Canada Communicable Disease Report
Vol. 24 (ACS-3)
15 August 1998

An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)*

STATEMENT ON JAPANESE ENCEPHALITIS VACCINE

Introduction

Japanese encephalitis (JE), the "Plague of the Orient", is the most important mosquito-borne viral encephalitis in Asia. Of the 45,000 cases reported per year, most are in young children and persons > 65 years of age^(1,2). The disease is rare in travellers. The annual incidence of disease in residents of endemic areas ranges from 1 to 10 per 10,000⁽³⁾. Table 1 lists countries where the disease occurs⁽⁴⁾.

Table 1 Risk of Japanese Encephalitis by Country, Region, and Season*

JE is caused by a flavivirus, which is most often transmitted by the night-time biting mosquito, Culex tritaeniorhynchus⁽⁵⁾. Infection rates in mosquitoes range from < 1% to 3%^(3,6). These mosquitoes breed mainly in rice fields some distance from human dwellings but have the ability to fly to inhabited areas to feed. Cases of JE have been reported from urban areas^(1,3,7,8). Wild and domesticated animals, such as pigs and birds, are the principal hosts for JE virus. Man is a dead-end host due to the short duration and the low titre of viremia⁽¹⁾.

Most infections do not result in illness. The ratio of apparent to inapparent infections is between 1:30 to 1:50⁽¹⁾. Children < 15 years of age are primarily affected, and seroprevalence studies indicate nearly universal exposure by adulthood^(3,7,9,10). The mortality rate of symptomatic disease is between 10% to 25%, depending on the level of supportive care. There is no known treatment^(1,7). Approximately 33% to 50% of survivors are left with permanent psychologic and neurologic sequelae^(1,5,7). The virus may infect the fetus transplacentally, resulting in abortion in the first and second trimesters^(1,7).

Transmission

Transmission may occur year-round, but epidemics usually begin during the rainy season when mosquito populations are maximal⁽¹⁾. In temperate regions, transmission tends to be between May and September. In sub-tropical and tropical areas, transmission is correlated with the abundance of mosquitoes and amplifying hosts, which fluctuate with the season, the amount of rainfall, and the migratory patterns of birds. Agricultural irrigation is also an important factor, as flooded rice fields are excellent breeding grounds⁽³⁾. The incidence of JE has been decreasing in China, Korea, and Japan but increasing in Bangladesh, Myanmar, India, Nepal, Northern Thailand, and Vietnam⁽¹⁾. Control measures include vector control, protection of animal reservoirs by screening of pig stalls, prevention of mosquito bites, and vaccination of both animals and humans⁽⁷⁾. Even in countries with high immunization rates and low rates of disease among residents, the virus can still be transmitted to travellers^(6,7). Table 1 describes the risk of JE by country, region, and season.

The risk of illness to most travellers is as low as 1 per million for short-term travel (< 4 weeks) depending on factors such as season, location, and duration of travel⁽³⁾. The risk to travellers to endemic areas can be extrapolated from incidence rates in the general population. For persons travelling to rural areas during the transmission season, the rate per month of exposure is 1 per 5,000^(3,6,10). In 1969, at least 10,000 Americans were infected in Vietnam, and 57 encephalitic cases were reported^(5,7). Twenty-four cases of JE have been reported in Western travellers from 1978 to 1992⁽³⁾.

Vaccination

The vaccine approved for use in Canada is an inactivated JE vaccine derived from infected neonatal mouse brain⁽³⁾. It has been licensed in Japan since 1954 and in Canada since March 1994. It is produced by The Research Foundation for Microbial Diseases of Osaka University (Biken) and distributed in Canada by Connaught Laboratories Ltd.⁽³⁾. Administration of JE vaccine does not change the rate of infection but protects against symptomatic disease⁽⁸⁾.

Randomized, placebo-controlled trials in Thai school children in 1984 indicated a vaccine efficacy of 91% (95% confidence interval- 70% to 97%) after two doses with no major side effects^(1,7). A large field trial in Taiwan in 1965 showed that two doses gave an efficacy of 80%, and a single dose had no demonstrable efficacy⁽³⁾. Three doses of vaccine are needed to provide adequate protective levels of neutralizing antibodies in non-immune vaccinees^(2,3).

