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Canada Communicable Disease Report
Volume 30 • ACS-1
1 February 2004
An Advisory Committee Statement (ACS)
National Advisory Committee on
Immunization (NACI)*
Update on Varicella
PDF
Version
28 Pages - 365 KB
Preamble
The National Advisory Committee on Immunization
(NACI) provides Health Canada with ongoing and timely
medical, scientific, and public health advice
relating to immunization. Health Canada acknowledges
that the advice and recommendations set out in this
statement are based upon the best current available
scientific knowledge and is disseminating this
document for information purposes. People
administering or using the vaccine should also be
aware of the contents of the relevant product
monograph(s). Recommendations for use and other
information set out herein may differ from that set
out in the product monograph(s) of the Canadian
licensed manufacturer(s) of the vaccine(s).
Manufacturer(s) have sought approval of the
vaccine(s) and provided evidence as to its safety and
efficacy only when it is used in accordance with the
product monographs.
Two varicella vaccines have become available in
Canada since the publication of NACI's varicella
vaccine statement(1) and subsequent
update(2). These are
Varivax® III (Merck Frosst Canada
& Co) and Varilrix®
(GlaxoSmithKline). This second update reviews the
epidemiology of varicella, provides information about
the two vaccines, and makes recommendations for their
use in Canada.
Epidemiology
Varicella (chickenpox) is mainly a childhood disease:
50% of children will have had the infection by 5
years of age and 90% by 12 years of age. Recurrences
of varicella-like rash have been reported by 4% to
13% of individuals who had previous varicella
infection. The risk factors identified for these
recurrences were young age (< 12 months) at first
infection and having a milder first
infection(3). The lifetime risk of having
at least one reactivation to herpes zoster (shingles)
is 15% to 20%. People who grew up in the tropics are
less likely to have acquired immunity to varicella
during their childhood and have higher rates of
susceptibility as adults after migrating to
Canada(4,5).
Healthy children < 12 years of age account for
approximately 90% of all varicella cases, 80% to 85%
of chickenpox-associated physician visits, 85% to 90%
of hospitalizations, nearly 50% of fatal cases, and
the majority of annual costs, most of which are
related to productivity losses by caregivers. The
complications of chickenpox include secondary
bacterial skin and soft tissue infections, otitis
media, bacteremia, pneumonitis, osteomyelitis, septic
arthritis, endocarditis, necrotizing fasciitis, toxic
shock-like syndrome, hepatitis, thrombocytopenia,
cerebellar ataxia, and encephalitis. It has been
estimated that chickenpox increases the risk of
severe invasive group A streptococcal infection among
previously healthy children by 40- to
60-fold(6,7).
When compared with children, adults are more likely
to be admitted to hospital for varicella (3- to
18-fold higher risk) and to have higher rates of
complications such as pneumonia (11- to 20-fold
higher) and encephalitis (1.1- to 2.7-fold
higher)(8-11). The risk factors identified
in adults for varicella pneumonia include underlying
chronic lung disease and smoking(12-17).
Although pregnancy has also been considered a risk
factor for varicella pneumonia with high mortality,
this was not substantiated by several studies, which
reported varicella pneumonia occurring in 3.4% to
9.3% of pregnant women (no higher than in nonpregnant
adults) and only one death out of a total of 418
patients(18-20).
There is currently no evidence that gestational
varicella is associated with an increase in
spontaneous abortion, stillbirth, or prematurity.
However, transplacental or perinatal infection can
have other serious outcomes.
First, congenital varicella syndrome, which is
characterized by cicatricial cutaneous scarring
and/or hypoplasia of an extremity, low birth weight,
microcephaly, ocular anomalies, and neurological
abnormalities, was reported in 0.4% of live births
when maternal infection occurred from conception
through the 12th week of gestation, and in
2% when infection occurred between the 13th and 20th
week of gestation(21). A smaller,
prospective study of 347 women who had varicella
during pregnancy found an overall congenital
varicella syndrome rate of 0.4%(20).
Second, herpes zoster during infancy was observed in
0.8% of infants when maternal infection occurred
between 13 and 24 weeks' gestation and 1.7% when it
occurred between 25 and 36 weeks'
gestation(1).
Third, severe neonatal varicella occurred in 17% to
30% of infants when the onset of maternal varicella
was from 5 days before to 2 days after birth. The
mortality rate in these infected infants was 20% to
30%, the likely explanation being that their mothers
did not have sufficient time to develop and transmit
protective antibody to the unborn
fetus(1).
The case fatality rates for varicella are highest
among adults (30 deaths/100 000 cases), followed by
infants (7 deaths/100 000 cases) and lowest among
children 1 to 19 years of age (1-1.5 deaths/ 100 000
cases)(22,23). In the United States,
adults account for only 5% of cases but for 55% of
the approximately 100 chickenpox deaths each year. In
Canada, 70% of the 53 reported chickenpox deaths from
1987 to 1996 occurred in those > 15 years of age.
Children with impaired immunity (e.g. resulting from
chemotherapy and radiotherapy for malignant disease)
are at risk of severe varicella and
death(24). Historically, visceral
dissemination of the virus has occurred in 30% and
mortality in 7% to 10% of these
patients(25). However, postexposure
prophylaxis with varicella zoster immune globulin
(VZIG) and/or treatment with intravenous antiviral
therapy have clearly improved the outcome of
varicella infection in these patients(26).
