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This site is being maintained for historical purposes, but has had no new entries since October 1998. To find more recent articles, please visit the following:
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Japanese Encephalitis Vaccines
Theodore F. Tsai, MJ.D., M.P.H., Arbovirus Diseases Branch, CDC, Fort Collins, Colorado, NCID;
Publication date: 01/01/1990
Table of Contents
Clinical Illness
Congenital Infection
Epidemiology
Endemic Areas of Asia
Travelers and Expatriates
Active Immunization
Inactivated Mouse Brain-Derived JE Vaccine
Vaccine Stability and Storage
Viral Strains
Dosage and Route of Administration
Inactivated Primary Hamster Kidney Cell-Derived JE Vaccine
Viral Strain
Dosage and Route of Transmission
Enhanced inactivated JE vaccine produced in primary hamster kidney cells
Live-Attenuated Vaccine
Vaccine stability and storage
Virus strain
Dosage and route of administration
Results of Vaccination
Inactivated Mouse Brain-Derived JE Vaccine
Immunogenicity
Efficacy
Persistence of immunity and protection
Inactivated Primary Hamster Kidney Cell-Derived JE Vaccine
Live-Attenuated JE Vaccine
Side Effects
Inactivated Mouse Brain-Derived JE Vaccine
Inactivated Primary Hamster Kidney Cell-Derived JE Vaccine
Live Attenuated JE Vaccine
Vaccine Indications
Endemic Areas
Expatriates
Travellers
Research Laboratory Workers
Public Health Results of Vaccination
POINT OF CONTACT FOR THIS DOCUMENT:
Tables
Fetal Outcome After Laboratory-Confirmed JE During Pregnancy
JE Cases in Expatriates and Travellers
JE In Unimmunized American And Other Western Military Personnel
Factors Associated With Risk For Acquiring JE During Travel to Asia
JE Vaccines
Recommended Immunization Schedule for Inactivated JE Vaccine
Passage History Of JE SA14-14-12 Virus
Efficacy Of SA14-5-3 Attenuated JE Vaccine Guangtong
Immunogenicity Of Inactivated JE Vaccine
Homologous And Heterologous Neutralization Antibody Responses
Immunogenicity Of Inactivated JE Virus Mouse-Brain-Derived Vaccine
Efficacy of Inactivated JE Vaccine
Efficacy Of Inactivated JE Vaccine Produced In Hamster Kidney Cells
Inactivated JE Vaccine Produced in Hamster Kidney Cells/2 Doses
Immune Response to SA14-14-2 Attenuated JE Vaccine
Protective Efficacy of SA14-14-2 JE Vaccine Children 1-10 years
Reported Side Effects Of Inactivated Mouse-Brain Derived JE Vaccine
Reported Neurological Manifestations Associated With JE 1965-80
Reported Neurological Manifestations Associated with JE 1965-70
Allergic Reactions Following Immunization With Activated JE Vaccine
Risk Of JE By Country, Region and Season
JE Immunization Coverage And Incidence
Figures
Reported Japanese Encephalitis Cases By Country, 1986 - 1990
Transmission Cycle Of JE Virus
Reported Cases Of Encephalitis By Age
History Of Development Of Inactivated JE Vaccine
Antibody Response After JE Vaccination
JE Incidence In Relationaship To Vaccine Distribution
JE Incidence In Relationship To Pesticide Consumption
Relationship Declining Land Area Rice Paddies/Cx.Tritaeniorhynchus
JE Incidence, Beijing 1950-1985
Introduction
Japanese encephalitis (JE) is a mosquito-borne arboviral disease of major public health importance in Asia. More than 35,000 cases and 10,000 deaths are reported annually from the region but official reports undoubtedly underestimate the true number of cases (1,2,3). After human immunodeficiency virus infection, JE may be the leading cause of viral encephalitis worldwide. If the annual incidence of herpes encephalitis, probably the most common sporadic viral encephalitis, is estimated at 5 per million, then approximately 25,000 such cases occur worldwide each year (5). Despite its regional distribution in Asia, with more than 3 billion people and 60% of the world's population, regional morbidity from JE may exceed worldwide morbidity from herpes encephalitis. JE is a health problem of a major scale preventable by immunization.Recurrent summer outbreaks of encephalitis in horses and humans, consistent with JE, had been observed in Japan since the last century. An outbreak of epidemic proportions occurred in the summer of 1924 in Japan and Korea. More than 6,000 cases, 60% fatal, were reported from Japan alone (6). Clinical and epidemiologic features of the illness suggest that this and subsequent outbreaks in 1927, 1934, and 1935 were epidemics of JE (7,8). In 1924, a filterable agent from human brain tissue was isolated in rabbits and in 1934, Hayashi transmitted the disease experimentally to monkeys by intracerebral inoculation (9). JE viruses isolated from human cases in Japan in 1935 and in Beijing in 1949 provided the prototype Nakayama, Beijing and P3 strains respectively that are in principal use in vaccine production. The virus initially was called Japanese B encephalitis (the modifying B has fallen into disuse) to distinguish the agent from the etiology of Von Economo's type A encephalitis, which had different epidemiologic characteristics. The mosquito-borne mode of JE transmission was elucidated with the isolation of JE virus from Culex tritaeniorhynchus mosquitoes in 1938 and in field studies that established the role of aquatic birds and pigs in the viral enzootic cycle.
During the first half of the century, JE was transmitted in a pattern of perennial outbreaks in Japan, Korea and presumably in China (1). In 1958, an epidemic of 6,897 cases was described in Korea and as recently as 1982, 2,975 cases were reported (6). Outbreaks in Japan through 1965 frequently produced 3,000-5,000 cases (6,7). In China, few specific data are available, but the virus was isolated from a human case in 1940 and the inference of long standing endemic transmission in eastern China is supported by early seroprevalence studies yielding rates exceeding 85% (10). JE outbreaks gradually diminished in size and frequency in Japan and more recently in Korea, paralleling various secular changes associated with development, including widespread immunization. JE remains hyperendemic in China, except in some areas where immunization rates are kept high.
Although sporadic cases of viral encephalitis had been noted in northern Thailand before 1969, epidemic transmission of JE was first recognized that year, when an outbreak leading to 685 cases occurred in the Chiang Mai valley. Yearly outbreaks numbering in thousands of cases and hundreds of deaths recurred in the northern region and JE became a leading cause of mortality and disability in children. In the last two decades, hyperendemic JE transmission has spread within Thailand and in 1974, the first of several epidemics was recorded in an adjacent area of the Chiang Mai valley in Burma. In Vietnam, JE has become a major public health problem in the densely populated deltas of the Mekong river in the south and of the Red river in the north. Incidence rates exceeding
20/100,000 are reported from areas of the northern delta near Hanoi. The continued public health impact of JE in the region has led to efforts in Thailand and more recently in Vietnam to implement programs of childhood immunization and vaccine production.
The first indication of JE transmission in Southwest Asia was from Sri Lanka where an outbreak that appears to have been JE was reported in 1948. Sporadic cases and later, epidemics of JE were first recognized on the Indian sub-continent around Vellor (11,12). Outbreaks recurred exclusively in southern India until 1978 when JE epidemics were reported for the first time in the north, in Bihar, Uttar Pradesh and West Bengal. JE now is hyperendemic in 3 principal foci on the subcontinent: Northern India and Southern Nepal, Central India (Andrha Pradesh) and South India (Goa, Karnataka, and Tamil Nadu). These areas of enzootic viral transmission have in common intensive rice cultivation supported by moderate to heavy rainfall or irrigation. In Sri Lanka and southern Nepal, hyperendemic transmission of malaria and JE have followed deforestation and development of areas in the Mahaweli river project and the Terairespectively (13). Throughout Asia, as a result of irrigation and development, JE and other mosquito-borne diseases have become prevalent in areas where low levels of enzootic transmission previously were maintained or in new areas, where conditions receptive to viral transmission have been created and the virus introduced (14). Agricultural development and irrigation are the principal forces changing patterns of JE transmission in Asia.
