Japanese Encephalitis Vaccines

Morbidity and Mortality Weekly Report (MMWR)MMWR
Japanese Encephalitis Vaccines
Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Recommendations and Reports
March 12, 2010 / 59(01);1-27


Prepared by

Marc Fischer, MD, Nicole Lindsey, MS, J. Erin Staples, MD, PhD, Susan Hills, MBBS

Division of Vector-Borne Infectious Diseases, National Center for Emerging and Zoonotic Infectious Diseases (proposed), CDC

This report originated in the National Center for Emerging and Zoonotic Infectious Diseases (proposed), Thomas Hearn, PhD, Acting Director, and the Division of Vector-Borne Infectious Diseases, Lyle Petersen, MD, Director.

Corresponding preparer: Marc Fischer, MD, Division of Vector-Borne Infectious Diseases, National Center for Emerging and Zoonotic Infectious Diseases (proposed), CDC, 3150 Rampart Road, MS P-02, Fort Collins, CO 80521. Telephone: 970-221-6489; Fax: 970-266-3568; E-mail: mfischer@cdc.gov.

Summary
This report updates the 1993 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the prevention of Japanese encephalitis (JE) among travelers (CDC. Inactivated Japanese encephalitis virus vaccine: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1993;42[No. RR-1]). This report summarizes the epidemiology of JE, describes the two JE vaccines that are licensed in the United States, and provides recommendations for their use among travelers and laboratory workers.

JE virus (JEV), a mosquito-borne flavivirus, is the most common vaccine-preventable cause of encephalitis in Asia. JE occurs throughout most of Asia and parts of the western Pacific. Among an estimated 35,000--50,000 annual cases, 20%--30% of patients die, and 30%--50% of survivors have neurologic or psychiatric sequelae. No treatment exists. For most travelers to Asia, the risk for JE is very low but varies on the basis of destination, duration, season, and activities.

JE vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JEV transmission season and for laboratory workers with a potential for exposure to infectious JEV. JE vaccine should be considered for 1) short-term (<1 month) travelers to endemic areas during the JEV transmission season if they plan to travel outside of an urban area and will have an increased risk for JEV exposure; 2) travelers to an area with an ongoing JE outbreak; and 3) travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or times outside of a well-defined JEV transmission season.

Two JE vaccines are licensed in the United States. An inactivated mouse brain--derived JE vaccine (JE-VAX [JE-MB]) has been licensed since 1992 to prevent JE in persons aged ≥1 year traveling to JE-endemic countries. Supplies of this vaccine are limited because production has ceased. In March 2009, an inactivated Vero cell culture-derived vaccine (IXIARO [JE-VC]) was licensed for use in persons aged ≥17 years. JE-MB is the only JE vaccine available for use in children aged 1−16 years, and remaining supplies will be reserved for use in this group.

Introduction
Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the most common vaccine-preventable cause of encephalitis in Asia (1,2). Japanese encephalitis (JE) occurs throughout most of Asia and parts of the western Pacific (1,3). Among an estimated 35,000--50,000 annual cases, approximately 20%--30% of patients die, and 30%--50% of survivors have neurologic or psychiatric sequelae (4,5). In endemic countries, JE is primarily a disease of children. However, travel-associated JE, although rare, can occur among persons of any age (6--9). For most travelers to Asia, the risk for JE is very low but varies based on destination, duration, season, and activities (9,10).

JEV is transmitted in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds (11,12). JEV is transmitted to humans through the bite of an infected mosquito, but disease develops in <1% of infected persons. JEV transmission occurs primarily in rural agricultural areas. In most temperate areas of Asia, JEV transmission is seasonal, and substantial epidemics can occur. In the subtropics and tropics, transmission can occur year-round, often intensifying during the rainy season.

This report provides recommendations for use of the two JE vaccines licensed in the United States for prevention of JE among travelers and laboratory workers. An inactivated mouse brain--derived JE vaccine (JE-MB) has been available since 1992 for use in travelers aged ≥1 year (13). In March 2009, the Food and Drug Administration (FDA) approved a new inactivated Vero cell culture-derived JE vaccine (JE-VC) for use in persons aged ≥17 years (14).