The medical and societal costs of chickenpox in
Canada have been estimated to be $122.4 million
annually or $353.00 per individual
case(27,28). Eighty-one percent of the
costs go towards personal expenses and productivity
costs, 9% towards ambulatory medical care, and 10%
towards hospital-based medical care.
Varivax® III and Varilrix®
The two vaccines are compared in Table 1 below.
Table 1. Comparison of Varivax®
III(29) and
Varilrix®(30)
|
|
Varivax® III
|
Varilrix®
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Manufacturer
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Merck Frosst Canada & Co
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GlaxoSmithKline
|
Date licensed in Canada
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26 June, 2002
|
13 October, 1999 (but marketed in Canada only
as of October 2002)
|
Earlier generation vaccines
|
Varivax® (licensed in December
1998, freezer-stable) and Varivax
II® (licensed in August 1999,
can be stored in the refrigerator for up to 3
months). These vaccines are no longer
available.
|
No prior formulations
|
Varicella virus strain (both from Oka seed
virus)
|
Contains live Oka/Merck strain, which has
undergone 31 serial passages in cell
culture(31).
|
Contains live Oka/RIT strain, which has
undergone 35 serial passages in cell
culture(31).
|
Minimum potency level
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Contains a minimum of 1350 plaque
forming units (PFU).
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Contains a minimum of 1995 PFU.
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Shelf life when stored at +2o C to
+8o C
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18 months; reconstituted vaccine must be used
within 30 minutes to minimize loss of potency.
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24 months; reconstituted vaccine must be used
within 90 minutes to minimize loss of potency.
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Immunogenicity
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In children 12 months to 12 years of age, a
single vaccine dose gave a seroconversion rate
of 98% at 4 to 6 wks after vaccination, with
antibodies persisting in 98% at 5 years and 96%
at 7 years after vaccination(32-34).
In adults and adolescents >= 13 yrs of age,
two doses of Varivax®
administered 4 to 8 wks apart gave
seroconversion rates of 75% to 95% and 99% at 4
to 6 wks after the first and second doses
respectively. Antibodies persisted in 97% at 2
years and 97% at 5 years after two doses of
vaccine(35,36).
|
A single vaccine dose gave a seroconversion
rate of > 98% in children 12 to 36 months
old and 97% in children 5 to 7 years old at 6
weeks after vaccination. Antibodies persisted
for at least 7 yrs after vaccination in
children immunized at 12 to 15 months of
age(37-40).
In a study of health care workers, the
seroconversion rate was 100% at 6 wks after the
second dose, and 96% were still seropositive at
1 year after vaccination(41).
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Clinical efficacy (based on prelicensure
studies)
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Children who received a single dose of
Varivax® containing 1000 to 1625
PFU and were followed for up to 9 years had an
average varicella breakthrough rate of 2.5% per
year (compared with14.8% per year in historical
controls). The majority of breakthrough cases
in vaccinated children were mild (< 50
lesions)(42,43). In household
contact situations, 16% of vaccinated children
had a mild form of varicella (as compared with
a historical attack rate of 87% in unvaccinated
children).
Similar results were obtained in adolescents
and adults who received two doses of
Varivax®, among whom 17%
reported breakthrough varicella following
household exposure. The majority reported
having < 50 lesions.
|
In 10- to 30-month-old children followed for an
average of 29 months after receiving a single
dose of Varilrix®, the
protective efficacy was 100% against severe
chickenpox (defined as > 30 lesions) and 88%
against varicella disease of any severity.
Breakthrough cases were mild (a median of 1
vesicle, and no fever)(37).
A Canadian study reviewed 431 children aged 12
months to 12 years, 3 years after they had
received a single dose of Varilrix®.
Overall, 80 children (18.6%) had breakthrough
varicella-like illness, giving an average
breakthrough rate of 3.1% per
year(44,45). The average duration of
breakthrough illness was < 5 days. Ninety
percent of the patients had < 50 lesions,
and 30% reported having fever.
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Herpes zoster after vaccination
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During > 84 400 person-years of follow-up of
children vaccinated with
Varivax® 12 cases of herpes
zoster were reported, corresponding to a rate
of 14 cases/100 000 person-years.
This compares with a herpes zoster rate of
68/100 000 among healthy children after
wild-type varicella infection(46).
In adolescents and adults, two cases of herpes
zoster occurred during > 12 300 person-years
of follow-up, for a rate of 16 cases/ 100 000
person-years. Herpes zoster secondary to
varicella vaccination was mild, and there were
no serious sequelae(47,48).
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The above-mentioned Canadian study reported
herpes zoster in three of the 431 study
participants (0.7%)(44,45). The
average zoster rate after immunization was 7.7
per 10 000 child- months of observation.
|
Adverse effects
|
In children < 13 years of age, local pain,
swelling, redness, hematoma, induration, and
stiffness occurred in 20% within 2 days of the
injection. Fever occurred in 15%, a
varicella-like rash at the injection site
occurred in 3% (median 2 lesions), and a more
generalized varicella-like rash in 4% (median 5
lesions) 5 to 26 days after the dose.
In adolescents and adults, local symptoms
occurred in 25% and 32% after the first and
second doses. Fever occurred in 10% after each
dose. A varicella-like rash at the injection
site occurred in 3% and 1%, and a more
generalized rash in 5% and 1% after the first
and second doses respectively.
|
In children < 13 years of age, local pain,
redness, and swelling occurred in 11% to 22% of
patients, varicella-like rash in 1%, and other
rash types in 10%. Reactions at the injection
site tended to be mild and transient. Fever was
reported by 11%.