Clinical Illness
The vast majority of infections are inapparent and only one in 25-1000 infections results in symptomatic illness (15-20). The principal clinical manifestation of illness is encephalitis; however, milder clinical presentations, such as aseptic meningitis or a simple febrile illness with headache, are common (16-33). The incubation period is 5-15 days. Illness usually begins with an abrupt onset of high fever, change in mental status and headache, followed gradually by disturbances in speech, gait or other motor dysfunctions. The initial presentation in children usually begins with gastrointestinal symptoms of anorexia, nausea, or abdominal pain. Irritability, vomiting and diarrhea or an acute convulsion may be the earliest objective signs of illness in an infant or child. Seizures occur in over three-fourths of pediatric patients but are observed less frequently in adults. Conversely, headache and meningismus are more common in adults.A progressive decline in alertness eventually leads to coma of varying degree. A majority of patients become totally unresponsive or responsive only to pain. Generalized weakness and changes in tone,
especially hypertonia and hyperreflexia, are the most common motor abnormalities, but focal motor deficits, including paresis and hemi- and tetraplegia, cranial nerve deficits (especially central facial palsy), and abnormal reflexes also may be present. Sensory disturbances are seen less frequently. Central hyperpnea, hypertension, pulmonary edema and urinary retention also may complicate the illness. Although symptoms suggest elevated intracranial pressure in many cases, papilledema and other signs of raised intracranial pressure are rarely seen and dexamethasone therapy does not improve outcome (34,35). Signs of extrapyramidal involvement, including tremor, mask-like facies, rigidity, and choreoathetoid movements are characteristic of JE, but these signs may be obscured initially by generalized weakness (33). Treatment is supportive.
In three cases, symptoms recurred several months after resolution of the acute illness (36). Recrudescent symptoms were linked to recovery of virus from persistently infected peripheral lymphocytes that circulated despite the presence of specific antibody. Persistent JE viral infections previously have been observed in experimentally infected mice (37,38). The significance of these observations and conditions under which JE virus persists in humans are unclear.
Approximately 25% of cases are fatal, some occurring after a brief prodrome and fulminant course lasting a few days and others after a more protracted course in coma. Young children (under 10 years) are more likely to die, and if they survive, they are more likely to have residual
neurological deficits. Overall, approximately one third of surviving patients exhibit serious residual neurological disability (39-43). Principal sequelae include memory loss, impaired cognition, behavioral disturbances, convulsions, motor weakness or paralysis, and abnormalities of tone and coordination. Persistent EEG abnormalities are common in children (42).
Poor prognosis has been associated with a short prodromal interval, clinical presentation in deep obtundation, respiratory dysfunction, prolonged fever, status epilepticus and the presence of Babinski's sign (44-46). The presence of virus in cerebrospinal fluid (CSF), high CSF alpha interferon levels, and low CSF levels of viral specific IgM and IgG antibodies are highly associated with a fatal outcome. These clinical laboratory findings are inter-correlated and together they probably reflect uninhibited CNS viral proliferation as the underlying cause of poor outcome (see below).
Clinical laboratory examination discloses a moderate peripheral leucocytosis with neutrophilia and mild anemia. The CSF usually is under normal pressure. Pleocytosis typically is in the range of ten to several hundred and rarely more than a thousand cells per cubic mm; however, a significant proportion of patients have fewer than 10 cells on an initial examination. Neutrophils may predominate in early samples but a lymphocytic pleocytosis is typical. CSF protein is moderately elevated in about 50% of cases.
Computed tomographic (CT) and magnetic resonance imaging (MRI) scans reveal low density areas and abnormal signal intensities in the thalamus, basal ganglia and putamen (47). The distribution of abnormalities
correlates with clinical findings of tremor, rigidity and abnormal movements that are common in the acute phase of illness.
Pathologic abnormalities are found chiefly in the CNS; however, inflammatory changes in the myocardium and lung and hyperplasia of reticuloendothelial cells in the spleen, liver and lymph nodes have been described (48). Cerebral edema and congested leptomeninges are visible on gross examination of the brain and punched-out necrolytic lesions in the grey matter may be conspicuous (48-54). Histopathologic examination discloses a characteristic pattern of microglial proliferation with the formation of microglial nodules surrounding dead or degenerating neurons in which viral antigen can be demonstrated by immunohistochemical staining (35,50). Gliomesenchymal nodules are distributed in the superficial and deep grey matter, including the brain stem, thalamus, basal ganglia, hippocampus and anterior horn cells of the spinal cord. Similar destruction of and microglial reaction around Purkinje cells also are evident in the cerebellum. Necrolytic lesions appearing as cysts are found in a similar distribution in the grey matter. In patients with residual neurologic impairment dying several years after resolution of the acute illness, scarred rarified foci are found in a characteristic distribution in the thalamus, substantia nigra and hippocampus (54).
Congenital Infection
Relatively little is known of the risks of JE acquired in pregnancy and the consequences of intrauterine infection. In areas where JE is endemic, children are exposed and become immune at an early age. Consequently, few women of childbearing age are at risk for the disease. JE virus is an established cause of abortions and abnormal births in pigs (55); however, the first associations of JE with adverse events in human pregnancy were reported as recently as 1980 (56,57).In a series of outbreaks in Uttar Pradesh, India, JE infections were documented in 9 pregnant women (Table 1). Four women who acquired JE in the first or second trimesters miscarried and JE virus was recovered from products of conception in 2 cases. In 5 women who acquired JE in the third trimester, no adverse outcomes of pregnancy were observed. JE viral specific IgM was not measured in the infants and it is unknown if they were congenitally infected. Experimental data also suggest that risk of congenital infection may be related to gestational age (58-60). Human placental organ cultures, obtained from medically terminated pregnancies at 8-12 weeks gestation, supported JE viral replication but tissues from full term pregnancies were resistant to infection (60).
The spectrum of adverse outcomes associated with congenital JE viral infections is undefined. It is unknown whether congenital JE viral infection causes malformations. It is also unclear whether asymptomatic JE infection in a pregnant woman leads to fetal infection or adverse outcome.
Virology
JE virus is one of 66 Flaviviridae, enveloped, positive sense, single stranded RNA viruses that largely are vector-borne (9,61). Morphologically, flaviviruses are spherical, approximately 40 nm in diameter, and composed of a lipid bilayer surrounding a nucleocapsid containing the 11 kb genome complexed with a capsid (C) protein. Surface projections on the membrane are composed of a glycosylated envelope (E) and membrane (M) proteins. A pre M glycoprotein, present in intracellular nascent virions, is cleaved to the M protein found in mature extracellular virions.Important biological activities are associated with the 53 kd E protein including hemagglutination, viral neutralization, virion assembly, membrane fusion and viral binding to cellular receptors. The hydrophobic carboxy terminus provides a membrane associated anchor. An extensive ectodomain, stabilized by disulfide bridging, is folded into three major regions, which are variably related to biologic functions and to antigenic determinants, representing flaviviral group specific, subgroup and viral specific epitopes. JE viral specific and cross reactive neutralizing epitopes have been mapped to specific regions of the E protein and immunization with vaccinia recombinants expressing pre M and E glycoproteins protects experimentally infected mice (61-65).
Binding of JE virions to certain cells of CNS lineage may be associated with the presence of specific neurotransmitter receptors (66). Following attachment and approximation to the cell membrane, virions enter the cell through local membrane disruptions (67). Virions are uncoated, releasing genomic RNA into the cytoplasm where viral replication proceeds. The single open reading frame is co-translationally processed by successive proteolytic cleavages into structural and nonstructural proteins (see above) (68). Viral RNA and protein are synthesized on smooth and rough endoplasmic reticulum (RER) and accumulate in RER cisternae where virions are assembled. Virions are released through the Golgi apparatus by secretory exocytosis (69-71).
JE virus is antigenically related to St Louis encephalitis (SLE) virus, West Nile virus and several flaviviruses found in Australia, e.g., Murray Valley encephalitis, Kunjin, Alfuy and Kokobera viruses (72,73).