The primary immunization series is three doses of vaccine, given at 0 time, 7 to 14 days, and 28 to 30 days after the first dose⁽¹⁾. The dose of the vaccine for children >= 3 years and adults is 1.0 mL subcutaneously. Children aged 1 to 2 years receive one-half the adult dose (0.5 mL). An accelerated series of three doses given at 0 time, 7 days, and 14 days can be used - if short of time - but the vaccine is more immunogenic when administered in three doses during a 30-day period than during a 2-week period^(2,3). The last dose of vaccine should be administered at least 10 days prior to travel to ensure an adequate immune response and access to medical care in the event of a delayed adverse reaction⁽¹⁾.

A recent study examining the persistence of JE virus neutralizing antibody concluded that antibody persists for at least 3 years following a primary three-dose series. In this small study, 94% of vaccinees had detectable antibodies that persisted to 3 years^(8,11). Booster doses may be given every 3 years if risk continues⁽⁴⁾. The booster dose is 1.0 mL for adults and 0.5 mL for children 1 to 2 years old.

Adverse reactions

Tenderness, redness, swelling, and other local effects have been reported in about 20% of vaccinees. Systemic side effects such as fever, headache, malaise, rash, chills, dizziness, myalgia, nausea, vomiting, and abdominal pains have been reported in about 10% of vaccinees^(3,6). Surveillance in Japan between 1965-1973 disclosed rare neurologic events such as encephalitis and encephalopathy at the rate of about 1 to 2.3 per million⁽³⁾. Since 1989, a new pattern of adverse reactions has been reported from Australia, Europe, and North America. These reactions are characterized by urticaria and angioedema of the extremities, face, and oropharynx. Most of these reactions have been treated successfully with antihistamines or oral steroids, but some patients required hospitalization for parenteral steroid therapy. Reactions after the first dose occurred at a median of 12 hours following vaccine whereas reactions after the second dose occurred at a median of 3 days post vaccination and as long as 2 weeks after vaccination⁽³⁾. A case-control study among U.S. military personnel found an association between reactions to JE vaccine and a past history of urticaria after hymenoptera envenomation, medications, physical or other provocations, and idiopathic causes⁽³⁾.

In two reports from travel clinics in Australia and Canada, these hypersensitivity reactions occurred at rates of 50 to 104 per 10,000 vaccinees⁽³⁾. In national surveillance from Denmark, Australia, the United Kingdom, and Sweden, rates of 0.7 to 12 per 10,000 were reported; the United States reported rates of 15 to 62 per 10,000⁽³⁾. A recent study in U.S. Marine Corps personnel examined 14,249 individuals who had received 36,850 doses of JE vaccine⁽¹²⁾. The reaction rates for doses 1, 2, and 3 were 16.1, 16.3, and 2.0 per 10,000 doses, respectively. Of the individuals who reacted, 68% had urticaria, 29% had pruritis alone, and 2.6% had wheezing alone. None of the reactions were life threatening. The variables associated with an increased likelihood of reacting to JE vaccine were pre-existing urticaria, rhinitis, asthma, and any allergy. Given the low probability of reacting to JE vaccine, a history of allergy should be considered a relative contraindication to vaccination⁽¹²⁾. The vaccine constituents responsible for these adverse events have not been identified⁽¹²⁾.

During administration of JE vaccine, epinephrine and other means to treat anaphylaxis should be available. The vaccinee should be watched for 30 minutes after vaccination and should be advised not to leave the country for 10 days after vaccination. Patients with an allergic history should be carefully counselled and advised to watch for signs and symptoms of an allergic reaction. There are no data supporting the efficacy of prophylactic antihistamine. Because this vaccine is produced in mouse brains, it should not be administered to persons with proven or suspected hypersensitivity to proteins of rodent or neural origin, nor should it be given to those with allergies to thimerosal.

There is no specific information on the safety in pregnancy. Vaccination is recommended when the theoretic risk of vaccine is outweighed by the risk of infection to the mother and fetus⁽³⁾.

No data exist about the safety and efficacy of JE vaccine in infants < 1 year of age⁽¹⁰⁾.

Data on the use of the vaccine in immunosuppressed states are limited. A small study of 139 children did not indicate a change in the pattern of adverse reactions or immune response after vaccine^(3,6).

No data exist on the effect of the concurrent administration of other vaccines, drugs, or biologics on the safety and immunogenicity of JE vaccine. Limited data suggest that immunogenicity is not compromised by the simultaneous administration of diphtheria, pertussis, and tetanus vaccine⁽³⁾. Vaccine should be refrigerated between 2^o C and 8^o C and not frozen at any time. It should be used within 8 hours of reconstitution⁽⁶⁾.

