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Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Japanese Encephalitis Vaccine

Introduction

Japanese encephalitis (JE) virus is the leading cause of viral encephalitis in Asia, where more than 50,000 cases occur each year. Clinically apparent infection with JE virus is seen only rarely in travellers. Countries where the disease occurs are listed in Table 8. The incidence of JE varies widely from year to year and between regions within countries. JE virus is an arthropod-borne flavivirus, a group that also includes yellow fever virus, West Nile virus and St. Louis encephalitis virus. The principal vectors are Culex mosquitoes that breed mainly in rice fields. Swine and certain species of wild birds are intermediate hosts in the transmission cycle. Conditions that support transmission of JE virus are primarily rural agricultural ones, but occasionally cases are reported from urban areas. Culex mosquitoes tend to bite in the evening and night, but day-biting species predominate in some regions.

There are no key changes in the recommendations for JE immunization since the publication of the 2002 Canadian Immunization Guide.

Epidemiology

The disease occurs in epidemic form in temperate and northern tropical regions and is endemic in southern tropical regions of Asia. Cases occur chiefly during the summer and autumn in temperate zones and during the rainy season in tropical zones. In areas where irrigation is the main factor affecting the abundance of vector mosquitoes, transmission may occur year round. For these reasons, the periods of greatest risk for JE virus transmission to travellers are highly variable and depend on such factors as season, location, duration of stay and the type of activities undertaken. Crude estimates for North Americans travelling to Asia place the overall risk of JE illness at less than 1 per million. However, for travellers to rural areas during the transmission season, the risk per month of exposure can be as high as 1 per 5,000. Rare case reports suggest that even short-term, resort-based travellers can occasionally contract JE.

The risk of JE transmission to the traveller may be significantly reduced by the appropriate use of bednets, repellents and protective clothing.

Most JE infections do not result in obvious illness. Between 50 and 300 infections occur for each clinical case identified. However, when encephalitis does occur, it is usually severe, with 10% to 25% mortality rates and residual neuropsychiatric problems in 50% of survivors.

The disease usually affects children, but in countries where it has been recently introduced all age groups may be affected. In addition to children < 10 years of age, advanced age may be a risk factor for developing symptomatic illness.

Japanese encephalitis acquired during pregnancy carries the risk of intrauterine infection and miscarriage.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada

  • JE-VAX® (Japanese encephalitis vaccine), Sanofi Pasteur Ltd. (distributor)

This vaccine is a highly purified, formalin-inactivated vaccine derived from mouse brain. The vaccine is based upon the Nakayama-INH strain; it is produced by the Research Institute of Osaka University (Biken) and distributed by Sanofi Pasteur Ltd. (Canada). The vaccine contains thimerosal as a preservative and other minor components.

Table 8. Areas where Japanese Encephalitis Has Been Recognized and Season of Epidemic Risk

Zone Country
Temperate regions
(Risk greatest July to October)
Bangladesh
China
Northern India
Japan
Kampuchea
Korea
Laos
Myanmar
Nepal
Far Eastern Russia
Northern Thailand
Northern Vietnam
Tropical regions
(Risk greatest during the rainy season.
Note that the rainy season varies some what from region to region
but is typically May to November)
Southern India
Pakistan
Indonesia
Malaysia
Philippines
Sri Lanka
Taiwan
Southern Thailand
Southern Vietnam

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

The vaccine has been widely used in Asian countries such as Japan, where JE vaccine has been approved since 1954. In a study of children in Northern Thailand, JE vaccine was demonstrated to have an efficacy of 91% (95% confidence interval 70%-97%) after two doses of vaccine. Another field trial demonstrated that less than 80% of vaccinees developed neutralizing antibody after two doses of vaccine, as compared with 99% after three doses. Some studies have demonstrated higher geometric mean titres in Asian compared to non-Asian subjects after vaccination; this may reflect prior exposure to JE or other flaviviruses circulating in Asia. In summary, immunogenicity studies indicate that three doses of JE vaccine are needed to provide adequate protective levels of antibodies in non-immune vaccinees. As vaccine efficacy is never 100%, all travellers should be advised to take personal protective measures against mosquito bites.

Recommended usage

The vaccine is indicated for active immunization against JE for people ≥ 1 year of age who will spend 1 month or more in rural areas in endemic or epidemic areas during the transmission season or in urban areas if the urban area is part of the endemic or epidemic area, especially if travel will include rural areas. However, there have been several reports of JE in short-term travellers to endemic regions. Immunization should therefore be considered for some people spending < 30 days in endemic areas, e.g., travellers to areas where there is epidemic activity, travellers making repeated short trips, or those with extensive outdoor rural exposure.

Immunization is recommended for all laboratory personnel working with JE virus.