Pathogenesis
After an infectious mosquito bite, viral replication occurs locally and in regional lymph nodes. Virions disseminate to secondary sites where further replication contributes to an augmented viremia. Central nervous system invasion probably occurs from the blood, by antipodal transport of virions through vascular endothelial cells (35,74,75). Infection spreads in the CNS by viral dissemination through the extracellular space or by direct intercellular spread. Sensitized T helper cells stimulate an inflammatory response by recruiting macrophages and lymphocytes to the perivascular space and into the parenchyma (35,75). Cells in the inflammatory response surround and clear infected neurons and later, these foci of degenerating neurons evolve into characteristic glial nodules (48-54). The predominant cell type in the CSF and in the parenchyma are helper/inducer (CD 4) T cells. B lymphocytes are confined chiefly to the perivascular space (75).The reasons that only one in several hundred infections develops into symptomatic neuroinvasive disease are enigmatic. Factors that contribute to risk for neuroinvasion are only partially known but probably include genetic and acquired host factors (76,77). Genetic resistance to infection has been described in mice and some observations suggest epidemiologic differences in case/infection ratios in Caucasian and indigenous Asian populations (16-20). Circulating antibody plays a critical role in modulating infection by limiting viremia in the pre-neuroinvasive phase and both JE viral specific and heterologous (e.g., dengue) antibodies contribute to protection. Experimentally infected monkeys immunosuppressed with cyclophosphamide have no measurable antibody response (78), and exhibit an increased susceptibility to paralytic encephalitis and a diminished CNS inflammatory reaction. The correlation of intrathecal antibody levels and outcome indicates that humoral immunity also is important in limiting infection after neuroinvasion (35,46,79-83).
Conditions that compromise the integrity of the blood-brain barrier also may be important factors increasing risk for neuroinvasion and neurodissemination. Several observations suggest a possible role for dual infection with another microbial agent as a risk factor (51,84-87). A disproportionate number of fatal JE cases have pathological evidence of neurocysticercosis at autopsy (51,85). Experimental dual infections of mice with herpes and JE viruses increases CNS dissemination of the later (86). There have been anecdotal observations of dual herpes and JE viral infections in autopsied human JE cases and in one epidemic, simultaneous CNS infections with mumps and JE were described (87). These observations support a potential role for concomitant CNS infection as a cofactor in JE pathogenesis; however, other physiologic or structural conditions that compromise the integrity of the cerebrovasculature or the blood-brain barrier also may contribute to risk. Atherosclerotic and hypertensive cerebrovascular disease are suspected as risk factors for St Louis encephalitis and by analogy should be investigated as risk factors for JE (88,89). Foreign bodies, such as ventricular shunts, may predispose to viral neuroinvasion but the importance of anatomical disruptions resulting from head trauma and previous surgery are unknown (90).
Simultaneous infections also may contribute to risk by altering the immune response to JE infection; diminished T cell associated immunity was shown in mice with experimental dual parasitic and JE viral infections (91,92). Athymic nude mice have an increased susceptibility to experimental subcutaneous or intraperitoneal infection with JE virus. In comparison to normal mice, nude mice have higher mortality rates, a faster progression to death and higher titers of infectious virus in brain (93). Specific JE viral immunity can be transferred passively with spleen cells from mice immunized with live attenuated JE vaccine (94). Mice immunized with live attenuated vaccine are able to resist experimental infections even when immunosuppressed with cyclophosphamide (94).
Diagnosis
Although a history of exposure to an endemic area and certain clinical features may suggest JE, clinical diagnosis is unreliable and laboratory confirmation, principally by serology, is necessary (95,96). JE virus occasionally can be recovered from blood in the pre-neuroinvasive phase but usually, patients presenting with encephalitis no longer are viremic. Virus can be recovered from CSF in about one third of patients, chiefly in cases that ultimately are fatal (97). JE virus produces cytopathic effects in Vero, LLCMK2 and PS cells and the virus kills suckling mice inoculated intracerebrally.Mosquito cell lines, C636 and AP61 cells, also are sensitive systems for viral isolation. Infection is silent in C636 cells and inoculated cultures must be examined for viral antigen by immunofluorescent (IF) or other techniques. Viral isolates are conveniently identified by IF with viral specific monoclonal antibodies or by neutralization.
The most widely used diagnostic method is IgM capture ELISA
(46,98-100). Specific IgM can be detected in CSF and or serum in approximately 75% of patients within the first 4 days after onset of illness and nearly all patients are positive 7 days after onset. In the majority of cases, IgM is detectable in CSF earlier than in serum; however, in some cases, the reverse holds and both fluids should be tested to maximize sensitivity.
In one small study, antigen bearing infected cells were identified in CSF by IF before intrathecal IgM was detected (101). Greater experience with this procedure is needed to determine the sensitivity of this approach to early diagnosis. The use of polymerase chain reaction to detect viral genomic material in CSF has not been reported.
A specific diagnosis also can be confirmed by demonstrating four fold or greater changes in antibody titer by conventional serologic procedures e.g. hemagglutination inhibition, complement fixation, IF, ELISA or neutralization. Heterologous flaviviral antibodies, e.g., to dengue and West Nile viruses are a potential source of false positive reactions. These infections can be differentiated by epitope blocking ELISA or by obtaining ELISA absorbance ratios to the respective antigens (99,102). Synthetic antigens produced from proteins of specific viral envelope domains also offer promise in improving the specificity of serologic diagnosis (103-105).
Epidemiology
Endemic Areas of Asia
Japanese encephalitis is transmitted in epidemics and/or in an endemic pattern in virtually every country of Asia (Figure 1) (1-3,106-126). Officially reported cases significantly underestimate the magnitude and extent of risk because of under-reporting and because of widespread immunization in some countries. Transmission is seasonal, roughly May to September, in temperate areas of the region: the People's Republic of China, Korea, Japan, subtropical areas of Southeast Asia and certain far- eastern locations in Russia. The transmission season is somewhat longer, April through October, in more southerly areas of the region. In tropical locations in Southeast Asia and on the Indian subcontinent, viral transmission follows the seasonal occurrence of rains and migratory patterns of avian vertebrate amplifying hosts. Viral transmission may occur year round in some sites.JE is principally a disease of rural agricultural areas, where vector mosquitoes proliferate in close association with pigs, wading birds, and ducks, the principal vertebrate amplifying hosts (Figure 2)
(2,126-131). Humans and horses may become ill after infection but they are incidental to the transmission cycle (131-133). The means by which JE virus overwinters in temperate locations has not been proven, although experimental studies and field observations suggest that the virus may be transmitted vertically in vector mosquitoes (134-138). Viral persistence in vertebrate hosts, such as bats or reptiles, and annual reintroductions of the virus through migrations of birds or wind-borne mosquitoes also have been hypothesized as mechanisms (139-140).
Cx. tritaeniorhynchus is the principal JE vector in most areas of Asia; Cx. vishnui, Cx. gelidus, Cx. pseudovishnui, and related species are the chief vector species in India (2,107,128,129,141-143). These and other, principally culicine species, use ground pools and especially flooded rice paddies as larval habitat. In temperate regions, vector mosquitoes emerge in May and by July and August, they have reached their peak in abundance. Viral infection rates in vectors and the mensal distribution of cases generally peak somewhat later, in August and September. Although risk for human infection is closely tied to vector abundance, which in turn is associated with precipitation, agricultural practices, and specifically the irrigated cultivation of rice, exert a more profound influence on vector bionomics. A single paddy may produce more than 30,000 adult mosquitoes in a single day (2,14,125,144-146). Thus, mosquito numbers are associated principally with periodic flooding of rice fields, especially in areas without a defined rainy season.
By virtue of high levels and lengthy periods of viremia after infection, pigs are the principal host for viral amplification (147-149). Large aquatic birds may subserve this function in areas where pigs are absent. Other domesticated animals, such as dogs, sheep, cows, and chickens, and peridomestic passerine birds and rodents may become infected, but fail to develop a sufficient viremia to support further viral amplification. JE mosquito vectors are zoophilic; consequently, cows and certain other animals may reduce human risk by diverting vector mosquitoes (zooprophylaxis). Immunization of pigs prevents abortion and stillbirths and also may reduce viral transmission by limiting or preventing viremia in pigs (11,150-153). A dampening of viral amplification in the enzootic cycle potentially limits numbers of infected vector mosquitoes and risk of epizootic transmission to humans.
In rural villages, all elements of the enzootic transmission cycle are found in close proximity to human residences and activities. Figure 3(not available at this time). Consequently, exposure and infection occur at an early age (2,19-22,26-31). In hyperendemic areas, half of all cases are in children under 4 years and nearly all cases are in children under 10 (Figure 4). Cases in males exceed those in females by a ratio of two to one, a difference that may reflect greater outdoor exposure in males. Overall, incidence rates range from 1-10/10,000 per year. Seroprevalence studies disclose nearly universal infection by early adulthood and in areas where enzootic viral transmission is particularly intense, seroprevalence rates may increase by 10% per year during childhood.