In adolescents and adults, local symptoms
occurred in 12% and 16%, fever in 29% and 20%,
and varicella-like rash in 0.9% and 1.3% after
the first and second doses respectively.
|
Use in immunocompromised patients
|
Not licensed for immunocompromised patients.
|
According to the manufacturer,
Varilrix® is indicated if the
total lymphocyte count in blood is > 1.2 x
109/L in patients with a) acute
leukemia in remission, b) malignant solid
tumours and who are receiving immunosuppressive
treatment, c) serious chronic medical diseases
(e.g. renal, pulmonary, rheumatoid,
neuromuscular, metabolic, and endocrine), and
d) for those awaiting organ
transplantation(30). NACI reviews
the evidence for and against these indications
and provides separate recommendations
later.
|
The following sections are common to both
vaccines:
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Dosage and route of administration
|
For both Varivax® III and
Varilrix®, the dosage is 0.5 mL
after reconstitution with the appropriate
diluent. The diluent may be stored in the
refrigerator (2o to 8o C)
or at room temperature (20o to
25o C). The dose should be
administered subcutaneously, the deltoid region
being the preferred site for injection. The
intramuscular (IM) route is not recommended for
either vaccine; however, the dose need not be
repeated if the vaccine is inadvertently given
IM(49). Both vaccines are available
in single-dose vials of lyophilized vaccine
(available in packages of 10) with the
corresponding single dose vials of diluent
(also available in packages of 10).
|
Boosters
|
Booster doses of either vaccine are currently
not recommended, as the duration of protection
from varicella in the absence of wild-type
boosting is unknown. In Japan, where vaccinated
individuals had had ongoing exposure (boosting)
to wild-type infection, protection lasted for
at least 20 years(50).
|
Co-administration with other vaccines
|
Both vaccines may be administered concomitantly
with measles-mumps-rubella (MMR), DTaP, IPV,
Hib, pneumococcal conjugate-7, meningococcal
C-conjugate, and hepatitis B and influenza
vaccines, using separate syringes and at
separate sites.
|
Vaccination in relation to use of
immunoglobulin preparations and blood products
|
A. Scheduling vaccination after receipt of
immune globulin (IG) or blood products:
Vaccination with either vaccine should be
deferred for the following specified intervals
after receipt of the following products (these
are similar to the intervals recommended for
MMR vaccine):
-
washed red blood cells (RBC) (0 mos),
reconstituted RBC (3 mos), whole
blood/packed RBC (6 mos), plasma/platelets
(7 mos).
-
palivizumab or Synagis® (0
mos), hepatitis B IG (3 mos), tetanus IG (3
mos), anti-Rho (D) IG (3 mos), rabies IG (4
mos), VZIG (5 mos).
-
intravenous IG (IVIG) according to the
dosage of IVIG used: 160 mg/kg (7 mos), 320
mg/kg (8 mos), 640 mg/kg (9 mos), > 1280
mg/kg (11 mos).
-
IG, based on dosage of IG used: <= 0.06
mL/kg (3 mos), 0.25 mL/kg (5 mos), 0.5
mL/kg (6 mos).
B. The use of immunoglobulin preparations
after vaccination:
No immunoglobulin products or VZIG for 14 days
after either vaccine, unless their use clearly
outweighs the benefits of vaccination.
|
Contraindications and precautions
|
Both vaccines have the following
contraindications and precautions: (a)
anaphylaxis with a previous dose of either
varicella vaccine, (b) a history of
hypersensitivity to any vaccine component
(neomycin, etc), (c) active, untreated
tuberculosis, (d) an active febrile illness
with temperature > 38.5o C, (e)
pregnancy (see later section), (f) avoidance of
the use of salicylates for at least 6 weeks
after vaccination, (g) for vaccine recipients
with a varicella-rash, avoidance of susceptible
high-risk individuals for the duration of the
rash.
|
Testing for Vaccine Immunogenicity
Antibody responses after wild-type varicella
infection may be > 10-fold higher than after
immunization with live attenuated Oka strain
vaccine(51,52). Assays to detect varicella
antibody include complement fixation (CF), latex
agglutination (LA), indirect immunofluorescence assay
(IFA), neutralization test (NT), enzyme-linked
immunosorbant assay (ELISA) and fluorescent antibody
to membrane antigen (FAMA). The CF test is considered
the least reliable, and NT and FAMA correlate best
with protection from disease but are cumbersome to
perform and not readily available. Commercial
antibody test kits rely on LA, ELISA or
IFA(53) and are usually able to detect
varicella antibody after wild-type infection, but
they may lack the sensitivity to pick up lower levels
of antibody after vaccination. In contrast, FAMA and
a more specific type of ELISA (glycoprotein ELISA or
gpELISA) appear to be more
sensitive(54-56). The prelicensure
Varivax® studies for the most part
used gpELISA, whereas the Varilrix®
studies used FAMA or other tests, hence making direct
comparisons difficult. In one study, immuno- genicity
appears to vary with the dose and vaccine
used(31), but the clinical significance is
unclear given that efficacy studies show similar
results for both products.
Impact of Vaccination in Canada and the U.S.
Between 2000 and 2003, five provinces and territories
(Prince Edward Island, Alberta, Northwest
Territories, Nunavut and Nova Scotia) implemented
routine, publicly funded varicella immunization
programs for children at 1 year of age. Three also
have catch-up programs for older children. Data from
these jurisdictions on immunization coverage and
varicella incidence rates in the postvaccine era are
not available. Vaccine uptake in regions without
publicly funded varicella immunization programs
remains low. In British Columbia (BC), a telephone
survey of parents conducted in 2003 showed that,
among children who had not previously had chickenpox,
vaccine uptake in 2- to 3-year-olds was 22% (95%
confidence interval [CI] 18% to 26%) and in 6- to
7-year-olds was 28% (95% CI 23% to 33%) (Reka
Gustafson and Danuta Skowronski, BC Centre for
Disease Control, Vancouver: personal communication).
