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Japanese encephalitis vaccine: Canadian Immunization Guide

For health professionals

Last complete chapter revision: September 2023

Recommendations for use of Japanese Encephalitis (JE) vaccine have been updated based on the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on Prevention of Japanese Encephalitis.

This information is captured in the table of updates.

On this page

Key Information

What

  • Japanese encephalitis (JE) is a disease caused by a mosquito-transmitted virus in parts of South Asia, Southeast Asia, East Asia and Oceania.
  • JE is rare among Canadian travellers. However, it is a severe disease with a high case fatality rate (approximately 20% to 30%). Further, many JE survivors (approximately 30% to 50%) suffer permanent cognitive, behavioural and/or neurological sequelae.
  • Travelling frequently and/or for an extended period to endemic regions, in particular if it involves significant exposure in rural areas, increases the likelihood of infection with the JE virus.
  • Travellers can reduce risk of JE in a number of ways, including by preventing mosquito bites and through the use of JE vaccine.
  • IXIARO® is the only JE vaccine authorized for use in Canada. A high rate of seroconversion (greater than 95%) is achieved with a two-dose primary series.
  • The most commonly reported adverse events following JE vaccination are injection site pain and tenderness, headache, myalgia and fatigue.

Who

  • JE vaccine should be considered for travellers who, by virtue of their itinerary, are believed to be at the highest risk for infection with the JE virus.
  • JE vaccine is authorized for use in persons aged 2 months of age and older.

How

  • The primary series consists of two separate doses provided 28 days apart.
    • Children aged 2 months to less than 3 years of age receive 0.25 mL per dose.
    • Individuals 3 years of age and older receive 0.5 mL per dose.
  • If time constraints preclude a 0 and 28-day schedule, an accelerated schedule (days 0 and 7) may be considered.
  • Booster doses may be considered for persons who are at continued risk for JE.

Why

  • Because JE is a rare disease among Canadian travellers, the expected benefit of receiving the vaccine is usually small and might be outweighed by expected harms (e.g., cost, inconvenience and adverse effects).
  • The absolute benefit of JE vaccine is likely higher for travellers who travel for a long period or take multiple trips to endemic areas and/or with extensive travel through rural areas.

Epidemiology

Disease description

Infectious agent

Japanese encephalitis (JE) is caused by a ribonucleic acid (RNA) virus from the family Flaviviridae. For additional information about the JE virus, refer to the Pathogen Safety Data Sheet.

Reservoir

The virus is primarily transmitted in an enzootic cycle that typically involves the Culex mosquito and wild birds. Spillover from this cycle, or from an epizootic cycle involving pigs as amplifying hosts can result in human infection.

Transmission

JE virus is transmitted to humans primarily through the bite of an infected mosquito. Mosquitoes acquire the virus from infected hosts (e.g., pigs and wild birds) and then transmit the virus to non-infected hosts (e.g., humans and horses). The principal vectors are Culex species mosquitoes that preferentially bite in the evening and night.

Larvae of Culex mosquitoes develop in standing water, such as rice fields. Thus, transmission of JE virus occurs primarily in rural agricultural areas where flooding irrigation is practiced; however, cases have been reported from urban areas.

Humans usually do not develop sufficient viremia to infect mosquitoes. Direct person-to-person spread of JE does not occur, except rarely, through intrauterine transmission. Blood transfusion and organ transplantation are possible modes of transmission based on experience with other Flaviviruses. The incubation period is 5 to 15 days.

Risk factors

A traveller's risk for developing JE is determined by multiple factors, including immunization status, use of protective measures against mosquito bites, location of travel, duration of exposure, season, and activities while travelling.  In general, the risk is extremely low for travellers, particularly for short-term visitors to major urban areas. Risk is thought to be relatively higher for those who:

  • Visit rural agricultural areas, especially those associated with rice production and flooding irrigation
  • Take multiple trips to and/or stay for extended periods in endemic regions
  • Participate in outdoor activities in rural areas, especially during the evening or night (when the mosquitoes are more active)

Based on available case reports, the overall risk of JE among Canadians travelling to endemic regions has been estimated to be approximately 1/10,000,000 trips. However, by virtue of their itinerary, it is expected that some travellers will be subject to a significantly higher relative risk. Refer to the CDC Yellow Book for an overview of countries with JE virus transmission.

Seasonal and temporal patterns

In most temperate areas of Asia, JE virus transmission exhibits a seasonal pattern typically starting in April or May and lasting until September or October. In the subtropics and tropics, transmission patterns vary and cases can occur sporadically or year-round but often increase rapidly during the rainy season.