In developed countries, such as Japan and Korea, JE incidence has fallen over several decades. Several factors have contributed to the decline, including immunization, secular trends toward a higher standard of living, a reduction in land under cultivation and other changes in agricultural practices, especially, increased use of pesticides and centralized pig production. These secular changes have been accompanied by a shift in the age distribution of cases toward older children and to adults. In Japan, age-specific incidence has become bimodal, with peaks in young children and in the elderly Figure 5 (not available at this time) (154). A similar pattern has been observed in developed areas within the PRC (155).
Risk factors for increased JE risk in the elderly have not been defined but they may parallel those for SLE, in which host-associated factors (e.g., cerebrovascular disease), rather than exposure factors are the principal components of risk with advanced age. The observation that JE virus persists in certain recovered patients also suggests the possibility of reactivated infection with declining immune competence in the elderly (see above).
Although risk for acquiring JE is greatest in rural areas, conditions that permit enzootic viral transmission exist within or at the periphery of many Asian cities. For example, JE cases in Taiwan are reported principally from Taipei and surrounding areas; in Vietnam, JE incidence is highest in and near Hanoi; and cases frequently are reported from suburban areas of major cities such as Bangkok, Beijing and Shanghai (155,156). Urban outbreaks have occurred recently in Lucknow, India. Sporadic reports of cases from Singapore and Hong Kong attest to the possibility of enzootic viral transmission near highly developed urban areas.
Travelers and Expatriates
Although JE vaccine is used principally in Asia to protect local populations, the vaccine also is marketed in developed countries, for travellers to and expatriates in Asia, especially the military.No systematic surveillance data are available on JE cases in travellers. However, data from published case reports, informal surveillance of laboratories that have a capability to diagnose the infection, and personal communications with ministries of health and travel clinics, indicate that risk for JE among foreign nationals in Asia is extremely low. Among 23 cases reported since 1978, 10 were known to be long term residents in Asia and of these, 7 were in U.S. military personnel or dependents (Table 2) (157-163). Only one case in an American traveller is known; 7 others were in military personnel or dependents, one was in a summer student, and in one case, the exposure history was unknown. Department of Transportation figures indicate that two to three million U.S. citizens travel to Asia by air each year; however, these figures are a crude estimate of the population at risk because most travellers have brief itineraries and they may not be exposed to areas associated with risk. Furthermore, between 1984-1987 some travellers to high risk areas may have availed themselves of vaccine in a CDC sponsored study. Nevertheless, these figures permit a crude estimation of annual incidence in American travellers of well under one in a million. Even if reports of traveller cases are too low by tenfold, the estimated incidence in American travellers still is within this order of magnitude.
An alternate estimate of risk can be derived by extrapolating from annual incidence rates in the resident population of a hyperendemic area. Annual incidence rates typically are in the range of 0.1 to 1/1000. Accepting the high estimate and recognizing that transmission is limited to about a five month period in most areas, the monthly risk in the resident population is 1/5000 per month or 1/20,000 per week.
Illness rates in residents of an endemic area, a large proportion of whom may be immune, undoubtedly underestimate risk to immunologically naive travellers. However, attack rates in unimmunized American, Australian and British soldiers exposed in Asia with one exception have been similar, ranging from 0.1 to 2.1/10,000 per week (Table 3) (17-20,162,164-169). Presumably, they had no background of immunity to flaviviruses and exposure in field conditions was extreme for many of the soldiers at risk. Furthermore, in some instances, these rates reflected exposure during years of epidemic transmission.
The relatively low risk for acquiring JE after a single mosquito bite can be appreciated by considering the following probabilities of infection and illness: (1) only bites of vector species are potentially infectious; (2) in extreme circumstances, viral infection rates in vector mosquitoes approach 3%; and (3) if an individual is infected, symptomatic neuroinvasive illness results in fewer than one in 200 infections. Cx. tritaeniorhyncus and other JE vectors feed chiefly in the crepuscular (twilight) periods at dawn and dusk and in the evening. Although they may enter houses to feed, they principally are exophilic and seek hosts outdoors. Travellers can further reduce their risk of exposure to infectious bites by avoiding outdoor exposure in the evening; wearing mosquito repellent and long sleeved shirts and trousers; and by using mosquito nets and sleeping in screened or air-conditioned rooms (170,172).
Risk for acquiring JE during travel is highly variable and depends on the destination and season of travel and activities of the individual (Table 4). Although travellers who remain in rural areas for extended periods are at greatest risk, cases have been reported in travellers after limited exposures to rural areas: a 10-year-old girl acquired JE after a few excursions into rural areas while on a two week holiday in Bali; and a case occurred in a 35-year-old British subject during travel to Hong Kong (157-158) (Table 2).
Passive Immunization
JE immune plasma and globulin are not commercially available. Experimental data in mice and anecdotal reports in human cases suggest a potential benefit of passive immunization (173,174). Experience from prophylaxis of tick-borne encephalitis with immune globulin indicates that antibody should be administered within a short period after tick exposure to be effective and that late administration, i.e., after 4 days, may worsen outcome (175). Although there are few data, early treatment with alpha interferon, perhaps in combination with immune plasma, may be the best approach to prophylaxis of illness after known exposure, such as in a laboratory accident (176-178). Contact the Centers for Disease Control or USAMRIID for availability of immune plasma.
Active Immunization
Worldwide, three JE vaccines are in widespread production and use (Table 5); however, only inactivated JE vaccine produced in mouse brain is distributed commercially and is available internationally (155,179-188).Inactivated JE vaccine and live attenuated JE vaccine, both grown in primary hamster kidney (PHK) cells, are manufactured and distributed exclusively in the People's Republic of China. Despite an apparently limited pattern of domestic distribution, more than 75 million doses of inactivated PHK vaccine and 25 million doses of live attenuated vaccine are produced and distributed annually in China, while all manufacturers in Japan produce approximately 11 million doses of mouse brain derived vaccine for domestic use in Japan. Biken, the principal Japanese manufacturer of inactivated mouse brain vaccine, distributes about 2 million doses abroad.
Although mouse brain-derived, inactivated JE vaccine is distributed internationally by Biken and the Korean Green Cross, the vaccines are not licensed and are available only on an investigational basis in most countries of Europe, North America, and Australia. After an American student in Beijing died of JE, CDC made the Biken vaccine available to American travellers and to the military under an IND exemption. More than 17,000 doses were distributed through travel clinics between 1984-1987. Since 1987, the manufacturer has distributed vaccine exclusively to the military because of liability concerns (159,160,171,189). The Biken vaccine is now under consideration for licensure in the United States and if approved will be distributed by Connaught Laboratories, Inc. as JEVax.
Inactivated Mouse Brain-Derived JE Vaccine
Mouse brain-derived inactivated JE vaccines were produced in Russia and Japan in the 1930s and efficacy was shown against Russian autumnal encephalitis (a synonym for JE) (190). During World War II, a simple uncentrifuged 10% suspension of infected mouse brain, inactivated with formalin, was produced in the United States as a vaccine for the military. The vaccine was variably immunogenic but field evaluations of efficacy could not be completed (191-195).A more stable inactivated chick embryo-derived vaccine also was developed by the U.S. military and an 80% efficacy was shown in children given a combination of mouse brain, and chick embryo-derived vaccines (196-200). However, the later vaccine was less immunogenic in adults and its efficacy in soldiers never could be evaluated. Although this vaccine was given to all U.S. soldiers assigned to the Asia from 1948-1951, use was discontinued in 1952 after review of available data failed to produce convincing evidence of immunogenicity and efficacy (166-169).