A similar telephone survey in Quebec City revealed
that only 37% of health care providers offered
varicella vaccine to parents of children aged 14 to
17 months(57).
Evidence for the benefit of varicella immunization
was demonstrated in three U.S. communities that
conducted active surveillance for varicella from 1995
to 2000 and had achieved immunization coverage levels
of 74% to 84% in children aged 19 to 35 months. The
number of varicella cases in these communities
declined by between 71% and 84%(58). The
decline occurred in all age groups, the greatest
being found in children aged 1 to 4 years. The
varicella hospitalization rates in these three
communities also declined, from 2.7-4.2/100 000
population in 1995-98 to 0.6/100 000 in 1999 and
1.5/100 000 in 2000. Of the 347 cases of breakthrough
varicella occurring in vaccinated children in one of
the communities (Antelope Valley, California ), 80%
were mild (< 50 lesions) (A. Jumaan, Centers for
Disease Control and Prevention, Atlanta: personal
communication).
Varicella mortality in the United States has also
declined, coincident with increasing vaccine coverage
levels from 15% in 1996 to 60% in 1999 and 76% in
2001. During the prevaccine era (1990-94) there was
an overall average of 105 varicella-related deaths
per year in the United States. This dropped to 46
deaths/year in 1999- 2000. The decline in mortality
was observed in both the 20 to 49-year age group
(from 35 deaths/year to 13 deaths/year, 63% drop) and
the under-20 age group (from 48 deaths/year to 10
deaths/year, 78% drop) over the same period (A.
Jumaan, Centers for Disease Control and Prevention,
Atlanta: personal communication).
Breakthrough Varicella
On the basis of prelicensure efficacy studies,
breakthrough varicella rates of 3% to 4% per year are
expected to occur after varicella vaccination, with
higher rates of 5% to 20% after household exposure to
wild-type virus. Since 1995 in the United States, the
great majority of postlicensure studies on varicella
outbreaks occurring in day-care centres and schools
have shown an overall vaccine efficacy of 70% to 90%
for varicella disease of any severity and 93% to 100%
for moderate to severe disease(59-64). An
exception was an outbreak in a New Hampshire day-care
centre, which showed an efficacy of only 44% for
varicella disease of any severity and 86% for
moderate to severe disease(65). The index
case was a previously vaccinated 4-year-old boy who
infected 15 others at the centre. Eleven of these 15
had also previously been vaccinated with
Varivax®. A history of having been
vaccinated >= 3 years previously was a risk factor
for breakthrough disease, and this raised the
possibility of waning immunity(65).
In a separate study, an inverse relation was observed
between the antibody titre achieved 6 weeks after
varicella vaccination and the subsequent risk for
breakthrough infection(66). The risk that
vaccinated individuals with breakthrough disease will
infect others appears to correlate with the number of
lesions that develop. When compared with unvaccinated
cases, vaccinated breakthrough cases with > 50
lesions were equally as likely to transmit the
infection to household contacts, whereas those with
< 50 lesions were only half as likely to transmit
the infection (J. Seward, Centers for Disease Control
and Prevention, Atlanta: personal communication).
These observations highlight the need to study
varicella outbreaks that may occur in jurisdictions
with increasingly higher vaccination coverage in
Canada.
Risk of Herpes Zoster
There is some evidence that the boosting of
cell-mediated immunity by exposure to wild-type
varicella infection reduces the risk of zoster in
adults(67,68). Adults who have had contact
with children in their households and in the
community have an associated graded protection
against zoster. The adults with the most contact with
children had roughly one-fifth the zoster risk of
those with the least contact with
children(69). Brisson and colleagues used
a mathematical model to hypothesize that the
introduction of a universal varicella immunization
program in childhood may trigger a temporary rise in
herpes zoster rates in the adult
population(70). Brisson's model makes many
assumptions but does not include the possibility of
immunizing adults to boost immunity against
zoster(70,71). Clinical studies looking at
this potential use are currently under way, and
preliminary results are expected by 2004-05.
In the United States, local surveillance programs
have so far not detected any appreciable rise in
adult zoster rates in Seattle, Washington (data
available for 1992-2001) or in Massachusetts (a less
sensitive system, with data from 1998-2000). Zoster
rates are also being monitored in Antelope Valley,
California, and preliminary results for 2000-01 have
not shown an increase among
adolescents(72). However, it may be too
early to detect an increase in zoster rates, and
ongoing surveillance is necessary (A. Jumaan, Centers
for Disease Control and Prevention, Atlanta: personal
communication). At the present time, the theoretical
risk of increased zoster occurring in the adult
population is not a reason for withholding the
vaccination of children. Surveillance for zoster
cases should be continued in order to detect whether
this risk materializes. If it does, the best
intervention would be to immunize adults rather than
to stop vaccinating children. Vaccination itself has
the added benefit of reducing the risk of herpes
zoster in the recipient (see Table
1). For example, studies using the live vaccine
in immunocompromised children with leukemia and the
inactivated vaccine in adult recipients of
hematopoietic transplants have demonstrated 67% and
60% reductions respectively in the risk
of zoster(73,74).