Methods
The Advisory Committee on Immunization Practices (ACIP) JE vaccine workgroup* first met in October 2006 to review available information on the risk for JE for travelers, begin revising recommendations for the use of the available vaccine, and develop recommendations for the use of a new vaccine. In addition to ACIP members, the workgroup included participants from CDC, FDA, National Institutes of Health, Department of Defense, Public Health Agency of Canada, European Centre for Disease Prevention and Control, American Academy of Pediatrics, International Society of Travel Medicine, American Society of Tropical Medicine and Hygiene, PATH JE Project, American Osteopathic Association, National Association of Pediatric Nurse Practitioners, Association of Immunization Managers, Washington State Department of Health, and the University of Liverpool. Workgroup members included persons with expertise in JE, infectious diseases, travel medicine, public health, biostatistics, immunization safety, and vaccine policy.

The workgroup reviewed JE epidemiology, incidence of and risk factors for travel-associated JE disease, measures available to prevent JE disease, and the efficacy, immunogenicity, safety, cost-effectiveness, and availability of JE vaccine. Primary sources were published, peer-reviewed studies; however, unpublished data also were considered. Articles were identified through searches of the PubMed, Global Health, and EMBASE databases, review of relevant bibliographies, and consultation with subject-matter experts.

The workgroup held regular conference calls and met three times. Recommendation options were developed and discussed. When definitive research evidence was lacking, the recommendations incorporated expert opinion of the workgroup members. The workgroup presented progress reports and preliminary recommendations to ACIP during its February 2008 and October 2008 meetings. Proposed recommendations and a draft statement were presented to ACIP and approved at the June 2009 meeting.

ACIP will review additional data as these are made available, particularly regarding any adverse events following receipt of JE-VC that are reported during postmarketing surveillance studies. Recommendations will be updated as needed.

Background
JEV Transmission
JEV is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to West Nile, St. Louis encephalitis, yellow fever, and dengue viruses (15,16). Four genotypes of JEV have been identified (17). JEV is an arthropod-borne virus (arbovirus) that is transmitted in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds (Figure 1) (12,18--22). Because of rapid population turnover with a large number of susceptible offspring and the development of high-titered JEV viremias, domestic pigs are the most important source of infection for mosquitoes that transmit JEV to humans (11,22--26).

JEV is transmitted to humans through the bites of infected mosquitoes. Humans usually do not develop a level or duration of viremia sufficient to infect mosquitoes (12,27). Therefore, humans are dead-end hosts, and human JE cases imported into nonendemic areas represent a minimal risk for subsequent transmission of the virus. Direct person-to-person spread of JEV does not occur except rarely through intrauterine transmission (1,28,29). On the basis of experience with similar flaviviruses, blood transfusion and organ transplantation also are considered potential modes of JEV transmission (30,31).

Culex mosquitoes, especially Cx. tritaeniorhynchus, are the principal vector for both zoonotic and human JEV transmission throughout Asia (11,12,18,21,32--39). Cx. tritaeniorhynchus is an evening- and nighttime-biting mosquito that feeds preferentially on large domestic animals and birds and only infrequently on humans. Cx. tritaeniorhynchus feed most often in the outdoors, with peak feeding activity occurring after sunset (20). Larvae are found in flooded rice fields, marshes, and other small stagnant collections of water (37,38). In temperate zones, this vector is present in greatest density from June through November; it is inactive during winter months (20,40,41). In certain parts of Asia, other mosquito species also might be important JEV vectors (12,36,38,40).

Epidemiology of JE
Geographic Distribution and Spread
JE occurs throughout most of Asia and parts of the western Pacific (Figure 2). During the first half of the 20th century, the disease was recognized principally in temperate areas of Asia including Japan, Korea, Taiwan, and mainland China (42--50). Over the past few decades, the disease appears to have spread south and west with increased JEV transmission reported in Southeast Asia, India, Bangladesh, Sri Lanka, and Nepal (35,44,48,51--62). In the 1990s, JEV spread east and was recognized for the first time in Saipan and then Australia, initially in the outer Torres Strait islands and subsequently on the northern mainland (63--65). The reasons for this increased geographic distribution are uncertain but might include population shifts or changes in climate, ecology, agricultural practices, animal husbandry, or migratory bird patterns (38,48,65). These factors could contribute to further spread, including potentially beyond Asia and the western Pacific.