Successive refinements of the mouse brain vaccine were introduced by research institutes in Japan leading to the current purified vaccine (Figure 6) (180,181,201,202). Mouse brain-derived vaccines are produced in Japan and elsewhere following a similar sequence of centrifugation, ultrafiltration, protamine sulfate precipitation, and formalin inactivation in the cold, followed by further purification by ultrafiltration, ammonium sulfate precipitation and continuous zonal centrifugation on sucrose density gradients. National standards in Japan specify minimum immunogenicity and potency in mice (compared with a vaccine standard) and maximum total protein (80 mcg/ml) and myelin basic protein content (2 ng/ml) among other specifications. Bulk vaccine is diluted with medium 199 and phosphate buffer to meet a potency standard (203). The vaccine is stabilized with gelatin and sodium glutamate and is preserved with thimerosal. In Japan, the vaccine is distributed principally in liquid form and it is lyophilized (to be reconstituted with sterile water) for international distribution.
Vaccine Stability and Storage
Lyophilized Biken vaccine is stable at 4 degrees C for at least one year and retains >90% of its potency after 28 weeks at 22 degrees C. At 37oC, lyophilized vaccine retains 95% of its original potency after 4 weeks. After reconstitution, vaccine is stable at 22 C for at least two weeks, but at 37 degrees C, potency declines to 85% (204).A field study in Thailand showed that seroconversion rates were higher after immunization with lyophilized vaccine than with liquid vaccine. A moderate loss of potency was demonstrated after liquid vaccine was exposed to simulated field conditions (205).
Viral Strains
A natural diversity of JE viral strains has been demonstrated in minor antigenic differences among strains and in biological characteristics such as growth in cell culture and in neuroinvasiveness in experimentally infected mice (206-217). Genetic characterization of diverse viral strains by limited sequence analysis has provided a topographic classification that correlates with certain epidemiologic characteristics (213). It is unclear whether these laboratory markers of strain variation are reflected in different clinical patterns of infection or virulence in humans.The Nakayama strain of JE virus, isolated from spinal fluid of a human case in 1935, and maintained by continuous mouse brain passage, has been the principal strain used in mouse brain-derived vaccines produced
throughout Asia (180,181,201). The strain was chosen because of good propagation characteristics and because it provided cross-protection against other JE viral strains in mice. Because of the expansion of epidemic JE to wider areas of Asia, cross-immunization studies were repeated with strains from diverse areas of Asia. Experimental studies in mice indicate that strains of the JaGAr-01/Beijing type (e.g., Beijing-1, known as P-1 in the PRC, and the equivalent P-3 strain, see below) confer a broader neutralizing antibody response against various JE viral isolates than the Nakayama strain Figure 7 (not available at this time) (218-220). Beijing virus grows to higher titer and the vaccine produces higher heterologous antibody titers in immunized mice compared with Nakayama vaccine.
In humans, however, respective immunogenicities of Nakayama and Beijing-1 vaccines are similar and although in each case seroconversion rates and antibody titers are higher to the homologous strain, there is little evidence that Beijing-1 vaccine provides better heterologous immunity (220,221). Efficacies of individual Beijing and Nakayama vaccines in humans have not been compared, however, in one field trial, bivalent vaccine, containing both Nakayama and Beijing antigens, was no more efficacious than standard vaccine made from the Nakayama strain alone (see below) (222). Biken, the principal Japanese manufacturer of JE vaccine, has used the Beijing-1 strain since 1989 in vaccine produced for domestic consumption. In the future, the Beijing strain may replace Nakayama virus in all JE vaccine manufactured by Biken.
Dosage and Route of Administration
In many areas of Asia, Nakayama vaccine is given subcutaneously in two 1.0 ml doses one to four weeks apart (0.5 ml for children one to three years), with a booster dose at one year and thereafter at three year intervals. In practice, immunization schedules are quite variable. The Biken package insert recommends an interval of one to two weeks for primary immunization; however, most recent immunogenicity studies use a four week interval. Primary vaccination begins at 18 months in Thailand and in Taiwan and for many Japanese children, at three years. In Taiwan, a third dose is given at 3 years and a final booster is administered in schools at 7 years. Boosters are offered yearly in some Japanese schools.Vaccine produced from Beijing-1 virus is formulated with a higher antigen concentration; the recommended dose is 0.5 ml and 0.25 ml for children under three (220,221).
Immunogenicity studies in western subjects indicate that 3 doses are necessary for an adequate antibody response (see below) (159,222-224). The ACIP recommends three doses on days 0, 7 and 30 (225). An abbreviated schedule of days 0, 7, and 14 also results in uniform seroconversion; however, neutralizing antibody titers are significantly lower (Table 6) (226). Approximately 80% of vaccinees respond after two doses and this schedule is not recommended (159). Recommendations for booster doses are based on limited data. A conservative approach is to give a booster dose one year after the primary series and thereafter at 3 year intervals or as determined by serologic monitoring (226).
There are no data on simultaneous administration of JE vaccine with other viral or bacterial vaccines or with other biologicals. It is unknown whether malaria prophylaxis with chloroquine or mefloquine adversely affects the immune response to JE vaccine. Previous experience with inactivated rabies vaccine suggests that this issue should be examined.
Inactivated Primary Hamster Kidney Cell-Derived JE Vaccine
Inactivated JE vaccine prepared in PHK cells is produced exclusively in the People's Republic of China. It has been the PRC's principal JE vaccine since 1968, when it supplanted a less immunogenic chick embryo cell culture-derived vaccine (155). Approximately 75 million doses are distributed annually. The PRC previously had relied on a succession of inactivated mouse brain and whole chick embryo-derived vaccines as described above. Attempts to produce JE vaccine in cell cultures were prompted by the desire to avoid brain antigens and allergic reactions associated with the crude vaccines and to improve immunogenicity and ease of production. Primary hamster kidney cells were discovered to be the best of several primary and continuous cell cultures as a substrate for viral propagation (227).Vaccine is prepared in primary cell cultures derived from kidneys of golden Syrian hamsters. Monolayers are washed of growth medium and infected with JE virus. One day later, infected monolayers are washed and refed. The supernatant cell culture fluid is inactivated with 0.5% formalin, stabilized with 0.1% human albumin and is tested for residual infectivity and potency. Liquid vaccine retains potency for more than 2 years at 4-8 degrees C.
Viral Strain
The P-3 strain of JE virus, recovered in 1949 from brain of a human case, is the basis for vaccine produced by several regional biologics institutes (Table 5). The strain, isolated in the same epidemic as the P-1 (Beijing-1) strain (see above), had been passaged 70 times in mouse brains and is maintained at the National Institute for Control of Pharmaceutical and Biological Products (NICPBP) in Beijing. Inactivated PHK cell-derived vaccine made from the P-3 strain is more immunogenic, produces a better heterologous antibody response (to Nakayama virus) and confers greater cross-protection in mice than the Biken mouse brain-derived Nakayama strain vaccine. The inclusion of both P-3 and Nakayama strains in a bivalent inactivated PHK cell culture vaccine was synergistic in mouse protection tests (155). This experimental formulation has not been evaluated in human trials.Dosage and Route of Transmission
Vaccine is administered subcutaneously, in two 0.5 ml doses, one week apart, to children six to 12 months of age. JE vaccine is given principally in large campaigns in early spring without concurrent administration of other vaccines. Booster doses are given one year later (0.5 ml) and at 6-10 years of age (1.0 ml). JE vaccine is included in Expanded Program of Immunization schedules in some demonstration areas e.g. Beijing, Shanghai. The vaccine costs approximately three U.S. cents per dose.Enhanced inactivated JE vaccine produced in primary hamster kidney cells
Experimental inactivated vaccines with higher potencies have been formulated by concentrating the standard inactivated PHK-derived vaccine through an ultrafilter (tenfold concentrated vaccine) followed by ultracentrifugation (purified virion vaccine). In a field trial, one subcutaneous 1.0 ml dose of either enhanced potency vaccine produced uniform seroconversion to homologous P-3 antigen and levels of heterologous antibody to Nakayama virus similar to those obtained with two doses of standard vaccine (155).Live-Attenuated Vaccine
Attenuated JE viral strains have been sought by passaging wild strains serially in various cell culture systems including PHK, chick embryo and embryonic mouse skin cells (183-188,227-231). Loss of neurovirulence in mice, hamsters, and/or pigs suggested the possibility of safe use in humans. However, in the case of OCT-541, a temperature dependent strain obtained by serial PHK cell passage, and the best characterized of the early attenuated viruses, overattenuation had led to a loss of infectivity in horses and in humans. Building on Hammon's work, workers at the NICPBP in Beijing pursued the attenuation of JE virus in PHK cells and developed a live attenuated JE virus SA14-14-2 vaccine strain, that was safe and immunogenic (Table 5). The vaccine's efficacy was demonstrated in field trials and was licensed in the PRC in 1988. Currently, 25 million doses are distributed annually in five southern provinces, but expanded production and distribution are planned.Several hundred ampoules of seed virus, prepared from the seventh passage level of SA14-14-2 virus, are maintained in lots at the NICPBP in Beijing. Lyophilized seed virus is provided to the production institute where it is passaged successively three times for the production seed. PHK cells are obtained from ten day old golden Syrian hamsters maintained in a closed colony at the Chengdu Biologics institute. Monolayers are inoculated with diluted virus and cells are fed with minimal essential medium containing 0.25% human albumin. Infected cell culture fluid with an infectious titer of approximately 10(8.5) pfu per ml is harvested and filtered and the resulting liquid vaccine is lyophilized. Gelatin, 1%, and sucrose, 5%, are added as stabilizers. Lyophilized vaccine is reconstituted with sterile saline (232).