Inadvertent Varicella Vaccination During
Pregnancy
Both Varivax® III and
Varilrix® are contraindicated during
pregnancy, and NACI recommends that women should
avoid pregnancy for at least 1 month (both product
monographs recommend 3 months) after the receipt of
any varicella vaccine.
A pregnancy registry has been maintained by Merck
Frosst & Co and the Centers for Disease Control
and Prevention in the United States for
Varivax® since its licensure in 1995
to determine whether the inadvertent administration
of the vaccine within 3 months before conception, or
at any time during pregnancy, is associated with
congenital varicella syndrome or other birth
defects(75). From 17 March, 1995, through
16 March, 2002, of 92 women in the registry who were
seronegative before vaccination and were followed
prospectively to delivery, 58 (63%) received the
vaccine dose during the first or second trimester.
These 58 pregnancies resulted in two spontaneous
abortions in the first trimester and 56 live births.
No cases of congenital varicella syndrome were
identified among the 56 live births (0%, 95%
confidence interval 0%-15.6%). Three live births had
congenital anomalies, none of which was consistent
with congenital varicella syndrome. This was
comparable to the background rate of congenital
anomalies reported in the U.S. population. However,
the registry has small numbers to date, and there was
insufficient power to detect an increased risk of
rare disorders or individual birth defects. Of
significance is the fact that 21 of the vaccinations
reported were due to the inadvertent administration
of Varivax® in place of VZIG because of product
confusion (VZIG is indicated after exposure to
varicella during pregnancy, but
Varivax® is not).
Fortunately, none of the 17 live births after this
product confusion resulted in congenital varicella
syndrome.
Clinicians are encouraged to report the outcome in
women who are inadvertently immunized with
Varivax® III during pregnancy to the
registry maintained by Merck Frosst Canada & Co,
Medical Services, tel: 1-(800)-684-6686. There is
currently no equivalent pregnancy registry maintained
by GlaxoSmithKline for Varilrix®.
Postexposure Use of Varicella Vaccine
Persons with wild-type varicella are contagious from
1 to 2 days before the onset of the rash until
lesions have crusted over(76). For
children, exposure is said to have occurred if the
susceptible child lives in the same household as, or
has had > 5 minutes (some experts require > 60
minutes) of face-to-face contact with, another
contagious child. For health care workers, having
> 15 minutes of face- to-face contact or spending
> 60 minutes in the room of a patient with
varicella is considered a significant
exposure(6,77). Varicella vaccination has
been shown to be effective in preventing or reducing
the severity of varicella if given to a susceptible
individual within 3 to 5 days after exposure to
wild-type varicella in households and homeless
shelters(78-81). Postexposure vaccination
may be helpful in controlling or preventing varicella
outbreaks in hospitals and day-care centres.
Varicella Immunization of Susceptible
Immunocompromised Individuals
Children and adults should preferably be immune to
varicella before any immunodeficiency diseases
arise. However, susceptible immunocompromised
individuals can be vaccinated if it is considered
safe and effective to do so. Apart from children
awaiting renal transplants and those with acute
lymphocytic leukemia (ALL), studies evaluating other
immunocompromised disorders involved small numbers of
children or adults, making it impossible to fully
assess vaccine safety and efficacy. These studies are
summarized below.
Children in remission from ALL
In the published literature, approximately 1000
children with ALL have been immunized with either
Varivax® (mostly used in North
American studies) or Varilrix® (the
European and some North American studies) over the
past 15 to 20 years(82-90). The
requirements for study entry were that patients had
no history of varicella infection and were
seronegative prior to vaccination. They had to be in
remission from ALL for > 1 year in most of the
studies and have a lymphocyte count of at least 0.7 x
109/L at the time of vaccination.
Maintenance chemotherapy had either been completed or
was withheld for 1 week before to 1 week after
vaccination. Many studies used FAMA for antibody
detection, whereas others used different antibody
detection tests, making comparisons difficult.
Investigators in the United States and Canada have
evaluated over 570 children using either
Varivax® (about 90% of the patients)
or Varilrix® (the remaining 10%) and
either a 1-dose (about 25% of the patients) or a
2-dose regimen (the remaining 75%)(82,84).
Eighty-two percent were seropositive by FAMA after 1
dose and 95% after 2 doses of vaccine, and
seropositivity was maintained in 87% of those tested
after 11 years of follow-up. Mild vaccine-related
rash was seen in 40% to 50% of those still receiving
chemotherapy and 5% to 10% of those who had completed
chemotherapy. Vaccinees with a varicella-like rash
infected 15% of their susceptible
siblings(86). Forty percent of those who
had a rash were treated with acyclovir. Local
reactions and/or fever occurred in 5% to 20% after 1
to 2 doses. Leukemia relapse was reported in 20% to
25% after vaccination (no different than controls).
Vaccine efficacy data are limited; of 123 children
exposed to varicella after immunization in the U.S.
and Canadian studies, 14% developed mild breakthrough
disease (with < 100 lesions).
In contrast, European investigators mostly used a
single dose of Varilrix® in children
with ALL(83,87-90). Seroconversion, as
measured by a variety of tests, was found in 68% to
95% at 6 to 10 weeks after vaccination. By 12 months
after vaccination, most studies documented a decline
in antibody levels. In two studies, 14 patients whose
antibody level had dropped received a second dose,
and 10 of these showed a boost in antibody
levels(83,87). Adverse events were mild,
and varicella breakthrough occurred in 18% to 26%
after a single dose(83,88).