Spectrum of clinical illness

Most JE infections are asymptomatic, with less than 1% of people infected with JE virus developing clinical disease. Acute encephalitis is the most commonly identified clinical syndrome, which is associated with 20% to 30% mortality rates, and 30 to 50% permanent cognitive, behavioural and/or neurological problems among survivors. JE acquired during pregnancy carries the risk of intrauterine infection and miscarriage. There is no antiviral treatment for JE; management consists of supportive care and long term support for those who suffer permanent sequelae.

Disease distribution

Incidence and prevalence

Global

JE occurs in parts of South Asia, Southeast Asia, East Asia and Oceania. The World Health Organization (WHO) estimates that more than 68,000 cases and up to 20,000 deaths occur annually. Risk varies between and within countries, from year to year and by season. For residents of endemic areas without a vaccination program, the burden disproportionately falls upon children living in rural areas. Travellers of all ages are potentially at risk and because the disease is zoonotic, risk is present even if disease among local residents has been controlled through immunization.

National

To date, there has been one confirmed case (2010) and one possible case (1982) of JE reported among Canadians returning from Asia.

Preparation Authorized for Use in Canada

Japanese encephalitis vaccine

  • IXIARO®: inactivated, Japanese encephalitis vaccine, Vero cell culture-derived, adsorbed. Valneva Austria GmbH, (JE)

For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.

Refer to Table 1 in Contents of Immunizing Agents Authorized for Use in Canada in Part 1 for a list of all vaccines authorized for use in Canada and their contents.

Immunogenicity, efficacy and effectiveness

Immunogenicity

A single dose of JE vaccine induces sufficient protective antibodies in 30% of vaccine recipients 10 days after vaccination and in 40% of vaccine recipients 28 days post-vaccination. A second dose of vaccine given 28 days after the first dose induces antibodies in more than 95% of vaccine recipients. The immunogenicity of the vaccine is lower in adults over 65 years of age, with seroconversion occurring in approximately 65% of vaccine recipients. The immunogenicity of the accelerated schedule (i.e., doses given at 0 and 7 days) has been demonstrated to be non-inferior to the regularly-dosed primary series. Vaccination with two doses of vaccine at the same time has been shown to increase the seroconversion rate to approximately 60% at 10 days post-vaccination.

Protective antibody concentrations decline over time with 80% to 95% of fully immunized vaccine recipients maintaining an adequate concentration at 6 months after the first dose and 58% to 83% maintaining adequate antibodies at 12 to 15 months after the first dose. A booster dose of vaccine following a recommended primary series induces an adequately protective boost to antibody concentration in those who have lost protective antibodies at 12 months after their first dose.

Efficacy and effectiveness

No efficacy or effectiveness data exist for the Vero cell culture-derived JE vaccine, IXIARO®. IXIARO® was authorized for use based on non-inferiority of serologic response compared to the previous mouse brain-derived JE vaccine and to the WHO threshold for protective antibody titre.

Recommendations for use

Travellers

JE vaccine should only be considered for individuals 2 months and older who are at increased risk of disease. JE vaccine should not be routinely recommended for persons travelling to endemic areas without identified risks. Refer to Risk factors for more information.

For optimal protection, the immunization series should ideally be completed at least 7 days before an individual travels to an area where there is a potential for exposure to JE virus to develop an adequate antibody response. However, this advice should not discourage use where timelines are shorter and the vaccine is indicated/desired by the traveller.

All travellers to JE endemic areas should be advised to use measures to protect themselves against mosquito bites which will also provide protection against other mosquito-borne diseases such as dengue and malaria.

Refer to the CDC Yellow Book for an overview of countries with JE virus transmission.

For detailed information on vaccine recommendations and alternative preventive strategies for prevention of JE refer to the CATMAT Statement on Prevention of Japanese Encephalitis.

Recommended schedule

Infants and children (2 months to less than 18 years)

The primary series for children 2 months to less than 3 years of age consists of two separate 0.25 mL doses; for children 3 years of age to less than 18 years, two separate 0.5 mL doses. The doses should be provided on day 0 and day 28.

Adults (18 years of age and older)

The primary series for adults consists of two separate 0.5 mL doses on day 0 and day 28. An accelerated schedule (days 0 and 7) can be used for adults aged 18 to 65 years if there is insufficient time to provide the vaccine in accordance with the recommended primary schedule.

In situations where there is insufficient time to provide a recommended or an accelerated schedule, a single dose of JE vaccine can be considered. Alternatively, simultaneous administration of two doses of JE vaccine (provided at separate injection sites) may also be considered as this approach has been shown to lead to higher seroconversion rates in adults compared to a single dose. However, protection is probably less effective than the standard schedule. Refer to Immunogenicity for more information.