Vaccine must meet standards for freedom from adventitious agents, absence of neurovirulence in adult mice and for stability against reversion to neurovirulence after intracerebral passage in suckling mice. Potency is established in mice by measuring protection against P3 viral challenge 14 days after immunization with a single vaccine dose. The vaccine should provide >80% protection against challenge with approximately 1000 mouse LD(50) (a 10(-5) dilution of standard viral challenge dose of approximately 108 mouse LD(50)). Vaccine titer must exceed 10(6.5) TCID(50)/ 0.1 ml and most lots have tenfold higher infectious titers (233).
Vaccine stability and storage
The infectious titer of lyophilized vaccine is unchanged after storage at 37 degrees C for 10 days, at room temperature for four months or at 4-8 degrees C for one year. After reconstitution with sterile saline or distilled water and storage at 23 degrees C, the vaccine's infectious titer is stable for 2-4h or 2h respectively (232,233).Virus strain
The vaccine parent strain, SA14, was isolated in 1954 from Cx. tritaeniorhychus mosquitoes captured in Xian (Table 7)(183-188,234-237). After its isolation and 11 serial passages in suckling mice, the virus was attenuated through 100 passages in primary hamster kidney cells. Neurovirulence in monkeys had been lost at this passage level. Further plaque selection and cloning in chick embryo cells and subpassages in mice and hamsters by peripheral and oral infection were necessary, however, to obtain a stable non-neurovirulent virus. The resulting virus, SA14-5-3, no longer reverted to an established criterion of neurovirulence after intracerebral passage in suckling mice but, the virus remained potent in protecting immunized mice from viral challenge. SA14-5-3 vaccine was shown to be safe in humans. Field trials in endemic areas disclosed seroconversion rates > 85%; however, in subjects from non- endemic areas, seroconversion rates of only 61% were obtained (183,186). Expanded field trials in southern China, involving more than 200,000 immunized children, confirmed the vaccine's safety and yielded efficacies ranging from 88 to 96% (Table 8) (238). However, the vaccine's poor immunogenicity in subjects from non-endemic areas, who had no preexisting flaviviral antibodies, suggested that SA14-5-3 virus, like previous live JE virus candidate vaccines, had been overattenuated and did not replicate uniformly in humans. To increase immunogenicity, SA14-5-3 virus was serially passaged five times by subcutaneous inoculation of suckling mice (184). After plaque selection and cloning twice in PHK cells, the SA14-14-2 strain was obtained. SA14-14-2 virus met criteria for stable attenuation but was more immunogenic in humans, producing seroconversion rates >90% in non-immune subjects (186,186). In mice, the vaccine conferred broad immunity against numerous JE viral strains (234).
Further evidence of the strain's reduced neurotropism comes from experimental studies in athymic nude mice. No deaths or histopathologic abnormalities were observed after intraperitoneal or subcutaneous inoculation of a viral dose >107 TCID50, and virus could not be recovered from brain 94. Although cyclophosphamide increases susceptibility of mice (and monkeys, see above) to virulent JE virus, cyclophosphamide treatment did not increase mortality of mice inoculated peripherally with SA14-14-2 virus (94).
SA14-14-2 virus, grown in BHK-21 cells as a swine vaccine, protects immunized sows against JE viral associated abortions. SA14-14-2 and the 2-8 strain, obtained from subpassaging a parent of SA14-5-3 virus, also are manufactured into effective equine vaccines 239,240. These pig and equine vaccines are distributed in various areas of the PRC. Other attenuated viruses such as the "m" strain are used in swine vaccines in Japan and other countries in Asia.
As a live vaccine, there is a potential that virus could be
transmitted to a mosquito during a vaccinee's viremic phase. SA14-14-2 virus has been isolated from blood of vaccinees, but it is present at titers below the oral infection threshold of mosquitoes. Attenuated JE 2-8 virus, which has a pedigree similar to that of SA14-14-2 virus, replicates in Cx. tritaeniorhynchus mosquitoes infected experimentally by intrathoracic inoculation. However, infected mosquitoes failed to transmit the virus and infection rates after oral feeding were low. The virus did not revert to a neurovirulent form after mosquito passage (239).
Dosage and route of administration
A 0.5 ml dose is administered subcutaneously to children at one year of age and again at two years. No other vaccines are given concurrently. There are no data on effects of simultaneous administration with other vaccines.
Results of Vaccination
Inactivated Mouse Brain-Derived JE Vaccine
Neutralizing antibody titers of >1:10 generally are accepted as evidence for protection and seroconversion. Passively immunized mice who acquire this level of neutralizing antibody are protected against challenge from 10(5) LD(50)'s of JE virus, a typical dose transmitted by an infectious mosquito bite. Indirect observations from human trials show similar rates of efficacy and seroconversion defined by this criterion (180,181). However, individual laboratories employ test procedures of varying sensitivity to measure neutralizing antibody. Plaque reduction neutralization tests are used most frequently but various procedural differences such as the choice of challenge virus strain, cell systems and addition of exogenous complement affect test sensitivity. Most importantly, differences in the interpretation of endpoints, ranging from 50% to 90% reduction in serum dilution tests, or the calculation of log neutralization indices (LNI) in tests using a single serum dilution, affect the calculated titer (174). Although titers reported from different laboratories generally are correlated, no international standard of protective antibody units currently is established.Immunogenicity
Immunogenicity studies from Asia, using vaccines prepared by the current manufacturing protocol and with the Nakayama or Beijing-1 strain, indicate nearly uniform seroconversion (>95%) after two doses (Table 9) and (Table 10) (241-251). Low seroconversion rates in an Indian study probably reflect the use of mice, which are extremely sensitive indicators of unneutralized virus, in antibody assays (243).Immunogenicity studies in Asian subjects should be interpreted in light of the immunologic background of vaccinees. Although some studies have been carried out in non-endemic areas or in subjects without JE viral antibodies, in others, undetected exposures to JE, dengue and other flaviviruses prevalent in Asia may have resulted in an augmented antibody response after immunization and apparently higher seroconversion rates.
This point has been underscored by immunogenicity studies in subjects from western countries, where flaviviral infections are rare; two doses generally have produced lower seroconversion rates and lower geometric mean antibody titers (GMT) than those reported from studies in Asia (Table 11) and Figure 8 (not available at this time). Moreover, as rapidly as 6-12 months after primary immunization with two doses, neutralizing antibody titers declined below 1:8 in 90% of vaccinees Figure 9 (not available at this time). A three dose primary schedule is superior, resulting in seroconversion of >90% of vaccinees and significantly higher neutralizing antibody titers (159,223,224). A comparison of long (days 0, 7 and 30) and short (days 0, 7 and 14) three dose schedules disclosed uniform seroconversion in all subjects but significantly higher neutralizing antibody titers in vaccinees immunized over 30 days (226).
Although previous exposure to dengue and certain other flaviviruses probably enhances the immune response to JE vaccine, vaccine derived immunity to yellow fever virus does not have a similar effect (226). Levels of neutralizing antibody are similar in vaccinees regardless of previous yellow fever vaccination history. In this respect, the antibody response to JE vaccine differs from the accelerated response to inactivated tick-borne encephalitis vaccine among yellow fever vaccinated individuals (252).
