Canada Communicable Disease Report
Vol. 25 (ACS-1)
1 May 1999

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*

STATEMENT ON RECOMMENDED USE OF VARICELLA VIRUS VACCINE

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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. Persons administering or using the vaccine(s) 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 only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

EPIDEMIOLOGY OF VARICELLA-ZOSTER VIRUS INFECTIONS

Varicella-zoster virus (VZV) is a DNA virus belonging to the herpesvirus family. As with other herpesviruses, VZV causes a primary illness (varicella or chickenpox), establishes latency in sensory nerve ganglia, and may reactivate at a later time causing herpes zoster or shingles. The lifetime risk of developing varicella is 95% and of having at least one reactivation is 15% to 20%.

VZV is spread by direct contact with virus shed from the characteristic skin lesions or in oral secretions. Airborne spread also occurs. Individuals with varicella can spread infection from 1 to 2 days prior to onset of the rash, up until the last lesion has crusted. However, the period of greatest infectivity is from the day before rash onset through the first few days of the rash. VZV is highly contagious, with an attack rate of 61% to 87% or higher among susceptible individuals exposed in a household setting^(1,2). Attack rates in other settings such as day care, school, and hospital are not well established but are felt to be much lower than that observed in households. The incubation period, defined as the interval between exposure to VZV and onset of symptoms, ranges from 10 to 21 days and in most cases is 14 to 16 days. There may or may not be prodromal symptoms of fever, malaise, and upper respiratory tract infection prior to rash onset. The characteristic lesions appear in successive crops during the first 3 to 4 days of illness. Lesions progress rapidly from macules to vesicles to pustules, and scab over within a few days. Disease severity increases with age and with immunosuppression^(3-6) (see "Spectrum of severity of varicella" below).

Infection in pregnancy, the fetus, and newborn

There are insufficient data to support the notion that varicella causes more severe illness in pregnant women than other adults⁽⁷⁾ (see Table 1 and "Spectrum of severity of varicella" below).

There is no evidence that gestational varicella is associated with an increase in spontaneous abortion, fetal death, stillbirth or prematurity. However, maternal infection during the first 28 weeks of pregnancy may result in transmission of VZV to the fetus and cause congenital varicella syndrome. Based on a prospective study of 1,739 women with VZV infection during pregnancy, the risk of developing congenital varicella syndrome was 0.4% if maternal varicella occurred prior to 13 weeks gestation and 2% if it occurred between 13 to 20 weeks gestation⁽⁸⁾. After 20 weeks, the risk is thought to be extremely small based on the rarity of case reports⁽⁷⁾. Features of the syndrome may include low birth weight (observed in 50% of 50 reported cases), cicatricial skin scarring (70%), ophthalmic abnormalities (66%), limb hypoplasia (50%), cortical atrophy (46%), and a variety of other anomalies including microcolon and neurogenic bladder⁽⁷⁾. Of 50 cases reported in the literature between 1947 and 1992, early death occurred in 28% by 14 months of age. Another possible consequence of intrauterine transmission of VZV is herpes zoster during infancy. This has been observed in 0.8% of infants if maternal infection occurs between 13 and 24 weeks gestation, and 1.7% if it occurs between 25 and 36 weeks gestation.

Finally, when the onset of maternal varicella is from 5 days before to 2 days after birth, severe neonatal varicella has been observed in 17% to 30% of infants. Among 22 infants whose varicella rash onset occurred between birth and 4 days, none died versus four (21%) deaths among 19 infants whose rash onset occurred between 5 and 10 days of age. This suggests that the former group was partially protected by the maternal antibody response to acute infection.

Immunocompromised hosts

Prior to the availability and regular use of varicella zoster immune globulin (VZIG) prophylaxis and antiviral therapy for varicella, infection in this population was associated with, on average, dissemination in 36% and death in 7%⁽⁹⁾. Provided recommendations for prophylaxis after exposure and early institution of therapy with intravenous antiviral therapy⁽¹⁰⁾ are followed, the current outcomes are much improved despite increasingly intense immunosuppressive chemotherapy regimens (see "Spectrum of severity of varicella" below).