Booster doses and re-immunization

A single booster dose of JE vaccine can be administered 12 to 24 months after the primary series to individuals who remain at risk and desire vaccine-induced protection. For adults 65 years and older, a single booster dose should be considered earlier (before 12 months) following the primary series. A second booster can be considered for persons who remain at risk for JE if more than 10 years have elapsed since the first booster.

Vaccination of specific populations

Pregnancy and breastfeeding

There are no data related to safety or efficacy of JE vaccine in pregnant or breastfeeding women. Pre-clinical studies of JE vaccine in pregnant rats did not indicate evidence of harm to the fetus or adverse effects with respect to fertility or pregnancy outcomes.

JE acquired during pregnancy carries the risk of intrauterine infection and miscarriage. Pregnant or breastfeeding women who must travel to areas where the risk of JE infection is high should be immunized as the risk of disease outweighs the unknown risk of vaccination.

Refer to Immunization in Pregnancy and Breastfeeding in Part 3 for additional general information.

Immunocompromised persons

If travel must be undertaken, immunocompromised persons may be immunized with JE vaccine; however, the antibody response may be suboptimal and the person should be advised to be diligent about mosquito protection measures. Booster immunizations should be considered earlier, if needed, as the duration of protection may also be much shorter. When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.

Refer to Immunization of Immunocompromised Persons in Part 3 for additional general information.

Workers

Laboratory personnel who work with JE virus should receive JE vaccine. Laboratory workers at continuous risk for acquiring JE should receive a booster dose 12 months after primary immunization. Refer to Booster doses and re-immunization for more information.

As with other travellers, healthcare providers working abroad should be considered for JE vaccination if they, by virtue of their itinerary, are believed to be at high risk for infection. Refer to Risk factors for more information.

Refer to Immunization of Workers in Part 3 for additional general information.

Serologic testing

Serologic testing is not recommended before or after receiving JE vaccine.

Administration practices

Dose and route of administration

Dose

Each dose of JE vaccine is 0.25 mL for infants and children aged 2 months to less than 3 years and 0.5 mL for individuals 3 years of age or older.

Route of administration

JE vaccine should be administered intramuscularly. Refer to Vaccine Administration Practices in Part 1 for general information on administration technique and infection prevention and control.

Interchangeability of vaccines

There are no data available regarding interchangeability of the currently available Vero cell culture-derived JE vaccine (IXIARO®) with the previous mouse brain-derived JE vaccine or other JE vaccines available internationally, either in primary series or in booster dosing. Refer to Principles of Vaccine Interchangeability in Part 1 for additional general information.

Concurrent administration with other vaccines

Data are limited regarding the safety and immunogenicity of JE vaccine when given concomitantly with other vaccines. In general, inactivated vaccines, such as JE vaccine, can be given concurrently with any other vaccine using different injection sites and separate needles and syringes. JE vaccine has been given concomitantly with hepatitis A vaccine without significant interference with safety and immunogenicity. Similarly, there was no interference with the immune response when JE vaccine was administered concomitantly with rabies vaccine. There are no data available regarding possible interference between JE vaccine and yellow fever vaccine.

Refer to Timing of Vaccine Administration in Part 1 for additional general information.

Storage Requirements

JE vaccine should be stored in a refrigerator at +2°C to +8°C. Do not freeze. Protect from light. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional general information.

Safety and Adverse Events

Refer to Vaccine Safety and Pharmacovigilance in Part 2 for additional information on vaccine safety.

Common and very common adverse events

Common adverse events occur in 1% to less than 10% of vaccine recipients. Very common adverse events occur in 10% or more of vaccine recipients.

Infants and children 2 months to less than 3 years of age

Most commonly reported adverse reactions in infants and children 2 months to less than 3 years of age included fever (28.5%), diarrhea (11.9%), influenza like illness (10.9%), irritability (10.9%), decreased appetite (8.2%) and vomiting (7.3%). Injection site reactions such as tenderness (4.2%), swelling (3.6%) and hardening (1.2%) have also been reported.

Children and adolescents 3 years to less than 18 years of age

Most commonly reported adverse reactions in children and adolescents 3 to less than 18 years of age included injection site reactions such as tenderness (14.7%), fever (10.4%), myalgia (7.1%), headache (6.1%), and fatigue (3.5%).

Adults (18 years of age and older)

Most commonly reported adverse reactions in adults included headache (20% of subjects) myalgia (13%), fatigue (12.9%), injection site pain (33%) and injection site tenderness (33%).

Uncommon, rare and very rare adverse events

Uncommon adverse events occur in 0.1% to less than 1% of vaccine recipients. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccine recipients.