Schedule and dosage

A series of three 1.0 mL doses is given on days 0, 7 and 30. When time does not permit, these may be administered on days 0, 7 and 14, but the antibody response to this accelerated schedule is lower and may not be as durable. Two doses of vaccine 7 to 14 days apart can provide reasonable protection (80% efficacy) for short periods of time (< 1 year).

Route of administration

The vaccine should be administered subcutaneously.

Booster doses and re-immunization

No definitive recommendation can be made regarding the timing of booster doses in travellers. In a study of a small number of adults, protective titres of neutralizing antibodies persisted for 3 years after primary immunization. No pediatric data are currently available. Booster doses of 1.0 mL (0.5 mL for children < 3 years) are generally recommended at intervals of 3 years.

Serologic testing

There is no indication for pre- or post-immunization serology.

Storage requirements

The lyophilized preparation should be stored at +2° C to +8° C. After reconstitution, the vaccine should be stored at a temperature between +2° C and +8° C and used within 8 hours.

Simultaneous administration with other vaccines

There are only limited data on the safety and immunogenicity of JE vaccine when given concurrently with other vaccines, drugs, or biologics. As a general rule, given that JE is an inactivated vaccine, it can be given simultaneously with any other vaccine.

Adverse reactions

Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.

JE vaccine has been associated with injection site tenderness, redness and swelling. Other local effects have been reported in an average of 20% of vaccinees (range < 1% to 31%). Systemic side effects, principally fever, headache, malaise, rash and other reactions such as chills, dizziness, myalgia, nausea, vomiting and abdominal pain, are reported in 5% to 10% of vaccinees.

In an immunization program for US military personnel in Okinawa, an over-all reaction rate of 62.4 per 10,000 vaccinees occurred, including reports of urticaria, angioedema, generalized itching and wheezing. These reactions were generally mild to moderate in severity. Nine out of 35,253 people who had been immunized were hospitalized, primarily to allow administration of intravenous steroids for refractory urticaria. None of these reactions was considered life-threatening. A more recent study of 14,249 U.S. military personnel (36-850 doses of vaccine) demonstrated overall reaction rates of 16/10,000 for the first two doses and only 2/10,000 for the third dose.

A Danish case control study in travellers suggests an overall risk of about 1/10,000 doses for allergic-type responses.

In the late 1980s and early 1990s, an apparent increase in the incidence of delayed systemic hypersensitivity reactions was reported in several developed countries. The reactions were characterized by urticaria, often in a generalized distribution, and/or angioedema of the extremities, face and oropharynx, especially of the lips. Distress or collapse due to hypotension or other causes led to hospitalization in several cases. Most of the reactions reported have been treated successfully with antihistamines and steroids given either orally or parenterally. Some individuals have complained of generalized itching without evidence of a rash. No deaths related to delayed hypersensitivity reactions to JE vaccine have been reported. An important feature of these reactions is the interval between immunization and onset of symptoms.

Delayed hypersensitivity reaction after a first dose of vaccine occurs a median of 12 hours after immunization; 88% of reactions occur within 3 days. The interval between a second dose and onset of symptoms is generally longer (median 3 days) and as long as 2 weeks. Reactions can occur after a second or third dose when preceding doses were received uneventfully.

Overall, the delay between vaccination and the onset of the delayed hypersensitivity reaction is less than 6 days in 80%-90% of cases. However, in a small minority of cases, a delay of 10-14 days has been reported.

Data on U.S. military personnel and Danish travellers suggest that the risk of developing a systemic allergic reaction is greater in younger subjects, women and those with a history of allergy (e.g., urticaria, allergic rhinitis, asthma), particularly to other immunizing agents. Post-marketing surveillance suggests that such late reactions continue to occur at a rate of approximately 6.3/100,000 doses in the United States. The vaccine constituents responsible for the late hypersensitivity syndrome have not been identified, although reactions to gelatin have been implicated in some cases.

Severe neurologic adverse effects such as encephalitis or encephalopathy have been reported after JE immunization but are very rare (approximately 0.2/100,000 doses in Japanese vaccine recipients and possibly fewer in North American vaccinees).

Contraindications and precautions

Allergic reactions (generalized urticaria or angioedema) to a previous dose of vaccine are contraindications to further doses. Possible allergic reactions exhibited as generalized urticaria and angioedema may occur after minutes or be delayed as long as 14 days after immunization. Most allergic reactions occur within 10 days, the majority occurring within 48 hours. Vaccinees should be observed for 30 minutes after immunization and warned against the possibility of delayed urticaria and angioedema of the face and airway. Ideally, vaccinees should not embark on international travel within 10 days of immunization because of the possibility of delayed allergic reactions. If travel must occur in less than 10 days from the time of vaccination, the benefits of vaccination must be weighed against the risk of a delayed allergic reaction.