EPIDEMIOLOGY OF VARICELLA IN CANADA

The age-related prevalence of varicella in Canada has been estimated in school settings via caregiver questionnaires in Winnipeg⁽¹¹⁾ and Quebec⁽¹²⁾ and by seroprevalence studies in Newfoundland (Dr. S. Ratnam, Newfoundland Public Health Laboratory, St. John's: personal communication, 1999). Figure 1 summarizes these data showing the proportion of the population still susceptible to varicella throughout childhood and adolescence.

Figure 1 Decrease in susceptibility to varicella with age as determined by seroprevalence data in Newfoundland (1992-1997) and school-based caregiver surveys in Manitoba (1996-1997) and Quebec (1995-1997)

Rate of physician visits and hospitalizations for varicella

Manitoba Health data from 1979 through 1997 were used to determine the variation in age-specific population-based rates of physician visits for varicella and herpes zoster⁽¹¹⁾ (Figure 2). These rates exceed population-based incidence rates from previous Health Canada reports^(13,14); however, the latter are based on passive reporting which underestimates the actual cases by a factor of five or more. During the same period the yearly number of hospitalized patients with varicella in Manitoba ranged from 43 to 126. The 19-year mean annual rate (95% confidence interval) for all Manitobans was 6.4 (5.3 to 7.5) per 100,000 population per year. Of those hospitalized, 92.5% were < 15 years of age and two-thirds of these were previously healthy children. A review of hospital charts for the fiscal year 1994 suggested accurate coding for varicella and at least 72% of cases were truly admitted for varicella or a related complication.

Figure 2 Mean and range of age-specific rates of varicella and herpes zoster based on Manitoba Health physician claim and hospital separation data for the entire province, 1979-1997

Spectrum of severity of varicella

Table 1 contrasts the age-related severity of varicella rash among otherwise healthy non-immune individuals and compares it to the frequency and intensity of rash associated with varicella vaccine as well as the severity of varicella among individuals who have been immunized with varicella vaccine^(15-22).

Children: Published data from the United States and the United Kingdom suggest that from 10% to 73% of children see a physician^(23-28) and from 0.1% to 0.6% are admitted to hospital^(23-26) as a result of varicella or an associated complication. The case fatality rate due to varicella is very low in children (approximately 1 to 3 per 100,000 cases). On the other hand, among deaths due to chickenpox in children aged < 15 years in the United States from 1990 through 1994 (an average of 43 children per year), 90% had no identifiable risk factors for severe varicella⁽²⁹⁾. In the United States, varicella is now the major cause of deaths due to diseases that are preventable by vaccines recommended for routine use in childhood (Dr. J. Seward, United States Centers for Disease Control and Prevention, Atlanta: personal communication, 1999).

Canadian data from a variety of sources suggest that during an acute episode of varicella from 30% to 65% of children see a physician and from 0.2% to 1.5% are admitted to hospital^{(11,12,30,31)}. The highest morbidity rates occur during the first year of life and after age 15 years. From 1973 through 1985, there were two to 12 deaths per year (total of 86 deaths) attributed to varicella in all ages; children < 10 years of age accounted for 59% of the deaths⁽¹³⁾. From 1987 through 1996, there were one to 16 deaths per year (total of 53) attributed to varicella in all ages; children < 10 years of age accounted for 26% of the reported deaths (Health Statistics Division, Statistics Canada, Ottawa: unpublished data).

Among reported deaths, in the decade from 1987 to 1996, in children aged < 10 years due to diseases currently preventable by routine childhood vaccination, 14 deaths were reported due to varicella compared to 11 deaths due to pertussis, three deaths due to measles and one death due to Haemophilus influenzae type b invasive disease (Health Statistics Division, Statistics Canada, Ottawa: unpublished data).