Serious adverse events following immunization may occur in less than 0.01% vaccine recipients and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with JE vaccine may occur in less than 0.01% of vaccine recipients.

No pattern of serious hypersensitivity, neurologic or other adverse events considered to be related to JE vaccine has been identified in the U.S. post market surveillance data. In two analyses of AE reported to the US Vaccine Adverse Event Reporting System (VAERS) following administration of IXIARO® with or without other vaccines; hypersensitivity events were reported at rates of 3.0 and 4.4 per 100,000 doses distributed, and 56% (20 of 36) occurred after concomitant administration of JE vaccine with other vaccines. Neurologic events were reported at rates of 2.2 and 1.2 events per 100,000 doses distributed. The neurologic adverse event reports included four reports of seizures which all occurred after administration of JE vaccine with other vaccines. VAERS data cannot generally be used to determine causality, especially with concomitant administration of vaccines.

Guidance on reporting Adverse Events Following Immunization (AEFI)

To ensure the ongoing safety of vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.

Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.

For additional information about AEFI reporting, please refer to Adverse Events Following Immunization in Part 2 and Reporting Adverse Events Following Immunization (AEFI) in Canada.

Contraindications and precautions

JE containing vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Table 1 in Contents of Immunizing Agents Authorized for Use in Canada in Part 1 for a list of immunizing agents authorized for use in Canada and their contents.

Administration of JE containing vaccine should be postponed in persons suffering from severe acute illness. Immunization should not be delayed because of minor or moderate acute illness, with or without fever. Refer to Contraindications and Precautions in Part 2 for additional general information.

Chapter revision process

This chapter was reviewed and updated based on the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on Prevention of Japanese Encephalitis. CATMAT recommendations on the prevention of Japanese encephalitis were developed using the GRADE process or were informed by literature reviews and expert opinion.

Acknowledgements

The Public Health Agency of Canada (PHAC) would like to acknowledge the contributions of CATMAT members M Libman, P Lagacé-Wiens, J Pernica, K Plewes, SW Schofield, S Vaughan, and PHAC participants N Mohamed, L Coward, C Jensen, O Baclic, J Zafack and E Abrams.

Selected references

  • Campbell GL, Hills SL, Fischer M, Jacobson JA, Hoke CH, Hombach JM, et al. Estimated global incidence of Japanese encephalitis: a systematic review. Bull World Health Organ 2011;89(10):766-774.
  • Centers for Disease Control and Prevention (CDC). Japanese encephalitis: CDC Yellow Book 2024 [Internet]. 2023 May 1 [cited 2023 Jul 28]. Available at: https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/japanese-encephalitis
  • Centers for Disease Control and Prevention (CDC). Use of Japanese encephalitis vaccine in children: Recommendations of the advisory committee on immunization practices, 2013. MMWR Morb Mortal Wkly Rep 2013;62(45):898-900.
  • Centers for Disease Control and Prevention (CDC). Japanese Encephalitis Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59(RR01):1-27.
  • Centers for Disease Control and Prevention (CDC). Japanese Encephalitis Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2019; 68(2);1–33. 
  • Centers for Disease Control and Prevention (CDC). Recommendations for use of a booster dose of inactivated vero cell culture-derived Japanese encephalitis vaccine: advisory committee on immunization practices, 2011. MMWR Morb Mortal Wkly Rep 2011;60(20):661-663.
  • Centers for Disease Control and Prevention (CDC). Grading of recommendations, assessment, development, and evaluation (GRADE) for use of inactivated Vero cell culture-derived Japanese encephalitis vaccine in children; 2014. Accessed May 16, 2016 at:  https://www.cdc.gov/vaccines/acip/recs/grade/je-child.html.
  • Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on Prevention of Japanese Encephalitis. 2019. Accessed January 2020 at: https://www.canada.ca/en/public-health/services/catmat/statement-prevention-japanese-encephalitis.html
  • Fischer M, Lindsey N, Staples JE, Hills S, Centers for Disease Control and Prevention (CDC). Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report. Recommendations & Reports 2010;59(RR-1):1-27.
  • Halstead SB, Jacobson J, Dubischar-Kastner K. Japanese encephalitis vaccines. In: Plotkin S, Orenstein WA, Offit P, editors. Vaccines. 6th ed. China: Elsevier Saunders; 2013. p. 312-351.
  • Valneva Austria GmbH. IXIARO® Product Monograph. 2018.
  • World Health Organization (WH). Japanese Encephalitis Vaccines: WHO position paper - February 2015. Weekly Epidemiological Record 2015;9(90):69-88.

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