Recommendations for vaccination

Table 2 presents evidence-based medicine categories⁽¹³⁾ for the strength and quality of evidence for each of the recommendations that follow.

TABLE 2 Strength and quality of evidence - summary sheet

1. Personal protection measures (e.g. insect repellents containing DEET, treated bed nets, remaining in screened areas, light-coloured clothing covering the skin, avoiding perfumes and perfumed toiletries) to prevent mosquito bites are very effective at preventing arthropod-borne diseases and are recommended for all travellers to JE endemic and/or epidemic areas (AI).

2. JE vaccine is very efficacious in preventing encephalitis due to JE virus (AI). JE vaccine is indicated for

• travellers spending >= 1 month in rural parts of endemic areas during a period of transmission^(3,10) (CIII), and
• travellers spending < 1 month, if travel includes areas experiencing epidemic transmission and extensive outdoor activities, in rural areas⁽³⁾ (CIII).

3. These special factors should be considered when advising travelers. Advanced age may be a risk factor for development of symptomatic illness. Infection acquired during pregnancy carries the risk of intrauterine infection and fetal death⁽¹⁰⁾ (BII).

4. The risk to short-term travelers (< 1 month) and those who confine their travel to urban areas and resorts is extremely low. These individuals should not routinely be vaccinated (CIII).

References

1. Vaughn D, Hoke C. The epidemiology of Japanese encephalitis: prospects for prevention. Epidemiol Rev 1992;14:197-221.

2. Poland JD, Cropp CB, Craven RB et al. Evaluation of the potency and safety of inactivated Japanese encephalitis vaccine in U.S. inhabitants. J Infect Dis 1990;161:878-82.

3. CDC. Inactivated Japanese encephalitis virus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993;42(RR-1):1-15.

4. CDC. Specific recommendations for vaccination and prophylaxis, Japanese encephalitis. In: Health information for international travel 1996-97. Atlanta, GA: National Center for Infectious Diseases, Division of Quarantine, CDC, U.S. Department of Health and Human Services, 1996:112-16.

5. Monath P. Japanese encephalitis - a plague of the Orient. N Engl J Med 1988;10:641-43.

6. Fanning WL. Japanese encephalitis virus vaccine. J Travel Med 1996;3:57-59.

7. Thisyakora U, Thisyakora C, Wilde H. Japanese encephalitis and international travel. J Travel Med 1995;2:37-40.

8. Kozarsky P. Japanese encephalitis vaccine - for whom? Travel Med Advisor Update 1995;5:21-22.

9. World Health Organization. Japanese encephalitis. Wkly Epidemiol Rec 1994;69:113-120.

10. Keystone JS. Japanese encephalitis. Travel Med Advisor Update 1992;2;13-16.

11. Gambel JM, De Fraites R, Hoke C et al. Japanese encephalitis vaccine: persistance of antibody up to 3 years after a three dose primary series. J Infect Dis 1995;171:1974.

12. Berg SW, Mitchell BS, Hanson RK et al. Systemic reactions in U.S. Marine Corps personnel who received Japanese encephalitis vaccine. Clin Infect Dis 1997;24:265-66.

13. MacPherson DW. Evidence-based medicine. CCDR 1994;20:145-47.

Members: Dr. K. Kain (Chairman); H. Birk; Ms. M. Bodie-Collins (Executive Secretary); Dr. S.E. Boraston; Dr. H.O. Davies; Dr. K. Gamble; Dr. L. Green; Dr. J.S. Keystone; Dr. K.S. MacDonald; Dr. J.R. Salzman; Dr. D. Tessier.

Ex-Officio Members: Dr. E. Callary (HC); R. Dewart (CDC); Dr. E. Gadd (HC); Dr. C.W.L. Jeanes; Dr. H. Lobel (CDC); Dr. A. McCarthy (DND).

Liasion Representatives: Dr. R. Birnbaum (CSIH); Dr. S. Kalma (CUSO); Dr. V. Marchessault (CPS); Dr. H. Onyett (CIDS); Dr. R. Saginur (CPHA); Dr. F. Stratton (ACE); Dr. B. Ward (NACI).

[Canada Communicable Disease Report]