Incidence and Burden of Disease
In the early 1970s, more than 100,000 cases of JE were reported each year, with the vast majority from China (49,66). Because of vaccine use, increased urbanization, changes in agricultural practices, and mosquito control, annual JE case counts have declined substantially during the past 30 years (66). Up to 30,000 cases of JE still are reported each year (5). However, as a result of poor diagnostic and surveillance capacity in many endemic countries, this number likely represents an underestimate of the true burden of disease (5,66). Among children in endemic countries, the incidence of laboratory-confirmed JE varies widely from year to year and area to area (range: 5--50 cases per 100,000 children per year) (12,41,42,47,66--70).

Ecologic and Seasonal Patterns
The risk for JE varies by local ecology and season. JEV transmission occurs primarily in rural agricultural areas, often associated with rice production and flooding irrigation, where large numbers of vector mosquitoes breed in close proximity to animal reservoirs (18,21). In some areas of Asia, these ecologic conditions might occur near, or rarely within, urban centers (71).

In temperate areas of Asia, JEV transmission is seasonal, and human disease usually peaks in the summer and fall (41,42,46,47,50,60,62,72). Seasonal epidemics can be explosive, with thousands of JE cases occurring over a period of several months. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season (48,51,56,70).

Age-Specific Patterns
In endemic areas, JE is primarily a disease of childhood, with the vast majority of cases occurring among children aged <15 years (41,46,47,50--52,60,62,70,73--75). However, in areas with childhood JE immunization programs, the overall incidence of JE decreases, and similar numbers of cases are observed among children and adults (42,43,50). In both Japan in 2002 and northern China in 2006, outbreaks were reported in which the majority of cases occurred among older adults (76,77). Because unvaccinated travelers from nonendemic countries usually are immunologically naïve, travel-associated JE can occur in persons of any age.

Clinical Manifestations and Diagnosis
Signs and Symptoms
The majority of human infections with JEV are asymptomatic; <1% of people infected with JEV develop clinical disease (12,67,68,73,77--79). Acute encephalitis is the most commonly identified clinical syndrome with JEV infection (12,72,80--82). Milder forms of disease (e.g., aseptic meningitis or undifferentiated febrile illness) also can occur but have been reported more commonly among adults (72,83,84).

Among patients who develop clinical symptoms, the incubation period is 5--15 days. Illness usually begins with acute onset of fever, headache, and vomiting (55,85,86). Mental status changes, focal neurologic deficits, generalized weakness, and movement disorders might occur over the next few days (55,82,85--90). Seizures are common, especially among children (85--87,90--92). The classical description of JE includes a parkinsonian syndrome with mask-like facies, tremor, cogwheel rigidity, and choreoathetoid movements (82,93). Acute flaccid paralysis, with clinical and pathological features similar to poliomyelitis, also has been associated with JEV infection (93,94). Status epilepticus, brain hypoxia, increased intracranial pressure, brainstem herniation, and aspiration pneumonia are the most common complications associated with poor outcome and death (82,85,91,95).

Although information on the burden of JEV infection in pregnancy is limited, miscarriages and an intrauterine infection following maternal JE have been reported. In India, four miscarriages were reported among nine infected pregnant women; all of the women who miscarried were in the first or second trimester of pregnancy (28,29). JEV was isolated in one of the four aborted fetuses, suggesting that intrauterine transmission of JEV can occur (28).

Clinical Laboratory Findings and Neuroimaging
Clinical laboratory findings with JE are nonspecific and might include moderately elevated white blood cell count, mild anemia, and hyponatremia (72,82,85,86,90). Thrombocytopenia and elevated hepatic enzymes have been noted (86). Cerebrospinal fluid (CSF) usually shows a lymphocytic pleocytosis with moderately elevated protein (52,55,72,74,82,85,87,90).

Magnetic resonance imaging (MRI) of the brain is better than computed tomography (CT) for detecting JEV associated abnormalities such as changes in the thalamus, basal ganglia, midbrain, pons, and medulla (96,97). Thalamic lesions are the most commonly described abnormality; although these can be highly specific for JE in the appropriate clinical context, they are not a very sensitive marker of JE (98).

