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

NACI UPDATE TO STATEMENT
ON VARICELLA 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.

This update to the NACI Statement on recommended use of varicella virus vaccine contains new recommendations related to improved storage and handling parameters of the currently available varicella vaccines, indications for immunization of immuno-compromised persons, and post-exposure use of the vaccine to prevent secondary cases. For more detailed and other information, readers are referred to the original statement⁽¹⁾.

Two varicella vaccines have been licensed in Canada since the publication of NACI’s original statement⁽¹⁾. These are: Varivax II^® (Merck Frosst Canada & Co.) and Varilrix^® (SmithKline Beecham Pharma). Varilrix^® (varicella virus vaccine, live, attenuated Oka- strain) was licensed in Canada on 13 October, 1999. At the time of publication of this update, it is not marketed in Canada.

Varicella (chickenpox) is largely a childhood disease, with 50% of children developing varicella by 5 years of age, and 90% by 12 years of age. Figure 1 shows the estimated age-related prevalence of varicella immunity due to natural disease based on Newfoundland serosurvey data and caregiver surveys in Manitoba and Quebec. The lifetime risk of developing varicella is 95% and of having at least one reactivation to herpes zoster is 15% to 20%. Persons from the tropics are less likely to acquire immunity in childhood and have higher rates of susceptibility as adults, especially if from rural areas^(2,3).

Varicella is often considered to be a fairly benign disease among otherwise healthy children < 12 years of age. However, not only does this group account for approximately 90% of all varicella cases, but also for 80% to 85% of varicella-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.

Complications include secondary bacterial skin and soft tissue infections, otitis media, bacteremia, osteomyelitis, septic arthritis, endocarditis, necrotizing fasciitis, toxic shock-like syndrome, mild hepatitis and thrombocytopenia. Studies in Canada and the United States (U.S.) have estimated that varicella increases the risk of severe invasive Group A beta hemolytic streptococcus (GABHS) infection among previously healthy children, by 40- to 60-fold^(4,11). Rare neurologic complications include cerebellar ataxia and encephalitis. Complications are more likely to occur when chickenpox is acquired in adolescence or adulthood, with higher rates of pneumonia, encephalitis and death. Case fatality rates among adults are 10 to 30 times higher than in children. In the U.S., adults account for only 5% of cases, but constitute 55% of an approximate 100 chickenpox deaths each year. In Canada, 70% of the 53 reported chickenpox deaths from 1987 to 1996 were among those > 15 years of age.

The medical and societal costs of varicella in Canada were estimated, from a multicentre study, as a total yearly cost of $122.4 million dollars, or $353.00 per individual case^(5,6). Eighty-one percent of the costs went towards personal expenses and productivity costs, 9% towards the cost of ambulatory medical care and 10% towards hospital-based medical care.

Varivax II®

Varivax II^® was licensed in Canada on 26 August, 1999. It has the same composition as Varivax^® (the first licensed varicella vaccine in Canada), but has a higher initial potency level at the time of lot release. The increased potency improves the product stability. Recommendations for storage of both Varivax^® and Varivax II^® include freezer storage at –15^o C, but Varivax II^® may be transferred to, and stored in, the refrigerator at +2^o C to +8^o C for <= 90 continuous days. In contrast, Varivax^® may only be stored
in the refrigerator for <= 72 hours. Immediately following production, Varivax II^® has a frozen shelf life of 18 months, and the expiry date is printed on the package. Upon removal from the freezer and placement into a refrigerator, the user must calculate the new 90-day shelf life using a “date wheel” supplied by the manufacturer, and write the new expiry date on the vial. As an alternative, NACI recommends that a period of exactly 3 months from the date of removal from the freezer may be used as the new expiry date. Once the vaccine is placed in the refrigerator, it should not be returned to the freezer.

Following reconstitution and storage for <=  30 minutes prior to administration, both products contain a minimum of 1,350 plaque forming units (PFU) of Oka/Merck varicella virus in a 0.5 mL dose, and provide the same level of protection against varicella infection.

It is expected that the improved stability profile of Varivax II^® will make this a more desirable product for general use.

