Description

Japanese encephalitis virus (JEV) is a mosquito-borne Flavivirus that is closely related to West Nile and St. Louis encephalitis viruses (1-3). JEV infection occurs throughout most of Asia and is the most common cause of encephalitis in that region (Map 4-6). Other than sporadic travel-associated cases, Japanese encephalitis (JE) has not been identified in Africa, Europe or the Americas.

JEV is transmitted in an enzootic cycle between Culex mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds (1-4). In endemic areas, up to 3% of the vector mosquitoes are infected with JEV. Although the mosquitoes prefer to feed on large domestic animals and birds, if an infected mosquito bites a human, infection and subsequent illness can occur. JEV is not transmitted directly from person to person. In areas where JE vaccine coverage or natural immunity of residents is high so that endemic cases do not occur, JE virus may still be transmitted in the enzootic cycle and non-immune visitors to that area may still be at risk for disease.

From 35,000 to 50,000 cases of JE are reported to WHO each year, resulting in an estimated 10,000 to 15,000 deaths annually. In addition, 30% to 50% of survivors have significant neurologic sequelae. Children are at greatest risk of infec-tion in endemic areas. Immunity to JEV from previous vaccination or naturally acquired immunity reduces the risk of illness. Although most adults living in endemic areas have acquired natural immunity, adult visitors to endemic areas are at risk for infection. Outdoor occupation and recreational exposure are also risk factors for infection.

Occurrence

JE transmission principally occurs in rural agricultural locations where flooding irrigation is practiced (2,3). In many areas of Asia, these ecologic conditions may occur near, or occasionally within, urban centers. Transmission is seasonal and occurs in the summer and autumn in the temperate regions of China, Japan, Korea, and eastern Russia. Elsewhere, seasonal patterns of disease may be extended or vary with the rainy season and irrigation practices. Thus, the risk of JE transmission varies by season and geographic area (Table 4-8 and Map 4-6).

Culex tritaeniorhynchus is the principal vector for transmission of JE and feeds outdoors from dusk to dawn (2,3). Larvae are found in flooded rice fields, marshes, and other small stable collections of water found around cultivated fields. In temperate zones, this vector is present in greatest density from June through September; it is inactive during winter months. In tropical parts of Asia, other mosquito species that breed in rice paddies may also be important vectors, and JEV transmission may occur over a longer season or even throughout the year.

Risk for Travelers

The risk to short-term travelers and those who confine their travel to urban centers is very low (1,4). Expatriates and travelers living for prolonged periods in rural areas where JE is endemic or epidemic are at greater risk. Travelers with extensive outdoor, evening, and nighttime exposure in rural areas, such as might be experienced while bicycling, camping, working outdoors, or sleeping in unscreened structures without bed nets, may be at high risk even if their trip is brief.

Clinical Presentation

The majority of human infections with JEV are asymptomatic, and only about 1 in 250 infected persons develops clinical disease (2-5). Encephalitis is the most common clinical manifestation of JEV infection. The incubation period is 5 to 15 days. Illness usually begins with sudden onset of fever with gastrointestinal symptoms and headache. Mental status or behavioral changes, focal neurologic deficits, generalized weakness, and movement disorders may develop over the next few days. Seizures are very common among children. Milder forms of disease such as aseptic meningitis or fever with headache can occur, more commonly among adults. There is no specific antiviral treatment for JE; therapy consists of supportive care and management of complications.

Clinical laboratory findings of JE include moderate leukocytosis, mild anemia, hyponatremia, and cerebrospinal fluid (CSF) pleocytosis with a lymphocytic predominance (2,3). 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 7 days following onset of symptoms. Clinicians should contact their state or local health departments or CDC for assistance with diagnosis.

Prevention

VACCINE

An inactivated mouse brain-derived JE vaccine (JE-VAX) has been licensed for use in the U.S. civilian population since 1992 (1,4,5). This vaccine is manufactured by Biken (Osaka, Japan) and distributed in the United States by Sanofi Pasteur. Although production of the mouse brain-derived vaccine was discontinued in 2006, stockpiles of the vaccine will be available for use in U.S. travelers for several more years. An inactivated cell culture-derived JE vaccine has been evaluated in the United States and other countries, and will likely also be approved for use in the United States in the next 1-3 years. Other inactivated and live attenuated JE vaccines are manufactured and used in Asia but not licensed for use in the United States (5,6).

Vaccination should be considered for persons who plan to live in areas where JE is endemic or epidemic, and for travelers whose activities include trips into rural farming areas (1,4). Short-term travelers, especially those whose visits are restricted to major urban areas, are at lower risk for infection and generally do not require the vaccine. Evaluation of an individual traveler’s risk should take into account itinerary and activities, and best-available information on the current level of JE activity in the travel area (Table 4-8).

The recommended primary immunization series is three doses of 1.0 mL each, administered subcutaneously on days 0, 7, and 30 (Table 4-9) (1). An abbreviated schedule (days 0, 7, and 14) can be used when the longer schedule is impractical. Both regimens produce similar rates of seroconversion among recipients, but neutralizing antibody titers are significantly lower following the abbreviated schedule (2,5). Two doses administered a week apart will confer short-term immunity among 80% of vaccinees. However, this schedule should be used only under unusual circumstances and is not routinely recommended (1). 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.