Laboratory Diagnosis
JEV infections are confirmed most frequently by detection of virus-specific antibody in CSF or serum (12,99--103). Because humans have low or undetectable levels of viremia by the time distinctive clinical symptoms are recognized, virus isolation and nucleic acid amplification tests (NAAT) are insensitive and should not be used for ruling out a diagnosis of JE (104,105). In one study in Thailand, of 30 nonfatal cases involving persons with JEV infection of the central nervous system (CNS), none had virus isolated from plasma or CSF (100). By contrast, JEV was isolated from CSF in five (33%) of 15 fatal cases, and from brain tissue in 8 (73%) of 11 fatal cases. More recent studies have shown the utility of NAAT for diagnosing JE in some patients with encephalitis or aseptic meningitis, but this method still lacks the sensitivity needed for routine diagnosis (84,106).

Acute-phase specimens should be tested for JEV-specific immunoglobulin (Ig) M antibodies using a capture enzyme-linked immunosorbent assay (MAC ELISA) (12,99--103). JEV-specific IgM antibodies can be measured in the CSF of most patients by 4 days after onset of symptoms and in serum by 7 days after onset (99,100). JEV-specific IgM antibodies in CSF indicate recent CNS infection and can help distinguish clinical disease attributed to JEV from previous vaccination (99). With clinical and epidemiologic correlation, a positive IgM test has good diagnostic predictive value, but cross-reaction with arboviruses from the same family can occur. Plaque reduction neutralization tests (PRNT) can be performed to measure virus-specific neutralizing antibodies. A fourfold or greater rise in virus-specific neutralizing antibodies between acute- and convalescent-phase serum specimens collected 2--3 weeks apart may be used to confirm recent infection or to discriminate between cross-reacting antibodies attributed to other primary flaviviral infections. In patients who have been infected previously by another flavivirus or vaccinated with a flaviviral vaccine (e.g., JE or yellow fever vaccine) and who then acquire a secondary flaviviral infection, cross-reactive antibodies in both the ELISA and neutralization assays might make identifying a specific etiologic agent difficult. Vaccination history, date of onset of symptoms, and information regarding other arboviruses known to circulate in the geographic area that might cross-react in serologic assays should be considered when interpreting results. Diagnostic testing for JE is available in select state public health laboratories and at CDC's Division of Vector-Borne Infectious Diseases in Colorado (available at http://www.cdc.gov/ncidod/dvbid/misc/arboviral_shipping.htm; telephone 970-221-6400).

Treatment and Management
JE therapy consists of supportive care and management of complications. No specific antiviral agent or other medication to mitigate the effects of JEV infection is available (107). In controlled clinical trials, corticosteroids, interferon alpha-2a, or ribavirin did not improve clinical outcome (108--110).

Outcome and Sequelae
JE has a case-fatality ratio of approximately 20%--30% (46,47,53,56,62,74,75,82,85--87,111,112). Although some motor deficits and movement disorders improve after the acute illness, 30%--50% of JE survivors have neurologic or psychiatric sequelae even years later (66,74,82,85,87,93,109,111,113--117). These include seizures, upper and lower motor neuron weakness, cerebellar and extrapyramidal signs, flexion deformities of the arms, hyperextension of the legs, cognitive deficits, language impairment, learning difficulties, and behavioral problems (82). Because of the lack of specific antiviral therapy, high case fatality, and substantial morbidity, prevention of JE through vaccination and mosquito precautions is important.

JE Among Travelers
For most travelers to Asia, the risk for JE is very low but varies on the basis of destination, duration, season, and activities (3,9,10,13,118). The overall incidence of JE among persons from nonendemic countries traveling to Asia is estimated to be less than one case per 1 million travelers. However, the risk for JE among expatriates and travelers who stay for prolonged periods in rural areas with active JEV transmission is likely similar to that among the susceptible resident population. Recurrent travelers or travelers on brief trips might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission (119--121). Short-term (<1 month) travelers whose visits are restricted to major urban areas are at minimal risk for JE. Because JEV is maintained in an enzootic cycle between animals and mosquitoes, in endemic areas where few human cases occur among residents as a result of vaccination or natural immunity, susceptible visitors might be at risk for infection. JE should be suspected in any patient with evidence of a neurologic infection (e.g., encephalitis, meningitis, or acute flaccid paralysis) who has recently returned from a country in Asia or the western Pacific in which JE is endemic.