The risk of herpes zoster after vaccination in
patients with ALL was assessed in two
studies(73,91). The herpes zoster
incidence in vaccinated children followed for 6
months to 10 years was 0.8/100 person-years and that
of controls was 2.5/100 person-years, suggesting that
vaccination had a protective effect. The risk of
herpes zoster was lower among (a) those who had
received two vaccine doses, (b) those who had no
vaccine-related rash or breakthrough disease, and (c)
those who had a history of household exposures to
varicella (without developing a rash).
Children with malignant solid tumours
In the published literature, there have been < 40
children with each solid tumour type (such as
rhabdomyosarcoma, Wilms' tumour, non-Hodgkin's
lymphoma) immunized with
Varilrix®(92-95). These children
received a single vaccine dose, administered either
10 days before chemotherapy was ever begun or during
an interval when chemotherapy was withheld from 1 to
3 weeks before to 1 to 3 weeks after vaccination.
Antibody testing by ELISA revealed that only 30% to
65% seroconverted at 4 weeks to 6 months after
vaccination. Adverse effects were mild, with rash
occurring in 5% to 10% and fever in 10% to 20%.
Clinical efficacy could not be assessed because of
small numbers.
Children after renal transplantation
In one study, 17 children received a single dose of
Varilrix® at a mean age of 52 months
(range 3 to 124 months) after renal
transplantation(96). The immunosuppressive
drug regimen was not modified, and the total
lymphocyte count was > 1.5 x 199/L at
the time of vaccination. According to the ELISA test,
the seroconversion rates were 11/17 (65%) at 4 to 8
weeks and 16/17 (94%) at 3 to 6 months after
vaccination. At 24 months, the majority of those
followed up were still seropositive. In one patient a
mild varicella-like illness developed 15 days after
vaccination, and three had mild varicella at 2 to 4
years after vaccination(96).
Children before renal transplantation
There have been over 530 pediatric renal transplant
candidates who received 1 to 2 doses of
Varilrix® before
transplantation(96-100). Patients received
their transplants from 1 month to 4 years after
completing vaccination. A second dose of vaccine was
provided only if patients did not respond to the
first dose, as measured by FAMA or ELISA tests. The
studies showed seropositivity in 60% to 95% at 6
weeks, 85% at 6 months, and 75% at 2 years after
vaccination. For the transplanted patients, 10%
seroreverted to negative at 2 years and 25%
seroreverted at 5 years after transplantation.
Adverse effects were generally mild. In one study,
breakthrough varicella was reported in 10% to 15% and
zoster in 7% of patients (as compared with 45% and
32% of unvaccinated control patients respectively).
Children before liver transplantation
Over 50 liver transplant candidates have received a
single dose of Varilrix® in the
published literature(98,101,102). The
antibody responses using ELISA or IFA in liver
transplant candidates were disappointing.
Seropositive results were found in only 30% to 85% of
patients at 8 weeks after vaccination, and antibody
levels did not persist over time. Mild breakthrough
disease occurred in 20% of liver transplant
candidates in one study.
Children and adults after bone marrow
transplantation (BMT)
There were 15 children who were immunized with a
single dose of Varilrix® at 12 to 23
months after BMT (seven autologous and eight
allogeneic transplants)(103). Antibody
responses measured using IFA showed 65%
seropositivity at 6 weeks, 90% at 6 to 12 months, and
65% at 24 months after vaccination. Clinical efficacy
in BMT patients could not be assessed, but adverse
effects were minimal. In another study, adults who
underwent autologous BMT for Hodgkin's and
non-Hodgkin's lymphoma received 4 doses of
heat-inactivated Oka/Merck vaccine at 30 days
before and 30, 60, and 90 days after
transplantation(74). Over the subsequent
12 months after transplantation, herpes zoster
occurred in 13% of vaccinated and 33% of unvaccinated
patients (p = 0.02). This inactivated vaccine
is not currently available.
Children with HIV infection
Forty-two HIV-infected children with asymptomatic
disease and a CD4 percentage of >= 25% were
vaccinated with 2 doses of Varivax®
given 3 months apart(104). Adverse effects
in the HIV-infected patients included rash in 2% to
5%, local reactions in 10% to 20%, and fever in 5% to
20%. Seroconversion by FAMA testing occurred in 50%
after 1 dose and 60% after 2 doses. Clinical efficacy
was not assessed in these patients.
Children with nephrotic syndrome
A Canadian study of 29 children with nephrotic
syndrome assessed 2 doses of Varivax®
given 4 to 6 weeks apart during disease remission or
at least 6 weeks after steroid treatment had been
stopped(105). None of the children had
prior varicella disease. None had renal failure.
Seropositive results by gpELISA testing were found in
100% after 1 dose and maintained in 100% at up to 2
years after vaccination. Adverse effects were
minimal, with no vaccine-related rashes; 25% had
local reactions. A similar study in Turkey on 20
children with nephrotic syndrome using a similar
protocol but with only a single dose of
Varilrix® found seroconversion rates
of 85% at 8 weeks after vaccination, with maintenance
of seropositivity after 2 years of
follow-up(106).
Recommended Usage
The goal of NACI's recommendations is to reduce the
morbidity and mortality due to varicella and its
complications in Canada. This is consistent with the
proceedings of the Canadian National Varicella
Consensus Conference held in May 1999, which
recommended the following: (a) that all provinces and
territories have a routine childhood varicella
immunization program by 2005 (including a catch-up
component for older children, adolescents and
adults), (b) that these programs be in place within 2
years of the availability of refrigerator-stable
vaccine(s), and (c) that by 2005, a
federal/provincial/territorial forum should establish
reduction goals for varicella-related
morbidity(6). NACI concurs with these
recommendations, since the requirement for a
refrigerator-stable vaccine has now been met with the
availability of Varivax® III and
Varilrix®.
