Marc Fischer, Anne Griggs, J. Erin Staples

Infectious Agent

Japanese encephalitis virus (JEV) is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to West Nile and St. Louis encephalitis viruses.

Mode of Transmission

• JEV is transmitted to humans through the bite of an infected mosquito, primarily Culex species. Wading birds are the main animal reservoir for the virus, but the presence of pigs greatly amplifies the transmission of JEV.
• Humans are a dead-end host in the JEV transmission cycle.

Occurrence

• JEV is the most common cause of encephalitis in Asia, occurring throughout most of Asia and parts of the western Pacific (Map 2-5). JEV has not been locally transmitted in Africa, Europe, or the Americas.
• JEV transmission principally occurs in rural agricultural areas, often associated with rice production and flooding irrigation. In some areas of Asia, these ecologic conditions may occur near or occasionally within urban centers.
• In temperate areas of Asia, transmission is seasonal, and human disease usually peaks in summer and fall. In the subtropics and tropics, seasonal transmission varies with monsoon rains and irrigation practices and may be extended or even occur year-round.
• In endemic countries, JE is primarily a disease of children. However, travel-associated JE can occur among persons of any age.

Risk for Travelers

• The risk for JE for most travelers to Asia is extremely low but varies according to season, destination, duration, and activities. Fewer than 40 cases of confirmed JE have been reported in travelers in the last 40 years.
• The overall incidence of JE reported among people from nonendemic countries traveling to Asia is <1 case per 1 million travelers. However, expatriates and travelers staying for prolonged periods in rural areas with active JEV transmission are likely at similar risk as the susceptible resident population (0.1–2 cases per 100,000 persons per week).
• Travelers on even brief trips are probably at increased risk if they have extensive outdoor or nighttime exposure in rural areas, including persons staying in resort areas or with family.
• Short-term travelers whose visits are restricted to major urban areas are at very minimal risk for JE.
• In endemic areas where there are few human cases among residents because of vaccination or natural immunity, JEV is often maintained in an enzootic cycle between animals and mosquitoes. Therefore, susceptible visitors still may be at risk for infection.

Clinical Presentation

• Most human infections with JEV are asymptomatic; <1% of people infected with JEV develop clinical disease.
• Acute encephalitis is the most commonly recognized clinical manifestation of JEV infection. Milder forms of disease such as aseptic meningitis or undifferentiated febrile illness can also occur.
• The incubation period is 5–15 days. Illness usually begins with sudden onset of fever, headache, and vomiting. Mental status changes, focal neurologic deficits, generalized weakness, and movement disorders may develop over the next few days.
  • A parkinsonian syndrome resulting from extrapyramidal involvement is a very distinctive clinical presentation of JE.
  • Acute flaccid paralysis, with clinical and pathological features similar to poliomyelitis, has also been associated with JEV infection.
  • Seizures are very common, especially among children.
• Clinical laboratory findings include moderate leukocytosis, mild anemia, hyponatremia, and cerebrospinal fluid (CSF) pleocytosis with a lymphocytic predominance.
• Case–fatality ratio is approximately 20%–30%. Among survivors, 30%–50% may still have significant neurologic or psychiatric sequelae, even years after their acute illness.

Diagnosis

• JE should be suspected in a patient with evidence of a neurologic infection (e.g., encephalitis, meningitis, or acute flaccid paralysis) who has recently traveled or resided in an endemic country in Asia or the western Pacific.
• Laboratory diagnosis of JEV infection should be performed by using JE-specific IgM-capture enzyme-linked immunosorbent assay (ELISA) on CSF or serum. JE-specific IgM antibodies will be present in the CSF or blood of almost all patients by 7 days following onset of symptoms. A fourfold or greater rise in JEV-specific neutralizing antibodies between acute- and convalescent-phase serum specimens may be used to confirm the diagnosis.
• Vaccination history, date of onset of symptoms, and information regarding other flaviviruses known to circulate in the geographic area that may cross-react in serologic assays need to be considered when interpreting results.
• Humans have low levels of transient viremia and usually have neutralizing antibodies by the time distinctive clinical symptoms are recognized. Virus isolation and nucleic-acid amplification tests (NAATs) are insensitive for the detection of JEV or JE viral RNA in blood or CSF and should not be used for ruling out a diagnosis of JE.
• Health-care providers should contact their state or local health department or CDC’s Division of Vector Borne Infectious Diseases at 970-221-6400 for assistance with diagnostic testing.

Treatment

There is no specific antiviral treatment for JE; therapy consists of supportive care and management of complications.