During 1973--2008, a total of 55 cases of travel-associated JE among persons from nonendemic countries were reported in the literature (6--8,119--139). A small increase in the number of reported cases occurred in each of the three most recent 10-year periods: 1999--2008 (n = 20), 1989--1998 (n = 17), and 1979--1988 (n = 14). Two cases were reported during 1973--1978, and for two additional published cases, the date of onset was unknown but occurred before 1993. Overall, 33 (60%) cases occurred in tourists, nine (16%) were in expatriates, and six (11%) were in soldiers; the type of travel was unknown in seven (13%) cases. The tourist category included three case-patients who were traveling to visit friends and relatives and two students on study-abroad programs. The case-patients were citizens of 17 different countries. The countries where infection was most commonly acquired were Thailand (n = 19), Indonesia (n = 8), China (n = 7), the Philippines (n = 5), Japan (n = 4), and Vietnam (n = 3). Among the 46 cases for which age was recorded, patients ranged in age from 1 to 91 years (median: 34 years); five (9%) of the 55 cases occurred among children aged ≤10 years and 10 (18%) among adults aged ≥60 years. Overall, 29 (53%) of the 55 case-patients were male, and 22 (40%) were female; sex was unknown for four cases (7%). Ten (18%) of the reported cases were fatal, 24 (44%) patients survived but had sequelae, and 12 (22%) patients recovered fully; outcome was unknown for nine (16%) patients. None of the patients was known to have received JE vaccine.

For 37 (67%) of the travel-associated cases, more complete information on itineraries and activities was available (8). Many reports documented exposures that likely increased risk for infection, including travel to rural areas, living in proximity to farms or in the jungle, staying in unscreened accommodations, or participating in outdoor activities such as trekking. Duration of travel for these cases ranged from 10 days to 34 years and was ≥1 month for 24 (65%) travelers. Of the 13 travelers staying <1 month, 10 (77%) had trip duration of 2--<4 weeks, and three (23%) traveled for 10--12 days. Among these shorter-term travelers, three (23%) travelers spent the majority of their time in rural areas, six (46%) stayed in coastal or nonrural areas but took day trips to rural areas or national parks, and one (8%) stayed in a coastal area and took day trips to unspecified destinations; no exposure-related information was provided for three (23%) travelers. No cases occurred among business or other short-term travelers who visited only urban areas.

Before 1973, >300 cases of JE were reported among U.S. military personnel or their family members (72,79,140--143). Of 15 JE cases reported among travelers from the United States during 1973--2008, only four were reported after 1992, when JE-MB was first licensed in the United States; none of these patients had received JE vaccine (7,122).

In 2004, an estimated 5.5 million entries of U.S. travelers occurred into JE-endemic countries (144). The proportion of these travelers who received JE vaccine or for whom JE vaccine should have been recommended is unknown. However, <30,000 doses of JE vaccine are distributed annually in the U.S. civilian market. A recent survey of adult travelers on direct flights from the United States to Asia determined that 415 (25%) of 1,691 participants described itineraries for which JE vaccination should have been considered according to ACIP recommendations, including 330 (20%) who planned to spend >30 days in a JE-endemic country and another 85 (5%) shorter-term travelers who planned to spend a substantial proportion of their time in endemic rural areas (145). Of these at-risk travelers, only 47 (11%) reported receiving ≥1 dose of JE vaccine. Among 164 unvaccinated at-risk travelers who had visited a health-care provider to prepare for their trip, 113 (69%) indicated that their health-care provider had not offered or recommended JE vaccine. In Europe, an assessment based on the number of JE vaccine doses distributed suggested that <1% of travelers to endemic countries received JE vaccine (118), underscoring the need for health-care providers to understand the risks for JE disease among travelers and the measures available to prevent it.

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Japanese Encephalitis Vaccines