JE vaccine is produced in mouse brains and therefore in individuals with known hypersensitivity to proteins of rodent or neural origin, a referral to an allergist is recommended to assess whether JE vaccine can safely be administered. JE vaccine should not be given to people with known hypersensitivity to any component of the vaccine.

A history of urticaria or angioedema particularly after other immunizing agents should be considered when weighing the risks and benefits of the vaccine for an individual patient.

Pregnancy and breastfeeding

There are no data that show whether JE vaccine can cause fetal harm when administered to a pregnant woman. Pregnant women who must travel to areas where the risk of JE infection is high should be immunized when the theoretic risks of immunization are outweighed by the risk of infection to the mother and developing fetus.

Although there are no data, breast-feeding is not considered a contraindication to JE vaccine.

Use in immunocompromised persons

People undergoing immunosuppressive therapy are likely to have a poor immune response to vaccines in general and killed vaccines in particular. JE immunization should be deferred, if possible, while patients are receiving such therapy. If travel must be undertaken, such patients may be immunized as already outlined, with the understanding that the antibody response may be suboptimal.

Selected references

Andersen MM, Ronne T. Side-effects with Japanese encephalitis vaccine. Lancet 1991;337(8748):1044.

Berg SW, Mitchell BS, Hanson RK et al. Systemic reactions in US Marine Corps personnel who received Japanese encephalitis vaccine. Clinical Infectious Diseases 1997;24(2):265-66.

Centers for Disease Control and Prevention. Inactivated Japanese encephalitis virus vaccine: recommendations of the Immunization Practices Advisory Committee (ACIP). Morbidity and Mortality Weekly Report 1993;42(RR-l):1-15.

Chambers TJ, Tsai TF, Pervikov Y et al. Vaccine development against dengue and Japanese encephalitis: report of a World Health Organization meeting. Vaccine 1997;15(14):1494-1502.

Defraites RF, Gambel JM, Hoke CH et al. Japanese encephalitis vaccine (inactivated, Biken) in US soldiers: immunogenicity and safety of vaccine administered in two dosing regimens. American Journal of Tropical Medicine and Hygiene 1999;61(2):288-93.

Gambel JM, DeFraites R, Hoke C. Jr et al. Japanese encephalitis vaccine: persistence of antibody up to 3 years after a three-dose series. Journal of Infectious Diseases 1995;171(4):1074.

Hoke CH, Nisalak A, Sangawhipa N et al. Protection against Japanese encephalitis by inacti vated vaccines. New England Journal of Medicine 1988;319(10):608-14.

Jelinek T, Nothdurft HD. Japanese encephalitis vaccine in travellers. Is wider use prudent? Drug Safety 1997;16(3):153-6.

Kurane I, Takasaki T. Immunogenicity and protective efficacy of the current inactivated Jap anese encephalitis vaccine against different Japanese encephalitis virus strains. Vaccine 2000;18(S2):33-5.

Liu Z-L, Hennessy S, Strom BL et al. Short-term safety of live attenuated Japanese encephalitis vaccine: results of a randomized trial with 26,239 subjects. Journal of Infectious Diseases 1997;176(5):1366-69.

Plesner AM, Arlien-Soborg P, Herning M. Neurological complications to vaccination against Japanese encephalitis. European Journal of Neurology 1998;5(5):479-85.

Plesner A, Ronne T, Wachmann H. Case-control study of allergic reactions to Japanese encephalitis vaccine. Vaccine 2000;18(17):1830-36.

Poland JD, Cropp CB, Craven RB et al. Evaluation of the potency and safety of inactivated Japanese encephalitis vaccine in U.S. inhabitants. Journal of Infectious Diseases 1990;161(5):878-82.

Robinson HC, Russell ML, Csokonay WM. Japanese encephalitis vaccine and adverse effects among travellers. Canadian Disease Weekly Report 1991;17(32):173-77.

Ruff TA, Eisen D, Fuller A et al. Adverse reactions to Japanese encephalitis vaccine. Lancet 1991;338(8771):881-82.

Sakaguchi M, Yoshida M, Kuroda W et al. Systemic immediate-type reactions to gelatin included in Japanese encephalitis vaccines. Vaccine 1997;15(2):121-22.

Takahashi H, Pool V, Tsai TF et al. Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. Vaccine 2000;18(26):2963-69.

Tsai TF. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13-15 October 1998. Vaccine 2000;18(S2):1-25.

Tsarev SA, Sanders ML, Vaughn DW et al. Phylogenetic analysis suggests only one serotype of Japanese encephalitis virus. Vaccine 2000;18(S2):36-43.

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