The above observations are from field studies of Nakayama strain JE vaccine. Asian subjects immunized with Beijing-1 strain vaccine exhibit seroconversion rates and neutralizing antibody titers similar to those elicited by Nakayama vaccine (Table 10). Production of heterologous antibody is similar after either vaccine (219-221). No immunogenicity studies of Beijing-1 vaccine in Western subjects have been reported; however, seronegative subjects were selected in two Asian studies.
Efficacy
Efficacy of the Nakayama vaccine has been evaluated in two masked randomized placebo (tetanus toxoid) controlled field trials. In the first evaluation, a less-refined prototype of the current vaccine was field tested in 1965 in Taiwan; two doses yielded an 80% efficacy in the first year after immunization (Table 12) (253-255). A subsequent masked randomized placebo controlled field trial in Thailand compared the efficacies of the currently produced monovalent Nakayama vaccine with a specially formulated bivalent vaccine also containing Beijing-1 antigen (Table 12) (222). Two doses of vaccine or placebo were given one week apart to children one year and older. After a two year observation period, efficacies of the monovalent and bivalent vaccines were identical with an overall efficacy of 91%. In this trial, lower incidences of dengue and dengue hemorrhagic fever also were observed in the JE vaccinated groups compared with the placebo group; however the differences were not significant.Persistence of immunity and protection
Studies in Asia to determine the persistence of vaccine derived immunity may be complicated by natural infections with dengue, West Nile or other flaviviruses and re-exposure to JE virus itself, which act to reinforce and broaden vaccine derived immunity to JE virus (79-83,243). Studies from an area of northern Japan where JE is not endemic and in Western subjects indicate a progressive decline in antibody levels in the first year after primary immunization (Figure 10) (201).Observations of vaccine efficacy in the field trial on Taiwan parallel these results; in the second year after immunization, protective efficacy declined from 80% to 55% (95% confidence interval 39-75%) (254). However, vaccine used in this trial was a less refined product than the currently produced vaccine. In the Thailand field trial of the current formulation, efficacy was shown through two years of observation. Further follow-up data are not available.
These and other data (Table 11) indicate the need for boosters after a two dose primary immunization series. A third dose generally is given at one year and subsequently at minimum intervals of 3 years (Figure 10). Booster doses are followed by significant rises in neutralizing antibody titer and uniform anamnestic responses in subjects who had reverted to seronegative.
Limited data are available on the persistence of immunity after primary immunization of Western subjects. After primary immunization with a three dose series, protective neutralizing antibody titers are retained for at least one year (GMT 85). Antibody titers at 12 months are unchanged from those observed 3 months after immunization (GMT 78); however the longevity of protective levels is unknown. A booster dose given at 12 months is followed by a significant anamnestic response (GMT 1,353) (226).
JE vaccine sometimes is administered with DTP vaccine in Thailand but data on the immune response after simultaneous administration of the vaccines have not been published.
Inactivated Primary Hamster Kidney Cell-Derived JE Vaccine
Two doses of inactivated PHK cell derived vaccine, given one week apart, produces a LNI >50 (equivalent antibody titer of >1:5) in 60-68% of children who have no pre-vaccination JE viral antibodies. Extensive randomized field trials among 480,000 children have demonstrated vaccine efficacies in the range of 76-95% (Table 13) (155,256,257).Although regional trials in Wuxi and Nanjing disclosed partial
protection against acquiring JE (efficacies ranging from 85-87%), more detailed clinical studies showed that cases in vaccinated children were milder than those in unvaccinated children. None of the 6 cases in immunized children resulted in death or neurologic sequelae while 3 of the 19 cases in unimmunized children were fatal and 6 led to sequelae (p = 0.05, Fisher's exact test, one tailed). These observations suggest a better clinical efficacy than the reported protective efficacy (155).
Immunity wanes rapidly after primary immunization with two doses and only 10% of vaccinees have LNIs >50 one year later. A booster dose results in an anamnestic response in 93-100% of recipients. After four years, seropositivity is maintained at an LNI of >50 in 64% of vaccinees and a subsequent booster dose is followed by 100% seroconversion (155,258). Protective efficacy was demonstrated over five years in a cohort immunized with a two dose primary series followed by a booster at one year (Table 14) (259).
Immune responses to single doses of concentrated or purified inactivated PHK cell vaccines (see above) were similar to those after two doses of the standard vaccine. All subjects seroconverted and respective geometric mean neutralizing antibody titers were 45, 72, and 46 (155). Although the immunogenicities of these enhanced inactivated vaccines appear to be excellent, no data on efficacy or persistence of immunity are available.
Live-Attenuated JE Vaccine
Relatively small immunogenicity studies have been reported with variable results. After a single dose, seroconversion occurs in 85-100% of nonimmune children, one to 12 years old and an antibody response gradient was observed in vaccinees given progressive dilutions of the vaccine (Table 15) (186-188,260). Lower seroconversion rates are obtained with vaccine dilutions that have infectious titers <10(6.5) TCID(50)/0.1 ml, the minimum standard of vaccine infectivity. Antibody titers remained elevated (>1:10) in only 31% of vaccinees 12 months after primary immunization (GMT of 17), but after a booster dose, all vaccinees seroconverted with a three to sixfold rise in titer.In a comparison of vaccines prepared from the SA14-5-3 and SA14-14-2 strains, the former vaccine was less immunogenic, resulting in seroconversion of only 61% of 13 vaccinees and a GMT of 5, compared with a 92.3% seroconversion rate in subjects receiving a similar infectious dose of SA14-14-2 vaccine. Study subjects were children from Heilongiang, a non-endemic area of northeastern China (186).
Efficacy trials in children 1-10 years old have yielded protection rates above 98% with extremely high confidence limits around the estimates (Table 16) (238,260,261). Equally good protection was observed through a second year after a booster dose was given. Efficacy of the prototype SA14-5-3 vaccine, which evidently has a lower immunogenicity, still was good, although protection was lower than that achieved with SA14-14-2 vaccine (Table 8) (238,260,261).
Side Effects
Inactivated Mouse Brain-Derived JE Vaccine
Local tenderness, redness, or swelling at the injection site occurs in approximately 20% of vaccinees. Mild systemic symptoms, chiefly headache, low grade fever, myalgias, malaise, and gastrointestinal symptoms are reported by 10-30% of vaccinees (Table 17) (159,222,224,226,241,242, 262).The vaccine's neural tissue substrate has raised concern about the possibility of postvaccination-neurologic side effects (263). The manufacturing process purifies the infected mouse brain suspension extensively and myelin basic protein (MBP) content is controlled below 2 ng/ml, well below the dose considered to have an encephalitogenic effect in a guinea pig test system. Experimental immunization of guinea pigs and Cynomologus monkeys with adjuvant and 50 times the normal dose of vaccine did not result in clinical or histopathological evidence of encephalomyelitis (264,265).
Passive surveillance of vaccine related adverse events (AE) in Japan is conducted through sentinel hospitals, clinics, and pharmacies and through manufacturers. Surveillance data on JE vaccine AE comes principally from the manufacturer (Biken and others). Few neurologic complications temporally related to JE vaccination have been reported (Table 18) and (Table 19) (220,266). Denominators are not available for the number of vaccinees in all years; however, rates in three intervals suggest that the incidence of neurologic complications following JE vaccination are similar to background rates for these disorders.
In one of the first mass applications of mouse brain-derived JE vaccine, in 1945, 53,000 American soldiers on Okinawa were immunized with a crude- inactivated-mouse-brain suspension after an outbreak occurred on the island (195). Acute vaccine-associated side effects, including the occurrence of acute neurological events were monitored. Eight neurologic reactions, principally polyneuritis, were observed. However, similar cases were reported concurrently in non-vaccinated individuals and it is unclear whether the illnesses were vaccine-related. One case of Guillain-Barre syndrome, temporally-related to JE immunization, has been reported among approximately 20,000 U.S. soldiers immunized with the vaccine since 1984 and no cases have been reported to the State Serum Institute among approximately 85,000 Danish vaccinees (226,267).
The low rates of vaccine-associated neurological events reported from Japan, results of experimental animal studies, and the limited quantity of MBP, if any, present in the current purified vaccine do not support a basis for vaccine-related neurologic complications.
