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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)
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Varivax® III
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Varilrix®
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Manufacturer
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Merck Frosst Canada & Co
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GlaxoSmithKline
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Date licensed in Canada
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26 June, 2002
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13 October, 1999 (but marketed in Canada only as of October 2002)
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Earlier generation vaccines
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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.
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No prior formulations
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Varicella virus strain (both from Oka seed virus)
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Contains live Oka/Merck strain, which has undergone 31 serial passages
in cell culture(31).
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Contains live Oka/RIT strain, which has undergone 35 serial passages
in cell culture(31).
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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).
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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.
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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.
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Adverse effects
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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.
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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.
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Use in immunocompromised patients
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Not licensed for immunocompromised patients.
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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.
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The following sections are common to both vaccines:
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Dosage and route of administration
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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).
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Boosters
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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).
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Co-administration with other vaccines
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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.
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Vaccination in relation to use of immunoglobulin preparations and blood
products
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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):
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washed red blood cells (RBC) (0 mos), reconstituted RBC (3 mos),
whole blood/packed RBC (6 mos), plasma/platelets (7 mos).
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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).
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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).
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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.
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Contraindications and precautions
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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.
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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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