Recommended usage

Varicella vaccine is recommended for persons >= 12 months of age who are susceptible varicella infection. Children 12 months of age to 12 years of age should receive one 0.5 mL dose of vaccine. Persons >= 13 years of age should receive two 0.5 mL doses, at least 4 weeks (28 days) apart. At this time, it is not known whether booster doses are necessary after primary vaccination. 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. 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, and because currently available commercial laboratory tests are not sufficiently sensitive to detect vaccine-induced antibodies. Persons who are immunocompromised may not achieve as high levels of protection from vaccination as those who are healthy.

Varicella is a common childhood disease, and the percentage of children who have had the infection increases with age. A reliable history of varicella disease is adequate evidence of immunity, and there is little value of administering the vaccine to such persons. A history of varicella disease should therefore be obtained prior to immunization.

For persons >= 13 years of age with an unknown history of prior varicella infection, serological testing prior to immunization may be helpful in determining the need for immunization. The cost of such testing may, or may not, be less than the cost of immunization, and screening should be based on cost of program delivery. In general, for a routine program, serologic screening before vaccination is not practical, but in individual cases such as older adolescents and adults who are likely to have had wild varicella, it may be considered.

Because about 95% of adults in Canada have had varicella, they need not routinely receive this vaccine. Specific groups of adults for whom the vaccine should be considered are listed below.

The persons for whom varicella vaccine is specifically recommended are:

To reduce the incidence and the majority of morbidity from varicella:

• Children between 12 and 18 months of age as a part of routine immunization, preferably at the same time as measles, mumps and rubella vaccine (MMR) is given (note: if varicella vaccine is given at the same visit as MMR, it should be given with a separate needle and syringe at a separate site; if not given at the same visit, MMR should be given first, and there should be at least 28 days between the administration of the two vaccines).
  
• Susceptible older children and adolescents.

To prevent congenital varicella syndrome and prevent morbidity and mortality in pregnancy and the newborn period:

• Susceptible women of child-bearing age (note: this vaccine should not be given during pregnancy).

To prevent transmission of varicella in health care
facilities:

• Susceptible health care workers.

To prevent severe illness among susceptible persons at high risk of severe varicella due to underlying disease:

• Children and adolescents on chronic salicylic acid therapy. The vaccine manufacturers, however, recommend that vaccine recipients should avoid use of salicylates for 6 weeks after varicella vaccination because of the association between Reye’s syndrome, natural varicella infection, and salicylates. While no cases of Reye’s syndrome have been reported in association with salicylates after varicella vaccine, physicians need to consider this theoretic risk against the known risk of Reye’s syndrome following wild varicella among children on long-term salicylates.
  
• Persons with cystic fibrosis.
• Susceptible household contacts of immunocompromised
  persons.

Immunocompromised persons – special considerations:

• Varicella vaccine should not be given to persons with blood dyscrasis, leukemia except acute lymphoblastic leukemia (see below), lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system, or persons with other defects in cell mediated immunity or treatment associated with T-cell abnormalities (e.g., intensive chemotherapy, high dose steroids, cyclosporine, azathioprine, methotrexate, tacrolimus).
  
• Consult an infectious disease expert prior to immunizing persons with congenital transient hypogammaglobulinemia, HIV-infected persons with normal immune status⁽¹⁰⁾, and solid organ transplant recipients (vaccine should be given a minimum of 4 to 6 weeks prior to transplantation). Some HIV infected children should be considered for immunization if asymptomatic or mildly symptomatic in CDC class
  N1 or A1 with age-specific CD4+ T-lymphocyte percentages of >= 25%. Such eligible children should receive two doses
  of varicella vaccine with a 3-month interval between doses. They should be encouraged to return for assessment if they experience a post-vaccination varicella-like rash.

There is no additional or undue risk in vaccinating the following persons:

• Patients with nephrotic syndrome or those undergoing hemodialysis and peritoneal dialysis if they are not on immunosuppressive medications.
• Patients on low dose steroid therapy (e.g., < 2 mg prednisone/kg/day to a maximum of 20 mg/day for < 2 weeks).
  
• Patients on inhaled or topical steroids.

To prevent severe varicella in susceptible adults:

• Susceptible adults who may be exposed occupationally to varicella (e.g., teachers of young children or day care workers).
• Other susceptible adults (e.g., immigrants from tropical
  climates).

