Author(s): Susan Hills, Nicole Lindsey, Marc Fischer

Infectious Agent

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

Transmission

JE virus is transmitted to humans through the bite of an infected mosquito, primarily Culex species. The virus is maintained in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily wading birds and pigs. Humans are incidental or dead-end hosts because they usually do not develop a level or duration of viremia sufficient to infect mosquitoes.

Epidemiology

JE virus is the most common vaccine-preventable cause of encephalitis in Asia, occurring throughout most of Asia and parts of the western Pacific. Transmission principally occurs in rural agricultural areas, often associated with rice cultivation and flood irrigation. In some areas of Asia, these ecologic conditions can 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 might be prolonged or even occur year round.

In endemic countries, where adults have acquired immunity through natural infection, JE is primarily a disease of children. Travel-associated JE can occur among people of any age, however. For most travelers to Asia, the risk for JE is extremely low but varies based on destination, accommodations, activities, and duration and season of travel.

Before 1973, >300 cases of JE were reported among soldiers from the United States, the United Kingdom, Australia, and Russia. During 1973–2020, 88 JE cases among travelers or expatriates from nonendemic countries were published or reported to the Centers for Disease Control and Prevention (CDC). Since 1993, when a JE vaccine became available in the United States, only 13 JE cases among US travelers have been reported to CDC (1993–2020).

The overall incidence of JE among people from nonendemic countries traveling to Asia is estimated to be <1 case per 1 million travelers. However, expatriates and travelers who stay for prolonged periods in rural areas with active JE virus transmission might be at similar risk as the susceptible, pediatric resident population, which is 6–11 cases per 100,000 children per year. Travelers, even on brief trips, might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Shorter-term (e.g., <1 month) travelers whose visits are restricted to major urban areas are at minimal risk for JE. In some endemic areas, few human cases occur among residents because of natural immunity among older people or vaccination, but JE virus is still maintained locally in an enzootic cycle between animals and mosquitoes. Therefore, susceptible visitors could be at risk for infection.

Clinical Presentation

Most human infections with JE virus are asymptomatic; <1% of people infected with JE virus develop neurologic disease. Acute encephalitis is the most recognized clinical manifestation of JE virus infection. Milder forms of disease (e.g., aseptic meningitis, undifferentiated febrile illness) also can 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 might develop over the next few days. The classical description of JE includes a parkinsonian syndrome with mask-like facies, tremor, cogwheel rigidity, and choreoathetoid movements. Acute flaccid paralysis, with clinical and pathological features like those of poliomyelitis, also has been associated with JE virus infection. Seizures are common, especially among children. The case-fatality rate is ≈20%–30%. Among survivors, 30%–50% have serious neurologic, cognitive, or psychiatric sequelae.

Common clinical laboratory findings include mild anemia, moderate leukocytosis, and hyponatremia. Cerebrospinal fluid (CSF) typically has a mild to moderate pleocytosis with a lymphocytic predominance, slightly elevated protein, and normal ratio of CSF to plasma glucose.

Diagnosis

Suspect JE in a patient with evidence of a neurologic infection (e.g., encephalitis, meningitis, acute flaccid paralysis) who recently traveled to or resided in an endemic country in Asia or the western Pacific. Laboratory diagnosis of JE virus infection should be performed using a JE virus–specific IgM-capture ELISA on CSF or serum. JE virus–specific IgM can be measured in the CSF of most patients ≥4 days after symptom onset and in serum ≥7 days after symptom onset.

Plaque reduction neutralization tests can be performed to confirm the presence of JE virus–specific neutralizing antibodies and to discriminate between cross-reacting antibodies from closely related flaviviruses (e.g., dengue virus, West Nile virus). A ≥4-fold rise in JE virus–specific neutralizing antibodies between acute- and convalescent-phase serum specimens can be used to confirm recent infection. When interpreting laboratory results, clinicians must consider vaccination history, date of symptom onset, and information regarding other flaviviruses known to circulate in the geographic area that might cross-react in serologic assays.

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 are insensitive in detecting JE virus or viral RNA in blood or CSF and should not be used for ruling out a diagnosis of JE. Contact the state or local health department or CDC’s Arboviral Diseases Branch, Division of Vector-Borne Diseases (970-221-6400) for assistance with diagnostic testing. See instructions for submitting CSF and serum specimens to CDC for testing.

Treatment

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

Prevention

Personal Protective Measures

Travelers can best prevent mosquito-borne diseases, including JE, by avoiding mosquito bites (see Sec. 4, Ch. 6, Mosquitoes, Ticks & Other Arthropods).