Despite the relatively high frequency of physician visits, it has been estimated that specific complications occur in only 5% to 10% of cases of varicella in otherwise healthy children^(3,25,32). Of these, about one-half involve secondary bacterial skin and soft tissue infections  usually due to Staphylococcus aureus or Group A beta-hemolytic streptococcus (GABHS). Otitis media may occur in up to 5% of cases. Serious secondary infections such as bacteremia, osteomyelitis, septic arthritis, endocarditis, necrotizing fasciitis, and toxic shock-like syndrome occur much less frequently. On the other hand, recent reports, including a population-based study in Ontario⁽³³⁾ and a day-care outbreak in Boston⁽³⁴⁾, indicate that varicella increases the risk of severe GABHS infection among previously healthy children, by a factor of 40- to 60-fold. Based on these and other data from Ontario⁽³⁵⁾ and Quebec (Dr. M. Douville-Fradet, Direction générale de la santé publique, Quebec: personal communication, 1999), it is estimated that preventing varicella could prevent at least 15% of cases of severe pediatric GABHS infection. Rare neurologic complications include cerebellar ataxia (about 1 per 4,000 cases) and encephalitis (about 1 per 5,000 cases). Mild hepatitis, defined as minimal to moderate elevation of liver enzymes, occurs in 20% to 50% of cases, but is usually asymptomatic. Similarly from 5% to 16% may have thrombocytopenia but few of these are clinically significant.

Data on the relative severity of varicella among hospitalized children according to the presence or absence of underlying disease were gathered through active surveillance by the Immunization Monitoring Program, Active (IMPACT)⁽³⁶⁾. From 1 January 1991 through 31 March 1996, a total of 1,323 patients with VZV infection were identified at 11 pediatric tertiary care Canadian centres. Of these, 861 (65%) were specifically admitted for varicella or a related complication. Table 2 compares clinical features of these 861 cases, according to prior health status. Of note, disease morbidity among the immunocompromised population was low, most likely due to prior prophylaxis with VZIG, rapid recognition of infection and admission to hospital, and nearly universal use of acyclovir predominantly by an intravenous route.

Adults: Relative to children, primary varicella is a more severe disease among adults, with a higher frequency of pneumonia, encephalitis, and death^(37,38). From 1.2% to 1.4% of all cases are admitted to hospital^(24,25). The case fatality rate due to varicella is 10 to 30 times higher. Although adults account for only 5% of all annual cases, they make up 55% of the 100 or so deaths due to varicella each year in the United States. As with children, the majority have no identifiable risk factor for severe disease⁽³⁷⁾. In Canada, 70% of reported deaths (37 of 53) due to varicella from 1987 through 1996 were in adolescents and adults (> 15 years of age) (Health Statistics Division, Statistics Canada, Ottawa: unpublished data).

There have been no systematic reviews of the severity of varicella among adults in Canada. A recent Swedish population-based study showed that there were 0.32 admissions for varicella per 100,000 adults⁽³⁹⁾. Of 305 adults admitted with varicella, none of 36 with pneumonia (12% of admissions) died, whereas two (9%) of 23 with encephalitis (8% of admissions) died. The commonly held notion that pneumonia associated with varicella among adults is a severe and potentially fatal disease, especially among pregnant women, has not been substantiated by population-based studies^(39,40). Roentgenographic abnormalities are frequent among adults with primary varicella but symptomatic pneumonia is much less frequent. Smoking is a risk factor for more severe disease, as shown by the occurrence of clinical pneumonia in 40% to 50% of smokers versus < 5% of non-smokers^(41,42).

Table 1 Age-related severity of varicella as indicated by frequency and severity of rash and fever relative to prior receipt of live-attenuated varicella vaccine, clinical syndrome, prior health, and age

Table  2 Patient characteristics, illness, and hospital course among children admitted to 11 Canadian tertiary care centres* for varicella or a related complication according to prior health status**, January 1991-March 1996

Burden of illness due to herpes zoster

The lifetime risk of developing herpes zoster is 15% to 20%. Figure 2 shows the age-related incidence of herpes zoster, based on hospital and physician claims in Manitoba, from 1979 to 1997⁽¹¹⁾. The rates, varying from a low of under 1 per 1,000 individuals in infants, to a high of 10 per 1,000 individuals in the elderly, are similar to previous reports from the United States^(43-45), and the United Kingdom^(46-48). Less is known about the morbidity of herpes zoster relative to that associated with varicella. Disseminated disease occurs  in about 2% of cases⁽⁴⁴⁾ and death is rarely attributed to herpes zoster alone. However, the most debilitating aspect of illness is post-herpetic neuralgia which lasts > 6 months in 9% to 35% of cases with the higher rates occurring in individuals aged >= 50 years.