The Canadian National Varicella Consensus Conference recommended the implementation of a universal immunization program against varicella, including a catch up component for older children and adolescents. The recommendation is contingent on factors such as cost and vaccine stability. NACI concurs with the recommendation that provincial/territorial immunization programs should be designed to protect all susceptible children and adolescents against varicella.

Post-exposure and outbreak use of varicella vaccine

Varicella vaccine has been shown to be effective in preventing or reducing the severity of varicella if given to a susceptible individual within 3 days, and possibly < 5 days, following exposure to varicella^(7-9). Such use has not been associated with increased rates of adverse events. Post-exposure use should be considered in
settings where it may be desirable to prevent secondary cases or to control an outbreak (i.e., hospitals and day nurseries). Post-exposure vaccination has particular value in preventing illness among susceptible individuals who may be at higher risk of complications (e.g., adults, selected immunocompromised persons for whom vaccine is recommended). Serologic testing for susceptibility need not be carried out prior to immunization in an outbreak situation, based on the specific circumstances.

For recommendations on use of varicella zoster immune globulin, please refer to the Canadian Immunization Guide, 5^th edition, 1998.

In jurisdictions without publicly funded varicella vaccine programs, the role of the public health department may be limited to providing recommendations about the availability and effectiveness of post-exposure vaccine, and referral to an appropriate health care provider. In hospital settings, primary prevention of varicella among health care workers through history-taking for prior disease, screening and immunization of susceptible persons before, or upon, employment is recommended over post-exposure vaccination.

References

1. National Advisory Committee on Immunization. Statement on recommended use of varicella virus vaccine. CCDR 1999;25(ACS-1):1-16.

2. Mandal BK, Mukherjee PP, Murphy C et al. Adult susceptibility
to varicella in the tropics is a rural phenomenon due to the lack of previous exposure. J Infect Dis 1998;178(Suppl 1):S52-4.

3. Kjersem H, Jepsen S. Varicella among immigrants from the tropics, a health problem. Scand J Soc Med 1990;18:171-74.

4. Health Canda. Proceedings of the National Varicella Consensus Conference. Montreal, Quebec May 5-7, 1999. CCDR 1999;25S5:1-29.

5. Law BJ, Fitzsimon C, Ford-Jones L et al. Cost of chickenpox in Canada: Part 1. Cost of uncomplicated cases. Pediatrics 1999;104:1-6.

6. Law BJ, Fitzsimon C, Ford-Jones L et al. Cost of chickenpox in Canada: Part 2. Cost of complicated cases and total economic impact. Pediatrics 1999;104:7-14.

7. Asano Y, Nakayama H, Yazaki T et al. Protection against varicella in family contacts by immediate inoculation with varicella vaccine.
Pediatrics 1977;59:3-7.

8. Arbeter AM, Starr SE, Plotkin SA. Varicella vaccine studies in healthy children and adults. Pediatrics 1986;78(Suppl):748-56.

9. Salzman MB, Garcia C. Postexposure varicella vaccination in
siblings of children with active varicella. Pediatr Infect Dis J 1998;17:256-57.

10. Levin MJ, Gershon AA, Weinberg A et al. and the AIDS Clinical Trials Group 265 Team. Immunization of HIV-infected children with varicella vaccine. J Pediatr 2001;139:305-10.

11. Davies HD, McGeer A, Schwartz B et al. Invasive group A
streptococcal infections in Ontario, Canada. N Engl J Med 1996;335:547-54.

12. Wise RP, Salive ME, Braun MM et al. Postlicensure safety
surveillance for varicella vaccine. JAMA 2000;284:1271-79.

* Members: Dr. V. Marchessault (Chairperson), Dr. A. King (Executive Secretary), J. Rendall (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. P. Orr,
Dr. B. Ward, A. Zierler.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. V. Lentini (DND),Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. R. Massé (CCMOH), K. Pielak (CNCI), Dr. J. Salzman (CATMAT), Dr. L. Samson, (CPS), Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC),
Dr. A. McCarthy (CIDS).

Ex-Officio Representatives: Dr. L. Palkonyay (BGTD).

† This statement was prepared by Dr. Monika Naus and approved by NACI.

[Canada Communicable Disease Report]