Immunization routes and schedules for children 1-3 years of age are identical except that 0.5-mL doses should be administered (Table 4-9) (1). No data are available on vaccine safety and efficacy in infants younger than 1 year.

The full duration of protection following primary immunization is unknown. However, preliminary data indicate that neutralizing antibodies persist for at least 2 years after a three-dose primary series. Booster doses of 1.0 mL (0.5 mL for children younger than 3 years of age) may be administered 2 years after the primary series (Table 4-9) (1). The duration of immunity after serial booster doses has not been well established.

Adverse Reactions

Inactivated mouse brain-derived JE vaccine has been associated with localized erythema, tenderness, and swelling at the injection site in about 20% of recipients (1,2,4,6). Mild systemic side effects (e.g., fever, chills, headache, rash, myalgia, and gastrointestinal symptoms) have been reported in approximately 10% of vaccinees. More serious allergic hypersensitivity reactions including generalized urticaria and angioedema of the extremities, face, and oropharynx have been reported at a rate of 180 to 640 cases per 100,000 vaccinees (1,2,4,6,7). Accompanying bronchospasm, respiratory distress, and hypotension was also reported in several of these patients. Most of these allergic reactions were treated successfully with antihistamines or corticosteroids; however, up to 10% of vaccinees with these reactions were hospitalized. One death possibly associated with JE vaccine has been reported in a person with a history of recurrent hypersensitivity reactions and anaphylaxis.

An important feature of these hypersensitivity reactions is the interval between vaccination and onset of symptoms (1,2,4,8). Although a majority of the reactions after the first immunization dose occurred within 12 hours after administration (88% occurred within 3 days), the interval between administration of a second dose and onset of allergic symptoms generally was significantly longer (median 3 days; range up to 2 weeks). Although the rate of adverse events was greater following the first and second doses, reactions have occurred following a second or third dose even when preceding doses were received uneventfully. Persons with a previous history of urticaria or angioedema are significantly more likely to develop a hypersensitivity reaction following receipt of JE vaccine. The specific vaccine constituents responsible for these adverse reactions have not been identified. Based on postmarketing surveillance data, the reported rates for allergic adverse events following the administration of inactivated mouse brain-derived JE vaccine doses were 0.8 and 6.3 per 100,000 doses in Japan and the United States, respectively (9).

The use of mouse brains as the substrate for virus growth has always raised concerns about the possibility of neurologic side effects associated with the JE vaccine (1,2,4,6). In Japan from 1996 to 1998, 17 neurologic disorders were reported following vaccination, for a rate of 0.2 events per 100,000 doses. In the United States during 1993-1999, two reports of serious neurologic adverse events were temporally associated with receipt of JE vaccine, for a similar rate of 0.2 events per 100,000 doses. Taken together, these data further support the conservative recommendations limiting the use of the vaccine to travelers at high risk of infection with JE.

Precautions and Contraindications

Vaccine recipients should be observed for a minimum of 30 minutes after immunization and warned about the possibility of delayed allergic reactions (1). The full course of immunization should be completed at least 10 days before departure, and vaccinees should be advised to remain in areas with access to medical care.

A history of allergy or hypersensitivity reaction to a previous dose of mouse brain-derived JE vaccine is a contraindication to receiving additional doses (1). Persons with multiple allergies or with a history of urticaria or angioedema for any reason may be at higher risk for allergic complications from the 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 of JE is high should be vaccinated when the theoretical risk of immunization is outweighed by the risk of infection.

PERSONAL PROTECTION MEASURES

Although JE vaccination is very effective against developing infection, travelers should still avoid mosquito bites to reduce the risk of other vector-borne infectious diseases (e.g., malaria, dengue, and chikungunya fever). Although repellents containing picaridin and p-menthane-3,8-diol (the active ingredient of oil of lemon eucalyptus) are also available in the United States and considered safe and effective for domestic use, their effectiveness against the mosquitoes that transmit JE is unknown and so DEET containing repellents should be used (see Chapter 2).

References

1. CDC. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1994;43(RR-1):1-38.
2. Halstead SB, Tsai TF. Japanese encephalitis vaccine. In: Plotkin SA, Orenstein WA, editors. Vaccines, 4th edition. Philadelphia: Saunders;2004:919-58.
3. Halstead SB, Jacobson J. Japanese encephalitis. Adv Virus Res. 2003;61:103-38
4. Marfin AA, Barwick Eidex RS, Kozarsky PE, Cetron MS. Yellow fever and Japanese encephalitis vaccines: Indications and complications. Infect Dis Clin N Am. 2005;19:151-168.
5. Solomon T. Flavivirus encephalitis. N Engl J Med. 2004;351:370-378.
6. Monath TP. Japanese encephalitis vaccines: current vaccines and future prospects. Curr Top Microbiol Immunol. 2002;267:105-38.
7. 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 Suppl 2:1-25.
8. Plesner AM. Allergic reactions to Japanese encephalitis vaccine. Immunol Allergy Clin North Am. 2003;23:665-97.
9. Takahashi H, Pool V, Tsai T, Chen RT, and the VAERS Working Group. Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. The VAERS Working Group. Vaccine 2000;18:2963-2969.