Specific recommendations for the use of varicella
vaccine are presented below. For each group, the
level of evidence given is based on research design
rating and recommendation grades for specific
clinical preventive action. Table
2 explains the ratings.
Table 2. Levels of evidence, as modified
from the Methodology of the Canadian Task Force
on Preventive Health Care(107,108)
(see http://www.ctfphc.org/ — History/
Methods)
|
Research design rating
|
I
|
Evidence from randomized controlled trial(s).
|
II-1
|
Evidence from controlled trial(s) without
randomization.
|
II-2
|
Evidence from cohort or case-control analytic
studies, preferably from more than one centre or
research group.
|
II-3
|
Evidence from comparisons between times or places
with or without the intervention; dramatic
results from uncontrolled studies could be
included here.
|
III
|
Opinions of respected authorities, based on
clinical experience; descriptive studies or
reports of expert committees.
|
Recommendation grades for specific clinical
preventive actions
|
A
|
There is good evidence to recommend the
clinical preventive action.
|
B
|
There is fair evidence to recommend the
clinical preventive action.
|
C
|
The existing evidence is conflicting and
does not allow for a recommendation for or
against use of the clinical preventive action;
however other factors may influence
decision-making.
|
D
|
There is fair evidence to recommend
against the clinical preventive action.
|
E
|
There is good evidence to recommend
against the clinical preventive action.
|
F
|
There is insufficient evidence (in
quantity and/or quality) to make a
recommendation; however other factors may
influence decision-making.
|
For healthy individuals (see Figure 1)
- Varicella vaccination is recommended for
individuals >= 12 months of age who are
susceptible to varicella(1,2,109) (I - A).
Either Varivax® III or
Varilrix® may be used, as both are
safe and effective. Children aged 12 months to 12
years should receive a single 0.5 mL dose of either
vaccine subcutaneously. Persons >= 13 years of age
should receive two 0.5 mL doses, at least 28 days (4
weeks) apart. It is not known whether booster doses
of either vaccine are necessary after primary
vaccination, and booster doses are currently not
recommended for healthy individuals (III - F).
- Either varicella vaccine can be administered at
the same time as MMR vaccine but with a separate
needle and syringe and given at separate sites. If
not given at the same visit, there should be at least
28 days (4 weeks) between the administration of
varicella and MMR vaccines(110) (I - A).
- The same varicella vaccine should be used if two
doses are required, as the interchangeability of the
vaccines has not been studied. There is no need to
restart the schedule if administration of the second
dose has been delayed (III - C).
- Children, adolescents or adults with a reliable
history of varicella disease need not be vaccinated.
For persons >= 13 years of age with an unknown or
negative history of prior varicella infection, an
option is to perform serologic testing to determine
the need for immunization, since up to 80% will be
immune despite a negative history (III - C).
- As about 95% of adults in Canada have had
varicella, they need not routinely be vaccinated.
Susceptible groups of adults for whom vaccination
(using a 2-dose schedule) should be a priority
include the following:
- Health care workers (HCWs) should have their
immunity to varicella determined by history of
previous infection or varicella vaccination, and
should be tested for antibodies if the history is
negative. Susceptible HCWs may be immunized with
either vaccine, both for personal protection and
to prevent the transmission of varicella in
health care facilities. Immunization before, or
at the time of, employment is preferred over
postexposure vaccination. HCWs who develop a
varicella-like rash after vaccination should
notify the infection control
practitioner/physician or occupational health
nurse in the health care facility, who can
determine whether they may care for
immunocompromised patients (including premature
infants) for the duration of the rash. The risk
of transmission appears to be minimal, especially
if the lesions can be covered. There have been
only three proven cases of transmission of
vaccine virus despite millions of vaccine doses
used to date (III - C).
- Susceptible teachers, day-care workers, and
others who are occupationally exposed to
varicella as well as adults from tropical
climates who are more likely to still be
susceptible to varicella should be immunized with
either vaccine (III - C).
- All susceptible household and other close
contacts of immunocompromised individuals should
be immunized with either vaccine, to reduce the
risk from wild-type varicella(111)
(II-3 - B).
- Susceptible individuals at risk of severe
varicella disease or its complications may be
vaccinated with either vaccine (III - C), including
the following:
- Persons receiving chronic salicylate therapy
(avoid salicylates for 6 weeks after
vaccination).
- Persons with cystic fibrosis.
- Persons with nephrotic syndrome or those
undergoing hemodialysis or peritoneal dialysis
for renal failure (and not receiving
immunosuppressive therapy).
- Postvaccination serologic testing for immunity is
not recommended in healthy (non-immunocompromised)
individuals because of the high level of immunity
conferred by both vaccines and because commercial
antibody tests may not be sensitive enough to detect
vaccine-induced antibody (II-3 - D).
- There is, as yet, insufficient evidence to
recommend the vaccination of adults to prevent herpes
zoster, although studies are under way (III - F).
For women of child-bearing age (see Figure 1)
- Non-pregnant women of child-bearing age who are
susceptible to varicella should be immunized with 2
doses of either vaccine; those who are vaccinated
should avoid pregnancy for 1 month after vaccination
(III - B).