ESTIMATES OF THE COST OF VARICELLA IN CANADA

A multicentre Canadian study, funded by the vaccine manufacturer, was recently completed to estimate the financial burden of varicella from both a medical perspective as well as from a societal perspective; it included both the costs of lost productivity and personal expenses borne by caregivers^(30,31). Independent assessments of the cost of uncomplicated (cases not requiring hospitalization) and complicated (cases involving hospital admission) varicella were carried out. In this small study (n = 179 uncomplicated cases and 200 complicated cases), costs were estimated as a total yearly cost of CAN$122.4 million or CAN$353.00 per individual case. Eighty-one percent of the cost went toward personal expenses and productivity costs, 9% toward the cost of ambulatory medical care, and 10% toward hospital-based medical care (daily bed cost comprised the largest part of the cost of hospital-based care).

Illness and financial burden due to nosocomial varicella outbreaks

There are no Canadian published estimates of the cost incurred due to varicella outbreaks in institutional settings, especially acute care hospitals. Studies in the United States have suggested the yearly cost for infection control varies from US$41,500 to US$55,934 and that the costs to control individual outbreaks vary from US$9,100 to US$19,000⁽⁴⁹⁾. More data are needed regarding the total impact of such events across Canada at pediatric and adult hospitals in primary care as well as tertiary care settings. Other impacts of varicella that are not well quantified include cancellation and the need for rescheduling of elective surgery, and the extent and cost of VZIG prophylaxis.

Establishing susceptibility to varicella

A history of past varicella is a highly reliable and valid way to determine that an individual is immune to varicella regardless of age. Conversely, a parental or personal history of no prior varicella is less reliable. For age 7 years, a parental report regarding a child's history of prior varicella as "definitely not", "probably not", or "uncertain", correlated with seronegativity to VZV in 91%, 79%, and 80% of cases⁽⁵⁰⁾. The respective figures for 10-year olds were 72%,  55%, and 50%. For adults, regardless of the strength of the history of no prior varicella, < 20% will be seronegative.

Several highly sensitive (86% to 97%) and highly specific (82% to 99%) tests are available to confirm immunity to VZV and include a wide variety of techniques such as neutralization, immunofluorescence, radioimmunoassay, enzyme-linked immunoassay (ELISA), and latex agglutination. The last two, using varicella glycoproteins as antigens, are the most widely available commercial test kits. In individuals who have no history or an uncertain history of prior varicella, serological testing may be considered. As the cost of serology rises, the benefit of screening goes down. Due to the high reliability of a history of prior varicella, individuals for whom serology is most cost beneficial include adolescents and adults with no prior history of having had varicella.

PREPARATION(S) USED FOR  IMMUNIZATION

A live attenuated varicella vaccine was developed in Japan in the early 1970s and designated the Oka strain vaccine. Vaccine preparations by a number of manufacturers derived from the Oka strain virus have since been licensed for use in Japan, United States, Korea, New Zealand, and some European countries. A lyophilized live attenuated Oka strain varicella vaccine, (Merck Frosst Canada Inc., VARIVAX^®), was licensed in Canada in December 1998. Another candidate vaccine is currently under consideration and supplementary statements on additional varicella vaccine products will be issued as needed.

The vaccine retains a potency of 1,500 plaque forming units (PFUs) or higher per dose for at least 18 months when kept frozen at or below -15^o C (+ 5^o F). When reconstituted (as per the manufacturer's directions) and stored at room temperature for 30 minutes, each 0.5 mL dose of the vaccine contains >= 1,350 PFUs of Oka/Merck varicella virus. Each 0.5 mL dose also contains 25 mg of sucrose, 12.5 mg hydrolyzed gelatin, trace amounts of fetal bovine serum and neomycin, and residual components of human diploid (MRC-5) cells. The vaccine does not contain preservatives.

