single-antigen varicella vaccine is licensed in
various countries for use in healthy children who are
either older than 9 months (Varilrix) or older than
12 months (Varivax and Okavax). The suggested
vaccination schedule is one dose for children up to
12 years, and two doses, 4–8 weeks apart, for people
13 years and older.3,132,133 HIV-infected children with age-
specific CD4 of greater than 15% or 25% can receive
varicella vaccine in the USA133 and Europe respectively. In
Europe, the varicella vaccine is licensed for use in
immunocompromised patients with 1200 or more
lymphocytes per µL blood. In healthy children, the
seroconversion rate after one dose of live, attenuated
varicella vaccine is 97–99%.122,123,133 About 87% of children
achieve a gp ELISA level greater than 5 units (an
approximate correlate of protection) following the first
dose of Varivax vaccine; 99% achieve this level after the
second dose.122
An MMRV combination vaccine (Proquad, Merck, NJ,
USA) was licensed in the USA in 2005 for use in children
aged 12 months to 12 years; and it is expected to be
licensed soon in Europe and elsewhere. The vaccine
contains a higher amount of varicella-zoster virus than
does the monocomponent varicella vaccine, and the same
amounts of measles, mumps, and rubella vaccine viruses
as does MMR. Seroconversion rates are greater than 98%
for these components after two doses of MMRV.134 A gp
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Year of publication Vaccine Study design Study setting Vaccine effectiveness (estimate and 95% confidence interval)
All disease Moderate or moderate/severe Severe
1997138 Varivax Retrospective cohort Child care centre outbreak 86% (73 to 92%) 100%
1999139 Varivax Retrospective cohort 2 school outbreaks 71%, 100% 93%, 100%
1999140 Varivax Prospective cohort 11 child care centres 84% (67–90%) 100%
2001141 Varivax Case control Community clinical practice 85% (78– 90%) 97%
2002142 Varivax Retrospective cohort School outbreak 84%
2002143 Varivax Retrospective cohort Child care centre outbreak 79% (66–88%) 95%
200293 Varivax Retrospective cohort Child care centre outbreak 44% (−6 to 67%) 86%
2003144 Varivax Retrospective cohort School outbreaks 85% (77– 90%) 96% (88–99%)
2004145 Varivax Case control Community clinical practice 87% (81–91%) 98% (93–99%)
2004146 Varivax Retrospective cohort School outbreaks 72% (3–87%)
200417 Varivax Household contact Households 79% (70–85%) 92% 100%
2004147 Varilrix Retrospective cohort Health maintenance organisation 92% (91–93%)
2004148 Varivax Retrospective cohort School outbreak 56% 90%
2005149 Varivax Retrospective cohort School outbreak 89% (79–94%) 96% (88–99%) 100%
2005150 Varivax Retrospective cohort School outbreak 87%
2005151 Varilrix Prospective cohort 8 child care centres 20% (0–40%) 93% (75–98%)
2005152 Varilrix Case control Community 88% (77–94%) 100%
2006153 Varivax Retrospective cohort School outbreak 82% (76–87%) 97% (94–99%)

Table: Varicella vaccine effectiveness—summary of postlicensure studies

ELISA level of more than 5 units can be measured in
about 90% of children after one dose of MMR; and 99%
of children after two doses.134 Apart from a measles-like
rash and fever 5–12 days after vaccination with MMRV,
rates of other local and systemic adverse events for this
vaccination schedule, and for concomitant MMR and
varicella vaccine were much the same.134
Another MMRV candidate vaccine (Priorix-Tetra,
GlaxoSmithKlein, Rixenart, Belgium) has been developed
for use in children older than 12 months of age, and was
licensed in Germany and Australia in 2006. In one study,
two doses of this MMRV vaccine were at least as
immunogenic as two doses of MMR and one dose of
single-antigen varicella vaccine.135 All children in both
vaccine groups had seroconverted to measles, rubella,
and varicella after the second dose, and more than 98%
had seroconverted to mumps in both groups.135 This
MMRV vaccine did not induce increased rates of local or
systemic adverse events compared with separate
administration of the MMR and single-antigen vaccines,
apart from an increased rate of low-grade fever (<39°C)
after the first dose of MMRV (68% vs 49% after separate
vaccine doses).135
Comparison between studies of varicella vaccine
efficacy is difficult or impossible.3 Only two randomised
controlled clinical trials have examined efficacy in healthy
children.136,137 In the US, trial investigators compared
varicella vaccine (17 000 pfu but erroneously reported as
8700 pfu) with placebo given to children aged 1–14 years,
and showed that the vaccine was 100% effective with 9
months of follow-up.3,136 In the European trial, high titre