-
Neither varicella vaccine should be used in
pregnant women (II-3 - D). Susceptible pregnant
women who report exposure to varicella should be
offered VZIG and not varicella vaccine,
and NACI cautions against possible product
confusion between vaccine and VZIG.
- Postpartum susceptible women who are
breastfeeding their newborn infants can be immunized
with either vaccine(107). Breastfeeding
need not be discontinued if a postvaccine rash
develops, especially if the rash can be covered.
Women who receive anti-Rho(D) IG should not be
immunized with either vaccine for 3 months afterwards
(III - C).
For postexposure situations
- Within 3 to 5 days of a known household exposure
to varicella, any susceptible healthy contacts >=
12 months of age should receive postexposure
vaccination. Either vaccine may be used, with the
number of doses as already stipulated for healthy
individuals (II-3 - A).
- In day-care, school, or institutional settings
where there is incomplete vaccination coverage,
susceptible attendees may be continually exposed to
others with wild-type varicella, each being
considered a postexposure situation. While
postexposure vaccination can be performed at any
time, a more effective approach is to have proof of
immunity to varicella (either a history of prior
varicella infection or vaccination) at entry, in
order to reduce the risk of varicella outbreaks
(III - C).
|
|
|
Differentiating Between the Vaccine Strain and
Wild-type Virus
Usually, it is not clinically important to
differentiate whether a varicella-like rash is caused
by the vaccine or wild-type strain. However, some
examples of situations in which the ability to
differentiate the responsible strain is particularly
helpful include the following: (a) when an
unanticipated severe postvaccine rash occurs, (b)
when a severe breakthrough varicella-like illness
requires admission to hospital, (c) when herpes
zoster occurs in a previously immunized (especially
immunocompromised) individual, (d) when a
varicella-like illness occurs in a previously
immunized HCW, with subsequent spread in the health
care setting, and (e) when a varicella-like illness
develops in a pregnant or immunocompromised contact
of a vaccinee with a varicella-like rash. The NML is
able to perform molecular testing to differentiate
wild-type from vaccine strains of varicella virus,
and this requires a swab to be taken from the base of
vesicular lesions and transported in viral culture
medium. The specimen can be sent to the NML via the
local provincial laboratory. For further information,
contact the Viral Exanthemata Laboratory at the NML,
tel: (204) 789-6085.
Reporting Varicella Vaccine-associated Adverse
Events (VAAE) and Breakthrough Disease
Vaccine providers are requested to report any
(both expected and unexpected) varicella
vaccine-related adverse events occurring within 6
weeks of vaccination to Health Canada's VAAE
surveillance system, using the standard report forms,
available at http://www.phac-aspc.gc.ca/im/pdf/hc4229e.pdf.
Please report anyone, especially immunocompromised
hosts or pregnant women, who develops
vaccine-strain chickenpox within 6 weeks of being
in contact with a vaccinee (with or without a
postvaccine rash). In addition, breakthrough
disease occurring months to years after
vaccination may be reported to the VAAE
surveillance system. The severity of the
breakthrough rash/illness should be indicated, as
follows: (i) mild (< 50 vesicular lesions),
(ii) moderate (50-500 vesicular lesions), or (iii)
severe (with any one of the following: > 500
vesicular lesions, associated complications, or
admission to hospital).
Areas for Further Research
The following areas were identified by NACI for
research in Canada:
- To assess the effectiveness of universal
immunization programs in Canada, surveillance systems
to monitor vaccine coverage and the incidence of
varicella and its complications (including zoster in
the adult population) are urgently needed.
Surveillance for adult zoster will help determine
whether implemented childhood immunization programs
have any impact on the incidence of zoster over the
subsequent 10 to 20 years.
- As in the United States, if varicella outbreaks
occur in jurisdictions with high vaccination
coverage, it would be important to determine the
clinical severity of breakthrough cases and to
identify the potential causes of vaccine failure
(primary vaccine failure and/or waning immunity).
This will help determine whether (a) the current
1-dose vaccination strategy for 12 month to 12
year-old children is adequate, and (b) whether the
starting age at vaccination should be moved from 12
months to 15 months.
- It is necessary to continue monitoring for
adverse effects related to varicella immunization and
to maintain a pregnancy registry for maternal and
fetal outcomes if pregnant women are inadvertently
immunized with either varicella vaccine.
- Apart from children with ALL and children who
have yet to undergo renal transplantation,
information on the use of varicella vaccine in
immunocompromised patients (especially adults) is
still limited. Further studies on the long-term
safety and efficacy of varicella vaccination in these
patients are needed. Questions remain about the
optimum number of vaccine doses to use, and whether
an inactivated varicella vaccine is safer or superior
to the available live, attenuated vaccines in these
populations.
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___________________________________
*Members: Dr. M. Naus (Chairperson), Dr. A. King
(Executive Secretary), Dr. I. Bowmer, Dr. G. De
Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill,
Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. B.
Tan, A. Zierler.
Liaison Representatives: S. Callery (CHICA), Dr. J.
Carsley (CPHA), Dr. T. Freeman (CFPC), Dr. A. Gruslin
(SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH), Dr.
B. Law (ACCA), Dr. V. Lentini (DND), Dr. A. McCarthy
(CIDS), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS),
Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC).
Ex-Officio Representatives: Dr. A. Klein and Dr. H.
Rode (BREC), Dr. R. Ramsingh (FNIHB), Dr. T. Tam
(CIDPC).
This statement was prepared by Dr. B. Tan and
approved by NACI.
[Canada Communicable Disease
Report]
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