Storage and handling requirements

Cold chain requirements must be strictly observed because VARIVAX^® is a highly heat sensitive vaccine. To maintain potency, the vaccine must be kept frozen at or below -15^o C (+ 5^o F). The manufacturer recommends storage in any freezer (e.g. chest, frost-free) that has a separate sealed freezer door. The vaccine retains potency in the freezer compartment of frost-free refrigerators despite their periodic increases in temperature. When unfrozen and prior to reconstitution, it retains potency when stored for up to 72 continuous hours at refrigerator temperature (2^o C to 8^o C [36^o F to 46^o F] ). Vaccine not used within this period should be discarded. Like other live viral vaccines, varicella vaccine should be protected from direct sunlight.

If vaccine is to be transported and used at a site distant from freezer storage, it should be kept frozen in a suitable container with an adequate quantity of dry ice so that dry ice remains if any unreconstituted vaccine must be returned to the freezer. Careful temperature monitoring of the container must be carried out to ensure that the temperature is maintained at or below -15^o C (+ 5^o F).

• Vaccine efficacy will be reduced if the vaccine is not handled and transported as recommended. To minimize the probability of vaccine being handled outside recommended temperatures for an unacceptable length of time, the vaccine must be reconstituted immediately prior to administration. Reconstituted vaccine must be discarded if not used within 30 minutes, because of possible loss of potency.
• Do not re-freeze either lyophilized or reconstituted vaccine.
• Vaccine providers should not administer the vaccine unless they are confident about the conditions under which it has been transported.

Immunogenicity

In pre-licensure studies of immune response to vaccines with a wide range of potency from 1,000 PFUs to 17,000 PFUs, consistently high seroconversion rates (>= 97% with ELISA antibody titers > 0.6) were achieved after single-dose vaccination in children (12 months to 12 years of age) and required two-dose vaccination administered at least 4 weeks apart in adolescents and adults (>= 13 years of age)⁽⁵¹⁾.

In clinical studies of healthy children, detectable varicella antibodies (ELISA > 0.6) have been reported in >= 99.0% of vaccinees who received one dose from 1 to 4 years post-vaccination⁽⁵¹⁾. The proportion of children with detectable antibodies remained consistently high (> 96%) up to 7 years post-vaccination, however the number of children tested decreased significantly. Among healthy adolescents and adults who received two doses 4 to 8 weeks apart, the proportion with detectable antibody levels remained > 97% up to 3  years post-vaccination.  In Japan, antibodies to VZV were reported in 97% of children 7 to 10 years after vaccination at levels comparable to those in children with a history of natural infection 7 to 10 years earlier⁽⁵²⁾.

Efficacy/Effectiveness

In pre-licensure placebo-controlled trials of the vaccine (17,000 PFUs per dose) among healthy children aged 1 to 14 years, the observed  protective efficacy was 100% in the first year and 96% in the second year post-vaccination^(16,53). No placebo-controlled trials have been done in adolescents and adults. In actual use, it is estimated that the vaccine will offer 70% to 90% protection against varicella of any severity and 95% protection against severe varicella for at least 7 to 10 years post-vaccination, the observation period reported to date⁽¹⁹⁾.

Current data regarding vaccine efficacy and persistence of antibodies in vaccinees have been based on studies performed in settings where the exposure to natural VZV remains highly prevalent and likely results in natural boosting. The effect of natural boosting on the level of protection provided by vaccination and the impact of  a decreased circulation of natural VZV on the duration of protection are unknown.

The severity of reported post-vaccination varicella (measured by the number of lesions and the maximum temperature level) appeared not to increase with time since vaccination. Varicella following vaccination is associated with significantly reduced numbers of lesions (Table 1).