(10 000–15 850 pfu) and low titre (630–1260 pfu) vaccine
were compared with placebo given to children
10–30 months old, and followed up for a mean of
29 months.137 On the basis of the reported attack rates,
vaccine efficacy was calculated by these authors as 88·2%
for the high titre vaccine and 55·3% for the low titre
vaccine.137
Post-licensure studies are easily compared since they
use standard vaccine doses (of ≥1350 pfu at expiration). A
decade of use of Varivax in the universal vaccination
programme in the USA has produced post-licensure data
from more than 15 studies. They show that varicella
vaccine is usually 80–85% effective (with a range of
44–100%), in prevention of all varicella disease and more
than 95% effective in prevention of moderate and severe
disease (table). For Varilrix, the three studies that have
been done estimated vaccine effectiveness as 88%, 92%,
and 20%.151,152 Most varicella cases in vaccinees are mild,
suggesting suboptimum induction of immunity.154
However, these mild cases can be contagious.17 Protective
effectiveness in the range of 81–86% has been maintained
for 2–8 years postvaccination in the USA, with reduced
opportunity for boosting through exposure to varicella-
zoster virus in recent years.145,155
In prelicensure clinical trials, and post-licensure
surveillance with more than 50 million doses used in the
USA and elsewhere, varicella vaccine has proven safe in
susceptible children and adults.136,156–158 Serious risks are
rare; 2·8 cases have been reported per 100 000 doses of
vaccine distributed.157 In post-licensure safety surveillance,
identification of vaccine virus has allowed accurate
description of adverse events. The vaccine virus has
occasionally been transmitted from healthy vaccinees to
healthy recipients.159 Also rarely, in children with
immunodeficiencies that were undiagnosed at the time

1370 www.thelancet.com Vol 368 October 14, 2006


of vaccination, the vaccine has caused severe infections
or disseminated disease, including pneumonia.160–162
Severe adverse events—including acute anaphylaxis,
ataxia, encephalitis, stroke, idiopathic thrombocytopenic
purpura, and pneumonia—have been reported after
vaccination in healthy children, but all are rare.163,164
Although few such events have been attributed to the
vaccine virus, they represent a plausible risk for this
live, attenuated virus.162 Of note, one post-licensure safety
evaluation of almost 90 000 vaccinated people reported
no cases of ataxia, encephalitis, or other severe
complications.158 No deaths have been attributed to the
vaccine virus. Herpes zoster can result from vaccine
virus, but this seems to happen at a lower frequency in
both immunocompromised and healthy vaccine
recipients than in those who contracted varicella
naturally.3,158,165
Passive immunisation with varicella zoster immuno-
globulin can sometimes prevent or more usually
ameliorate clinical varicella in people who are exposed to
the virus at high risk of severe disease.132,166 It is frequently
used for exposed people for whom varicella vaccine is
contraindicated, including immunocompromised sus-
ceptible children, neonates whose mothers acquire
varicella from 5 days before to 2 days after birth,
adolescents, and adults, as well as premature infants and
pregnant women. Various formulations of varicella zoster
immunoglobulin are available in the USA (where it is an
investigational drug),167 and in Canada, Australia, and
Europe. Most require administration within 96 h of
exposure, but the UK product can be used for up to 7 days
after exposure. Some trials in healthy children have
shown that high-dose acyclovir, given orally 7–14 days
after exposure for 5 to 7 days, is effective in prevention or
modification of varicella.168–170 Data on the postexposure
efficacy of acycolivir in immunocompromised children
are sparse. However, high-dose acyclovir might be useful
in addition to varicella zoster immunoglobulin or alone if
the recommended time window for giving varicella zoster
immunoglobulin has passed in this high risk group.
Varicella vaccine is also effective postexposure and can
prevent or modify illness in up to 90% of exposed people
if given within 3 days, and in 67% of people if given
within 5 days of exposure.18,171,172
Varicella vaccination programmes
Varicella vaccine has now been licensed and is widely
available throughout the world. The goal of a vaccination
programme determines the strategy used. Because
varicella is mainly a childhood disease, prevention of
varicella and its attendant morbidity and mortality is best
accomplished through universal vaccination of children.
