ARCHIVED - Update on Varicella
Canada Communicable Disease Report
An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)*
Volume 30 • ACS-1 • 1 Februray 2004 Update on Varicella
PDF Version, 28 Pages - 365 KB
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.
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.
Merck Frosst Canada & Co
Date licensed in Canada
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
Contains a minimum of 1350 plaque forming units (PFU).
Contains a minimum of 1995 PFU.
Shelf life when stored at +2o C to +8o C
18 months; reconstituted vaccine must be used within 30 minutes to minimize loss of potency.
24 months; reconstituted vaccine must be used within 90 minutes to minimize loss of potency.
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).
Clinical efficacy (based on prelicensure studies)
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.
Herpes zoster after vaccination
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.
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).
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.
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:
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).
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):
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).
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
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).
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.
|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).
For susceptible, immunocompromised individuals
There are many categories of immunosuppressive disorders, with different levels of severity. While varicella vaccination may be considered for patients with select immunodeficiency disorders, it is contraindicated in persons with T-cell dysfunction. The vaccination of patients who were not suspected of having associated T-cell immunodeficiency has led to rare and serious outcomes, such as disseminated or prolonged disease with the vaccine strain(112-115). Consequently, some experts believe that susceptible individuals with known immunodeficiency should not receive live varicella vaccine(116). In such cases, VZIG prophylaxis should be offered when these immunocompromised individuals are exposed, and acyclovir therapy started if wild-type varicella develops.
Since the issues that have to be considered before immunizing any immunocompromised person against varicella are complex, NACI recommends that a specialist who has expertise in the use of varicella vaccine be consulted. The following general principles may be applied (see Figure 2):
Children and adults with the following isolated immunodeficiency diseases and known intact T-cell systems may be vaccinated with either vaccine, following the same age-appropriate dosage schedule as for healthy persons(117) (III - C):
Humoral (immunoglobulin) deficiency diseases
Neutrophil deficiency disorders
Complement deficiency diseases
Asplenia - either congenital absence, surgical removal, or functional (e.g. sickle cell disease).
- Children and adults with immunodeficiency diseases affecting T-cell function (e.g. severe combined immunodeficiency [SCID] and AIDS) should never receive live varicella vaccine, i.e. vaccination is contraindicated (II-3 - E). Patients with a medical history suggestive of immunodeficiency disorders (e.g. positive family history for congenital immunodeficiency disorder or HIV infection, associated failure to thrive, recurrent and/or severe viral/bacterial/fungal infections) should not be immunized until they have been fully investigated and T-cell dysfunction ruled out.
- Varilrix® may be used to immunize susceptible children with acute lymphocytic leukemia (ALL) in remission. Although Varivax® III is not currently licensed for this indication, it has and can be used in research settings. Strict attention to the following conditions must be observed prior to vaccination (II-3 - B):
- The patients should have been in remission from ALL for at least 12 months.
- The total lymphocyte count should be at least 1.2 x 109/L, and patients must not be receiving radiation therapy at the time of vaccination.
- If patients are still receiving maintenance chemotherapy, it should be withheld for at least 1 week before to 1 week after immunization.
- Up to 2 doses of Varilrix® may be administered, 1 to 3 months apart. The Varilrix® product monograph recommends a single dose but indicates that additional dose(s) may be required without giving specific guidelines. The North American studies suggest that 2 doses (mostly using Varivax®) are more immunogenic than a single dose.
- Clinicians may consider performing antibody testing 2 to 3 months after the last vaccine dose using locally available laboratory tests (see Figure 2). If antibody is detected, there is no need to use more specialized tests. The patient who has detectable antibody after vaccination generally need not receive VZIG on future exposure to wild-type varicella. However, any breakthrough illness should be assessed for severity and the need for treatment with acyclovir. If antibody is not detected by the local virology laboratory, serum may be sent to the National Microbiology Laboratory (NML) in Winnipeg for gpELISA testing. If antibody is not detected by gpELISA testing, the patient should be offered VZIG on future exposure to wild-type varicella and acyclovir treatment considered if breakthrough disease occurs (Figure 2).
- For further information on reference testing for varicella- zoster virus, contact the Viral Exanthemata Laboratory at the NML, tel: (204) 789-6085.
- Susceptible patients who have been cured of ALL may be immunized with either vaccine (1 to 2 doses) at least 1 week after completing chemotherapy (similar to the patients in remission but receiving chemotherapy). Susceptible patients who have been cured of malignancies other than ALL may also receive either vaccine, according to the age-appropriate dosage schedule for healthy individuals, provided that >= 3 months have passed since the end of immunosuppressive treatment(118) (III - C).
- Susceptible patients awaiting renal and liver transplants may be immunized with 1 to 2 doses of either vaccine, the last dose being given at least 4 to 6 weeks before transplantation, provided they are not receiving immunosuppressive treatment for the underlying organ disease (II-3 - B). Because of the necessary wait period before transplantation, vaccination may be practical only in the context of elective (familial) transplants. There are currently no data regarding varicella immunization of other organ transplant candidates (e.g. cardiac and lung), and no firm recommendations can be made at this time for these groups of patients. After any solid organ transplantation, varicella-susceptible patients should not be immunized for at least 2 years, since these individuals are usually taking a variety of chronic anti-rejection drugs, such as prednisone, cyclosporine, tacrolimus, sirolimus, mycophenolate, or OKT3. Immunization with either varicella vaccine may be considered >= 2 years after transplantation, when the patient is deemed to be receiving minimal immunosuppressive therapy. Until further data are available, the same age-appropriate dosage schedule as for healthy persons may be followed (III - C).
- For susceptible children and adults awaiting BMT or stem cell transplantation (SCT), varicella immunization is not indicated, as these patients go through myeloablative treatments that will likely cancel the benefit of vaccination. The vaccination of donors immediately before bone marrow or stem cell harvest is also not recommended, as there are currently no safety data nor is there proof that immunity can be transferred from the donor to the recipient. The vaccination of a susceptible transplant recipient at >= 2 years after BMT or SCT may be considered, provided there is minimal immunosuppression and no graft versus host disease(117). Until further data are available, the same age-appropriate dosage schedule as for healthy persons may be followed (III - C).
- Children > 12 months of age with asymptomatic or mildly symptomatic HIV infection (CDC class N1 or A1) and with age-specific CD4 percentages of >= 25% may be vaccinated with 2 doses of either vaccine with a 3-month interval between doses(104,107) (II-3 - B).
- Susceptible children and adults with medical conditions that require low dose steroid therapy (< 2 mg prednisone/kg daily to a maximum of 20 mg/day for < 2 wks) or who are taking inhaled or topical steroids may be safely immunized with either vaccine. The same age-appropriate dosage schedule as for healthy individuals should be followed (III - C).
- The use of either varicella vaccine is currently not recommended for the following groups of susceptible patients (except in the context of research trials), as there are no (or only limited) safety and efficacy data (III - F):
- Children or adults undergoing immunosuppressive treatment for acute myelogenous leukemia (AML) or for any malignant solid tumours.
- Adults undergoing treatment for ALL.
- Adults with asymptomatic HIV infection.
- Children or adults with chronic inflammatory diseases (e.g. inflammatory bowel disease, collagen-vascular disease, nephrotic syndrome) already receiving significant immunosuppressive therapy (e.g. with high dose steroids, azathioprine); however, they may be immunized with either vaccine at least 6 to 12 weeks after they have completed or temporarily stopped the immunosuppressive therapy.
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.
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