Preventive Measures for Travelers

Personal Protection Measures

• No drugs for preventing JEV infection are available.
• The best way to prevent mosquito-borne diseases, including JE, is to avoid mosquito bites (see the Protection Against Mosquitoes, Ticks, and Other Insects and Arthropods section later in this chapter).

JE Vaccines

• An inactivated mouse brain-derived JE vaccine (JE-VAX, manufactured by sanofi pasteur) has been licensed for use in adult and pediatric travelers (≥1 year of age) in the United States since 1992. Although production of JE-VAX was discontinued in 2006, stockpiles of the vaccine will be used for U.S. travelers until they are depleted.
• An inactivated cell culture-derived JE vaccine (IXIARO, manufactured by Intercell) was approved for adult travelers (≥18 years of age) in the United States on March 30, 2009. Recommendations for its use will be available at www.cdc.gov/travel. Other inactivated and live attenuated JE vaccines are manufactured and used in Asia but not licensed for use in the United States.

Inactivated Mouse Brain-Derived JE Vaccine (JE-VAX)

• A randomized controlled trial among 65,000 children in Thailand showed an efficacy of 91% (95% CI 70%–97%) after two doses.
• From 88% to 100% of adults from nonendemic settings developed neutralizing antibodies after receiving three doses of vaccine.
• The duration of protection after primary immunization is unknown, but circulating neutralizing antibodies appear to last for at least 2–3 years.
• Booster doses produce an anamnestic response in neutralizing antibody titers.

Recommendations for the Use of JE Vaccine for Travelers

• Decisions regarding the use of JE vaccine for travelers must balance the low risk for disease and the small chance of an adverse event following immunization.
• The U.S. Advisory Committee on Immunization Practices (ACIP) currently recommends JE vaccine for travelers who plan to spend a month or longer in endemic areas or areas with ongoing transmission. Vaccine should also be considered for shorter-term travelers whose itineraries may put them at increased risk for JEV exposure, such as rural stays during the rainy season.
• Evaluation of an individual traveler’s risk should take into account itinerary, activities, and best-available information on the current level of JE activity in the travel area (Table 2-15). Complicating the concept of risk assessment, however, is the fact that sporadic cases of JE have very rarely occurred in travelers whose itineraries would not ordinarily have indicated a risk for JE (e.g., a resort hotel in Bali, a standard tour of China).

Vaccine Safety and Adverse Events

• Inactivated mouse brain-derived JE vaccine has been associated with localized erythema, tenderness, and swelling at the injection site in about 20% of recipients.
• Mild systemic side effects (e.g., fever, chills, headache, rash, myalgia, gastrointestinal symptoms) have been reported in approximately 10% of vaccinees.
• Serious allergic hypersensitivity reactions, including generalized urticaria and angioedema of the extremities, face, and oropharynx, have been reported. Accompanying bronchospasm, respiratory distress, and hypotension have been observed in some of these patients, although there have been no fatalities among vaccine recipients with these symptoms.
• Estimates of the frequency of these reactions range from 20 to 600 cases per 100,000 vaccinees and vary by country, year, case definition, surveillance method, and vaccine lot.
• Most hypersensitivity reactions occur within 24–48 hours after the first dose, when they occur following a subsequent dose, the onset of symptoms is often delayed (median: 3 days; range: up to 2 weeks).
• Most reactions can be treated with antihistamines or corticosteroids on an outpatient basis; however, up to 10% of vaccinees with rare severe reactions are hospitalized.
• At least four deaths due to anaphylactic shock temporally associated with receipt of this vaccine have been reported in the world literature, which includes endemic country national vaccine programs. None of these patients had evidence of urticaria or angioedema, and two had received other vaccines simultaneously.
• Moderate to severe neurologic symptoms, including encephalitis, seizures, gait disturbances, and parkinsonian syndrome have been reported, with an incidence of 0.1 to 2 cases per 100,000 vaccinees.
• In addition, there have been case reports of children in Japan and Korea with severe or fatal acute disseminated encephalomyelitis (ADEM) temporally associated with JE vaccination.

Vaccine Dose and Administration

• For travelers ≥3 years of age, the recommended primary immunization series for JE-VAX is three doses of 1.0 mL each, administered subcutaneously on days 0, 7, and 30.
• An abbreviated schedule (days 0, 7, and 14) provides similar rates of seroconversion but significantly lower neutralizing antibody titers.
• Immunization routes and schedules for children 1 and 2 years of age are identical except that 0.5-mL doses should be administered.
• Vaccine recipients should be observed for a minimum of 30 minutes after immunization and warned about the possibility of delayed allergic reactions.
• The last dose should be administered at least 10 days before beginning travel to ensure an adequate immune response and access to medical care in the event of any delayed adverse reactions.
• Booster doses may be administered 2–3 years after the primary series. The timing and immune response of subsequent boosters have not been studied in travelers.