Herpes zoster following vaccination

Among 9,454 healthy children (12 months to 12 years of age) and 1,648 adolescents and adults (>= 13 years of age) vaccinated in clinical trials, 11 cases and two cases of herpes zoster respectively were reported, equivalent to an estimated incidence of herpes zoster following vaccination of 19 cases per 100,000 person years in children and 23 cases per 100,000 person years among adolescents and adults⁽⁵¹⁾. Restriction endonuclease analysis has proven (in 11 of the 13 cases) that vaccine strain virus can establish latency and reactivate as herpes zoster. In all populations studied (children, adolescents and adults, and immunocompromised persons), the reactivation rate appears to be less frequent and the disease less severe than following natural infection. The long-term effect of live attenuated varicella vaccine on the incidence of herpes zoster, particularly among vaccinees exposed to wild-type virus is unknown. Several years of observation will be required before the true incidence of post-vaccination herpes zoster can be determined.

Transmission of vaccine virus

Transmission of vaccine virus to susceptible contacts as measured by clinical evidence is rare. To date, all reported incidents have occurred in contacts of  individuals who developed a post-vaccination varicella rash^(19,51). To date, there is no clinical evidence that vaccine-strain virus transmitted from one subject to another gains in virulence, and limited sequence analysis of transmitted viruses shows no evidence of reversion to the more virulent wild-type (natural) virus.

Combination with other vaccines

In general, live vaccines given concomitantly with inactivated vaccines show satisfactory immune response⁽⁵⁴⁾. If necessary or convenient, varicella vaccine may be safely given with measles, mumps, and rubella vaccines; PENTACEL^® or QUADRACEL^®, at separate sites and with separate syringes at a single visit. Concomitant administration is particularly recommended when health-care providers anticipate that a routine vaccination may be unduly deferred or missed. If not given concomitantly with measles, mumps and rubella vaccines, varicella vaccine should be given at least 28 days later. Other live vaccines should be administered at the same time as, or at least 28 days apart from varicella vaccine.

RECOMMENDED USAGE

Table 3presents the evidence-based categories for particular recommendations, followed by a discussion of recommended usage.

Table 3 Evidence-based recommendations

Varicella vaccine is recommended for primary vaccination of healthy persons >= 12 months of age who are susceptible to the disease. Children aged 12 months to 12 years should receive full contents of a single-dose vial of vaccine (about 0.5 mL of reconstituted vaccine), according to the manufacturer's instructions in the product monograph. Persons >= 13 years of age should receive two full doses, at least 28 days apart. There is no need to restart the schedule if administration of the second dose has been delayed. The vaccine should be administered subcutaneously. Post-immunization serological testing for immunity is not recommended because of the high level of immunity conferred by the vaccine.

Immunocompromised persons: Varicella virus vaccine is currently not licensed for use in persons who are immunosuppressed. However, the vaccine may be beneficial in selected cases and consideration should be given to its use in those individuals in consultation with specialists knowledgeable in both the immunosuppressive disease and the vaccine. A research protocol is available to obtain varicella vaccine for use in patients who have acute lymphoblastic leukemia. Physicians can obtain further information about this protocol from the VARIVAX^® Coordinating Center (Telephone: 215-283-0897).

Other considerations: Booster doses after primary vaccination are not indicated at this time. The vaccine is currently not indicated for individuals with a previous history of varicella to prevent or ameliorate herpes zoster.

Contraindications

Current contraindications to the use of varicella virus vaccine are the following:

A history of hypersensitivity: A history of hypersensitivity to any component of the vaccine, including gelatin and neomycin is a contraindication (a history of contact dermatitis to neomycin is not a contraindication).

Immunocompromised persons: The vaccine is not routinely recommended for persons with illnesses resulting in immuno- suppression. A primary or acquired immunodeficiency state is a relative, but not an absolute, contraindication to vaccination as the vaccine may be beneficial in selected individuals (see "Recommended Usage" above).