Vaccine

One JE vaccine is licensed and available in the United States, an inactivated Vero cell culture–derived vaccine, IXIARO, manufactured by Valneva Austria GmbH. IXIARO was approved in March 2009 for use in people aged ≥17 years, and in May 2013 for use in children aged 2 months through 16 years. Other inactivated and live attenuated JE vaccines are manufactured and used in other countries but are not licensed for use in the United States.

Indications for Travelers

Based on each traveler’s planned itinerary, assess the risks for mosquito exposure and JE virus infection and discuss ways to reduce these risks. Advise all travelers going to JE-endemic countries of the importance of personal protective measures to reduce the risk for mosquito bites. The decision whether to vaccinate should be individualized and include consideration of the risks related to the specific travel itinerary, likelihood of future travel to JE-endemic countries, the high rate of death and disability when JE occurs, availability of an effective vaccine, the possibility but low probability, of serious adverse events after immunization, and the traveler’s personal perception and tolerance of risk.

Travel location, duration, activities, accommodations, and seasonal patterns of disease in the areas to be visited each influence risk for exposure. Interpret the data in Table 5-14 cautiously, because JE virus transmission activity varies within countries and from year to year, and surveillance data are often incomplete. Additional information on factors that increase risk is provided in Japanese encephalitis vaccine: Recommendations of the Advisory Committee on Immunization Practices.

The Advisory Committee on Immunization Practices (ACIP) recommends JE vaccine for people moving to a JE-endemic country, longer-term (e.g., ≥1 month) travelers to JE-endemic areas, and frequent travelers to JE-endemic areas. Consider JE vaccine for shorter-term (e.g., <1 month) travelers with an increased risk for JE based on planned travel duration, season, location, activities, and accommodations. In addition, consider vaccination for travelers going to JE-endemic areas but who are uncertain of specific destinations, activities, or duration of travel.

ACIP does not recommend JE vaccine for travelers with very low risk itineraries (e.g., shorter-term travel limited to urban areas, travel that occurs outside a well-defined JE virus transmission season).

Efficacy & Immunogenicity

No efficacy data are available for IXIARO. The vaccine was licensed in the United States based on its ability to induce JE virus–specific neutralizing antibodies as a surrogate for protection. In pivotal immunogenicity studies, 96% of adults and 100% of children developed protective neutralizing antibodies 28 days after receiving a primary immunization series of 2 doses administered 28 days apart. In a trial among adults aged ≥65 years, 65% were seroprotected at 42 days after the 2-dose primary series. An accelerated primary series of 2 doses administered 7 days apart was studied among adults aged 18–65 years and was noninferior to the conventional dosing schedule.

In a study where a booster dose was administered to adults at 15 months, 96% of subjects were still seroprotected ≈6 years later. In a study conducted among 150 children in a JE-endemic country who received a booster dose at 11 months, 100% were seroprotected at 24 months after the booster dose.

Administration

The primary vaccination dose and schedule for IXIARO varies by age (Table 5-15). To administer a 0.25-mL dose, expel and discard half of the volume from the 0.5-mL prefilled syringe by pushing the plunger stopper up to the edge of the red line on the syringe barrel before injection. For all age groups, the 2-dose series should be completed ≥1 week before travel.

Booster Doses

A booster dose (third dose) should be given at ≥1 year after completion of the primary IXIARO series if ongoing exposure or reexposure to JE virus is expected.

Limited data are available on the use of IXIARO as a booster dose after a primary series with the mouse brain–derived inactivated JE vaccine. Three studies have been conducted, 2 in US military personnel and the other at 2 travel clinics in Europe. Results showed that among adults who had previously received at least a primary series of mouse brain–derived inactivated JE vaccine, a single dose of IXIARO provided good protection through 12–23 months.

Safety & Adverse Reactions

IXIARO was licensed in the United States based on safety evaluations in almost 5,000 adults. Since licensure, >1 million doses of IXIARO have been distributed in the United States without any identified safety concerns. Local symptoms of pain and tenderness were the most reported symptoms in a safety study among 1,993 adult participants who received 2 doses of IXIARO. Fatigue, headache, and myalgia were each reported at a rate of >10%. In children, fever was the most reported systemic reaction in studies. Serious adverse events are reported only rarely.

Precautions & Contraindications

A severe allergic reaction after a previous dose of IXIARO or any other JE vaccine, or to any component of IXIARO, is a contraindication to administration of IXIARO. IXIARO contains protamine sulfate, a compound known to cause hypersensitivity reactions in some people.

No studies of IXIARO in pregnant people have been conducted. Pregnancy is a precaution against the use of IXIARO, however, and in most instances, clinicians should defer vaccinating pregnant people. Further discussion (including the possibility of delaying travel) is merited before recommending vaccination to the pregnant person who must travel to areas where the risk for JE infection outweighs the theoretical risk from immunization.

CDC website: Japanese Encephalitis