Targeted programmes (eg, for health-care workers,
household contacts of immunocompromised people,
susceptible adolescents or adults) offer either direct or
indirect protection to high-risk individuals in the
population. A vaccination programme for susceptible
www.thelancet.com Vol 368 October 14, 2006
Seminar
adolescents and adults could potentially prevent about
30% of varicella deaths and hospital admissions if high
coverage could be achieved in these age-groups.173,174
The USA has a universal varicella-vaccination
programme and other countries have added varicella
vaccine to their childhood immunisation schedule—eg,
Uruguay, Qatar, parts of Italy and Israel, Taiwan,
Germany, Australia, Canada, and South Korea. Many
European countries, such as Switzerland, recommend
the vaccine for specific risk groups such as
immunocompromised people, health-care workers, and
susceptible adolescents and adults. Availability of a
combination MMRV vaccine, recently licensed in the
USA, Germany, and Australia and expected in other
countries soon, might simplify implementation of
childhood varicella vaccination programmes in countries
considering such programmes. In developing countries,
the health burden caused by other diseases is higher
than that of varicella, so varicella vaccination is a low
priority for introduction into their national immunisation
programmes.175 However, more countries should
consider recommending varicella vaccine for health-
care workers.176
A programme of varicella vaccination has the potential
to change the epidemiology of herpes zoster as well as
varicella. Immunocompromised children who are
vaccinated against varicella have a reduced risk of
developing herpes zoster,165 as do healthy vaccinated
children.177 However, data from longer follow-up studies
are needed to see if these lower risks are sustained
throughout life.177 Mathematical models have predicted
that, in the long term, as vaccinated children aged into
adulthood, occurrence of herpes zoster in the population
would fall.178 However, in the short and medium term
(20–60 years), such models have predicted an increase of
herpes zoster in the population.178,179 In Canada, the USA,
and the UK, rates of herpes zoster were increasing before
varicella vaccination programmes, which complicates the
interpretation of possible changes in herpes zoster
epidemiology.180,181 Although there are reports that herpes
zoster has increased in the USA in recent years,182,183
neither study compared their data with pre-vaccine
baseline incidence rates for herpes zoster. One of the
studies attributed the increased incidence in 10–17 year
olds to increased use of steroids. A different study
suggests that the increase in herpes zoster in the USA
began before the universal vaccination programme was
implemented in 1995,184 and yet another study, that had
baseline data available, did not find an increase in herpes
zoster between 1992 and 2002.185
Postvaccine epidemiology
In the USA, since the introduction of the childhood
varicella vaccination, varicella cases, hospital admis-
sions, and deaths have fallen by more than 80% in
children, and to a lesser extent in adults and infants,
who are protected by indirect effects (so-called herd
1371
 Seminar
14
12
10 <10 years
Rate (per 100 000 population
10–19 years
20–49 years
0–49 years
8 Experience in the USA has shown that a one-dose
6 overall disease incidence and severe morbidity and
4
2
0 a two-dose immunisation programme for children in the
1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
Figure 4: Rates of hospital admission with varicella as the primary diagnosis by age and year
immunity).181,186–189 By 2000, when vaccine coverage in
young children ranged from 74–84%, varicella cases
were reduced by 71–84% in active surveillance sites.186
By 1999–2001, the rate of deaths in which varicella was
the underlying cause was 92% lower in children aged
1–4 years than in the 5 years preceding the vaccination
programme (1990–94).188 Over the same period the
varicella mortality rate was reduced by 74–89% in
infants younger than 1 year and people aged
5–49 years.187,188 The equivalent drop in varicella deaths
in adults older than 50 years was 16%, which is
consistent with the low positive predictive value of
varicella on death certificates in this age group in the
USA.189 By 2002, hospital admissions due to varicella
had fallen by 88%, compared with rates in 1994–95
(figure 4).190 By 2004, vaccine coverage in children
19–35 months of age had reached 88% nationally.177
Despite these successes, varicella outbreaks have been
reported lately in highly vaccinated school pop-
ulations.146,153 These outbreaks have been smaller than
those in the pre-vaccine era. However, along with
concern that improved protection is needed for the
15–20% of vaccinees who are not fully protected after
one dose, they have prompted consideration of a two-
dose policy for varicella vaccine.153,191
Future directions
In developed countries, if varicella costs and medical
and social benefits are considered, universal childhood
vaccination programmes will probably be cost-
saving.19,20,192 Wider availability of a combination MMRV
vaccine could aid implementation of such programmes.
Studies that include models of the expected increase and
then fall in prevalence of herpes zoster suggest that a
varicella vaccination programme will probably be cost
saving only in the longer term, as vaccinated cohorts
1372
reach adulthood.193 Developing countries might choose
targeted vaccination strategies, which could reduce the
health burden of varicella in adolescents, adults
(including pregnant women), and immunocompromised
people.
A two-dose or second opportunity vaccine policy for
measles is now routinely used throughout the world.
immunisation programme in young children reduces
mortality in the population, but might not provide
sufficient population immunity to prevent breakthrough
disease and continued disease transmission.153 In June,
2006, the US Advisory Committee on Immunization
Practices194 reviewed available scientific evidence,
including that for cost-effectiveness, and recommended
USA. The two-dose schedule—which has been shown to
produce substantially higher levels of immunity in
vaccine recipients—is likely in the long run to provide
improved disease control. Finally, the availability of a
zoster vaccine for adults aged 60 years and older now
offers the possibility to prevent or modify herpes zoster
and its complications.27
Conflict of interest statement
U Heininger’s institution has received research grants to undertake
studies of the epidemiology of varicella from GlaxoSmithKline,
Switzerland. Further, he has received speaker fees, served on advisory
boards unrelated to varicella vaccines, and accepted invitations to attend
scientific meetings from all major vaccine manufacturers. JF Seward has
no conflict of interest.
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