Pregnancy: The effects of varicella virus vaccine on fetal development are unknown therefore vaccine should not be given to pregnant women. Women of childbearing age who are vaccinated should avoid pregnancy for 1 month following vaccination. To date, there are no data to suggest that live attenuated varicella vaccine accidentally given during pregnancy is teratogenic. The manufacturer in collaboration with CDC has established the VARIVAX^® Pregnancy Registry to monitor maternal-fetal outcomes of pregnancy in women who are inadvertently given varicella virus vaccine within a period of 3 months before or at any time during pregnancy. All instances of immunization of pregnant women occurring in Canada should be reported to Merck Frosst Canada Inc., Medical Services (Telephone: 1-800-684-6686).

Precautions

No transmission unless a rash is present: There is no evidence that varicella vaccine virus is transmitted in the absence of a rash. Healthy persons who develop a varicella-like rash following vaccination may carry a minimal risk of transmitting vaccine virus to susceptible close contacts. If a rash develops, it should be covered where possible and if not possible, contact with susceptible persons at high risk for severe complications (including the immunocompromised and newborns) should be minimized for the duration of the rash. Vaccinated health-care workers should be excluded, or change their work assignments, only if the rash cannot be covered and if they are involved in the care of high-risk patients.

Interference with passive immunity: There are no data about the interference of immune response to varicella vaccination by passively acquired antibodies. However, because varicella vaccine is a live vaccine, it may not result in good immune response if given following transfusion of blood (except washed red blood cells) or plasma, or administration of immune globulin (IG) or VZIG. The length of time for possible deferral of vaccination is variable, ranging from none (washed red blood cells) up to 10 months (intravenous IG for treatment of idiopathic Kawasaki disease)⁽⁵⁴⁾.

Following administration of varicella vaccine, IG including VZIG should be deferred unless the benefits outweigh those of vaccination. If an IG preparation is given < 14 days after varicella vaccine, vaccination should be repeated at an interval corresponding to the recommended deferral period (as described above) unless serologic testing indicates that antibodies were produced. If the IG product is given > 14 days after the vaccine, vaccination does not have to be repeated.

Steroid therapy: Live vaccines are generally contraindicated in persons undergoing long-term systemic steroid therapy although it is likely that individuals taking low maintenance doses of immunosuppressive drugs could receive varicella vaccine safely. It is recommended that varicella vaccine use in children receiving high doses of systemic steroids should be considered in consultation with knowledgeable specialists.

Common illnesses:  Minor illnesses such as the common cold, with or without fever, are not contraindications to immunization. Moderate to severe illness with or without fever is a reason to defer routine immunization with most vaccines; this is to avoid superimposing adverse effects from the vaccine on the underlying illness or mistakenly identify a manifestation of the underlying illness as a complication of vaccine use. The decision to delay vaccination depends on the severity and etiology of the underlying disease.

Breastfeeding: Breastfeeding is not a contraindication to varicella vaccination of the mother or child, if indicated. Varicella vaccine may be given to persons in households with a newborn.

ADVERSE REACTIONS

Varicella vaccine is very safe. Reactions are generally mild and include injection site reactions (20%), non-injection site rash (3% to 5%) and low-grade fever (15%) (Table 1). Serious adverse reactions such as pneumonia, febrile seizures, encephalitis, anaphylaxis, and death have occurred rarely in temporal association with varicella vaccine. However, there is no evidence of a causal relationship for any of these reactions.

In a double-blind placebo-controlled study of 914 healthy children and adolescents who were serologically confirmed to be susceptible to varicella, the only adverse reactions that occurred at a more significant rate (p < 0.05) among vaccinees compared to placebo recipients were pain (26.4% in vaccinees vs. 17.5% in placebo recipients), redness at the injection site (5.0% vs. 2.5%) and varicella-like rash (4.0% vs. 2.0%)⁽¹⁶⁾. Pneumonitis (< 1%) and febrile seizures (< 0.1%) have been reported rarely in vaccinated children but no causal relationship has been established⁽⁵¹⁾.

With the exception of hypersensitivity, a reaction to the first dose of varicella vaccine is not a contraindication to a subsequent dose.