Precautions and Contraindications

• A history of allergy or hypersensitivity reaction to a previous dose of mouse brain-derived JE vaccine is a contraindication to receiving additional doses.
• Proven or suspected hypersensitivity to thimerosal or proteins of rodent or neural origin is a contraindication to vaccination.
• Persons with a previous history of urticaria are more likely to develop a hypersensitivity reaction following receipt of JE vaccine. This history should be considered when weighing the risks and benefits of the vaccine for an individual patient.
• No specific information is available on the safety of JE vaccine in pregnancy. Therefore, the vaccine should not be routinely administered during pregnancy. Pregnant women who must travel to an area where risk for JE is high should be vaccinated when the theoretical risk for immunization is outweighed by the risk for infection.
• No data are available on vaccine safety and efficacy in infants <1 year of age.
• Two small studies of inactivated JE vaccine in children with underlying medical conditions did not show a change in the adverse reactions or immune response after vaccination.

References

1. CDC. Inactivated Japanese encephalitis virus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1993;42(RR-01):1–16.
2. Marfin AA, Eidex RS, Kozarsky PE, et al. Yellow fever and Japanese encephalitis vaccines: indications and complications. Infect Dis Clin North Am. 2005;19(1):151–68.
3. Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis. 2002;35(2):183–8.
4. Halstead SB, Tsai TF. Japanese encephalitis vaccine. In: Plotkin SA, Orenstein WA, editors. Vaccines, 4th edition. Philadelphia: WB Saunders; 2004. p. 919–58.
5. Solomon T. Flavivirus encephalitis. N Engl J Med. 2004;351(4):370–8.
6. Tauber E, Kollaritsch H, Korinek M, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet. 2007;370(9602):1847–53.
7. Gambel JM, DeFraites R, Hoke C, et al. Japanese encephalitis vaccine: Persistence of antibody up to 3 years after a three-dose primary series. J Infect Dis. 1995;171(4):1074.
8. WHO. Japanese encephalitis vaccines. weekly Epidemiol Rec. 2006;81(34/35):331–340.
9. Martin DA, Biggerstaff BJ, Allen B, et al. Use of immunoglobulin M cross-reactions in differential diagnosis of human flaviviral encephalitis infections in the United States. Clin Diag Lab Immunol. 2002;9(3):544–549.
10. Burke DS, Nisalak A, Ussery MA,et al. Kinetics of IgM and IgG responses to Japanese encephalitis virus in human serum and cerebrospinal fluid. J Infect Dis. 1985;151(6):1093–9.
11. Beasley DWC, Lewthwaite P, Solomon T. Current use and development of vaccines for Japanese encephalitis. Expert Opin Biol Ther. 2008;8(1):95–106.
12. Hoke CH, Nisalak A, Sangawhipa N,et al. Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med. 1988;319(10):608–14.
13. Defraites RF, Gambel JM, Hoke CH Jr, et al. Japanese encephalitis vaccine (inactivated, BIKEN) in U.S. soldiers: Immunogenicity and safety of vaccine administered in two dosing regimens. Am J Trop Med Hyg. 1999;61(2):288–93.
14. Monath TP. Japanese encephalitis vaccines: current vaccines and future prospects. In: Current topics in microbiology and immunology: Japanese encephalitis and West Nile virus infections. In: Mackenzie JS, Barrett AD, Deubel V, editors. Berlin: Springer-Verlag 2002. p. 105–38.
15. Plesner AM. Allergic reactions to Japanese encephalitis vaccine. Immunol Allergy Clin North Am. 2003;23(4):665–97.
16. Takahashi H, Pool V, Tsai T, et al. Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. The VAERS Working Group. Vaccine. 2000;18(26):2963–9.
17. 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(2):265–6.
18. Sohn YM. Japanese encephalitis immunization in Korea: past, present and future. Emerg Infect Dis. 2000;6(1):17–24.
19. Puthanakit T, Aurpibul L, Yoksan S, et al. Japanese encephalitis vaccination in HIV-infected children with immune recovery after highly retroactive antiretroviral therapy. Vaccine. 2007;25(49):8257–61.
20. Yamada A, Imanishi J, Juang R-F, et al. Trial of inactivated Japanese encephalitis vaccine in children with underlying diseases. Vaccine. 1986;4(1):32–4.
21. CDC. Japanese Encephalitis Among Three U.S. Travelers Returning from Asia, 2003–2008. MMWR Recomm Rep. 2009;58(27):737–40.