POST-EXPOSURE MANAGEMENT

There are no conclusive data supporting post-exposure efficacy of varicella vaccine. Limited studies of previous vaccine formulations have reported protective efficacy of >= 90% when children (12 months to 12 years of age) are vaccinated within 3 days of exposure^(55,56). Even though varicella vaccine has not been proven to be protective when given after exposure, it is not harmful. It will protect the individual in the future if the current exposure does not result in infection. Where post-exposure prophylaxis is being considered for outbreak control, consultation with the local public-health department is recommended.

Recommendations for the use of antiviral medications and VZIG for the treatment and prophylaxis of persons exposed to VZV have previously been published and when followed improve the outcome in persons at risk for severe disease^(10,54). Immunocompromised persons exposed to vaccinees with a post-vaccination rash do not need to receive antivirals or VZIG.

LIMITATIONS OF KNOWLEDGE AND PUBLIC-HEALTH ISSUES

This vaccine is not universally accepted by health-care professionals and the public. As with any newly licensed vaccine, in order to maximize vaccine coverage, it will be very important that immunization programs include education activities targeting health-care professionals and the general public. To maximize the benefits from a universal vaccination program, it will be necessary to achieve and sustain high vaccination coverage levels.

Varicella vaccine has been studied extensively but some issues will only be fully understood after the vaccine has been in use in a large population for many years. The critical issues include inadequate data regarding

• duration of vaccine-induced immunity
• potential interference of immune response to varicella vaccine from passively transferred antibodies
• potential rare adverse events
• long-term epidemiological impact of vaccination on varicella and herpes zoster, especially if low levels of vaccine coverage are achieved
• coverage levels required to prevent emergence of susceptible cohorts in older populations

While the lack of definite data regarding these issues may raise concern about implementing a universal varicella vaccination program, it must be stressed that almost all individuals in the population acquire the wild varicella virus which is much more aggressive and has more serious complications than those seen with the milder vaccine strain. These serious complications associated with severe varicella can be almost completely prevented with the vaccine.

POST-MARKETING SURVEILLANCE

Studies are needed to monitor the potential shift in disease epidemiology and the need and timing for booster vaccination. Surveillance of vaccine coverage, adverse reactions and disease (varicella and herpes zoster) incidence will be critical to monitor the impact or success of any vaccination programs, monitor changes in the distribution of the disease, and identify additional interventions that may be necessary (e.g. repeat doses of vaccine at a later age). Close monitoring of the cold chain, including potential cold chain breaches as well as their adverse outcomes on vaccine delivery, effectiveness and safety, will also be critical because VARIVAX^® is the most heat-sensitive vaccine of all products currently included in the routine immunization schedule.

References

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4. Balfour HH Jr, Rotbart HA, Feldman S et al. Acyclovir treatment of varicella in otherwise healthy adolescents. J Pediatr 1992;120:627-33.

5. Wallace MR, Chamberlin CJ, Sawyer MH et al. Treatment of adult varicella with sorivudine: a randomized, placebo-controlled trial. J Infect Dis 1996:174:249-55.

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12. Boulianne N, Duval B, De Serres G et al. History of varicella in children aged 8 to 10 years old and the perception of their parents of the usefulness of the varicella vaccine. Poster presentation. 3rd National Immunization Conference, 6-9 December 1998, Calgary, AB.

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*  Members: Dr. V. Marchessault (Chairperson), Dr. J. Spika (Executive Secretary), N. Armstrong (Advisory Committee Secretariat Officer), Dr. G. De Serres, Dr. P. DeWals, Dr. I. Gemmill, Dr. B. Law, Dr. M. Naus, Dr. P. Orr, Dr. W. Schlech III, Dr. B. Ward.

Liaison Members: Dr. J. Carsley (CPHA), Dr. G. Delage (CPS), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. J. Livengood (CDC), Dr. N. MacDonald (CIDS), Dr. A. McCarthy (ND), Dr. J. Salzman (CATMAT), Dr. J. Waters (ACE).

Ex-Officio Members: Dr. L. Palkonyay (LCDC), Dr. R. Pless (LCDC).

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