An apparently new pattern of allergic AE following JE vaccination has been recognized since 1989, principally among travellers immunized in Europe, North America and Australia (159,162,262,267,268). The reactions have been characterized by generalized urticaria and/or angioedema, especially of the face, oropharynx and extremities. Swelling of the lips and fusiform swelling of the fingers have been reported frequently. Some reactors, however, have complained of generalized itching alone, without objective signs of rash or hypersensitivity. Other cases have been complicated by erythema multiforme, erythema nodosum, joint swelling and wheezing. In a few patients, facial and upper airway swelling led to respiratory distress and potentially were life-threatening. Distress or collapse due to hypotension or other causes necessitated hospitalization in several cases. Angioedema and urticaria generally have responded to treatment with antihistamines or oral corticosteroids but in recalcitrant cases, hospitalization and parenteral steroid therapy were needed. A death temporally related to JE immunization was reported in a man who had had a history of recurrent hypersensitivity phenomenon; however he also had received plague vaccine and the cause of death was not established at autopsy (162).
An important feature of the allergic reaction is the potential for a delayed onset, particularly in recipients of a second or third dose. In one study, the median interval between immunization and onset of an allergic manifestation was 24 hours for vaccinees receiving their first dose (range, minutes after immunization to 6 days). Among reactors to a second dose, an even greater delay has been typical, with a median interval of 2-3 days and an upper range of 9 days (162,267-268). Reactions have developed after a second or third dose when previous doses were given uneventfully. Most studies have reported reactions principally after a second or third dose; however, a prospective study disclosed similar allergic reaction rates after first and second doses (7 and 9 per 10,000 doses respectively) (162).
Risk of an allergic AE (defined as urticaria and/or angioedema) after JE vaccine has varied widely in several studies (Table 20), reflecting chiefly the circumstances of vaccine administration and of AE surveillance.
Rates as high as 0.5-1.0% were reported from travellers clinics (Canada and Fairfield Hospital, Australia) in circumstances where ascertainment probably was high (262,268). Passive national surveillance systems have yielded tenfold lower rates, in the range of 5/10,000 vaccinees (267,269). Three studies in U.S. citizens disclosed rates of approximately 20/10,000 in adult vaccinees but significantly higher rates were observed in military dependents, who primarily were children < 18 (Table 20) (162).
A case-control study following a mass immunization campaign in military personnel found that previous history of an allergic disorder that included a cutaneous manifestation, such as drug eruption, hymenoptera venom or food allergy, or urticaria following physical or unknown provocations, was associated with an elevated risk for developing an allergic AE after JE vaccination (relative risk 3.2, 95% confidence interval 1.8-5.7). A history of allergic rhinitis, atopic dermatitis, or asthma alone was not associated with an increased risk for a vaccine-associated allergic AE (162).
Allergic reactions, including urticaria and angioedema, have been associated intermittently with JE vaccine produced in mouse brain. Allergic side effects including urticaria, angioedema and moderate dyspnea were observed in recipients of the crude mouse brain vaccine administered on Okinawa in 1945. Similar reactions to purified successors of the vaccine have not been reported through the national AE surveillance system in Japan. Nor were allergic reactions observed among recipients of 161,000 doses in Denmark from 1983 to 1989 or in Australia from 1987-1990. However, in the same time period, two vaccinees with anaphylaxis or delayed urticaria were observed in a series of U.S. vaccinees (Table 20). Since 1989, 31 vaccinees with urticaria or angioedema were reported in Denmark through an unchanged AE surveillance system (p < 10-6, Poisson) and after 1990, 7 similar cases were reported for the first time in Australia (267,268).
Although these observations suggest a change in the contents of vaccine distributed since 1989, inspection of manufacturer's quality control records and of manufacturing procedures did not disclose a deviation from accepted standards. Allergic AE have been associated with 11 of 45 lots produced from April 1988 to January 1991. No allergic AE were attributed to 26 lots distributed exclusively to Asian countries (270). AE surveillance may have been less sensitive in these locations or there may have been differences in susceptibility to allergic AE in these vaccinees. Although it is uncertain whether the recently recognized pattern of allergic AE is associated only with certain lots, a wider association seems possible. These observations suggest that potentially allergenic components may be produced intermittently or remain in variable amounts in the finished vaccine.
Although the pathogenesis of these allergic reactions is unknown, a similar syndrome was described previously in recipients of diploid cell derived rabies vaccine in whom symptoms developed after a delay of as long as one week after booster immunization (271). Immunologic studies of reactors demonstrated IgE antibodies to human albumin, added to the vaccine as a stabilizer, and chemically altered by the inactivating agent, beta propionolactone (272). Allergic reactions in recipients of crude mouse brain vaccine in Okinawa were attributed to formalin altered proteins in the vaccine. Serologic and skin test studies of JE vaccine reactors are in progress to elucidate the pathogenesis of delayed allergic reactions and to identify the offending vaccine component.
Inactivated Primary Hamster Kidney Cell-Derived JE Vaccine
Few adverse reactions have been reported in connection with inactivated PHK cell-derived vaccine. Local reactions, including swelling at the injection site, are observed in about 4% of vaccinees and mild systemic symptoms, such as headache and dizziness, are reported by < 1% of vaccinees. Fever above 38 C previously was a complication in 12% of vaccinees but with a reduction of bovine serum in the currently formulated vaccine, febrile reactions have been halved. An urticarial allergic reaction was seen in only 1 of nearly 15,000 vaccinees surveyed (273).Live Attenuated JE Vaccine
Tens of millions of vaccine doses have been distributed without complication. Close studies of experimentally immunized subjects have documented the absence of local or systemic symptoms after immunization. Specifically, headache and symptoms that might be associated with neuroinvasive infection have not been described. Nor have fever and signs and symptoms of systemic infection been conspicuous after immunization. In one study of 867 children, temperatures were monitored over a 21 day period after immunization. Temperatures above 37.6 C were recorded in <0.5% of vaccinees and the proportion of febrile vaccinees was constant over the entire observation period, evidence against a vaccine-related febrile illness after a specific incubation period. In a related study of 588,512 vaccinees, fever was recorded in 0.46% of subjects, rash in 0.08%, dizziness in 0.03% and nausea in 0.03% (186,187,273).
Vaccine Indications
Endemic Areas
In rural areas of Asia, intense JE virus transmission in the enzootic cycle leads to a high risk of exposure at an early age. Universal primary immunization is indicated for children between one and two years. The peak risk of infection is in children between one and four years, reflecting perhaps, the protective effects of maternal immunity and patterns of outdoor activity that place young children at risk. However, cases occur in children through the first decade of life. In most areas with risk of enzootic transmission, immunity should be maintained by boosters through age 10.In urban areas of developed countries, e.g., Tokyo and other major Japanese cities, Hong Kong and Singapore, risk is extremely low and universal immunization is unnecessary. Selective immunization of regions where JE risk is higher, because of agricultural development and geography, is practiced in Thailand and Japan. In the PRC, universal childhood immunization in major cities is justified because viral transmission may occur at low levels within metropolitan areas and at higher rates in suburban areas. Conditions leading to epidemic transmission are unpredictable, and at intervals, such as occurred in Beijing in the late 1970's, epidemics may lead to large numbers of urban cases.
Expatriates
JE viral transmission is variable regionally in Asia and within specific countries. Viral transmission is seasonal in most areas and there may be secular changes in risk, from year to year, in a given location. (Figure 1) and (Table 21) provide specific details on locations and seasonality of risk by country. In some cases, data are incomplete and extrapolations have been made from available information; assessments reflect the author's own interpretation. Patterns of viral transmission may change and physicians and travellers are cautioned to consult public health officials for current data and trends.JE vaccine is recommended for expatriates whose principal residence is in an area where JE is endemic or epidemic (for practical purposes, expatriates are defined as residents through a transmission season). Risk for acquiring JE among expatriates is variable and depends principally on the specific location of intended residence, conditions of housing, nature of activities and the possibility of unanticipated exposure to high risk areas (see section below). For example, a family moving to Tokyo, Hong Kong or Singapore, need not consider immunization unless members expect to travel extensively in areas where the disease is endemic. However, in Beijing and Shanghai, where JE virus is transmitted in suburban areas, expatriates probably should be immunized because of the likelihood of periodic exposure to these nearby high risk areas.
Travellers
JE vaccine is recommended for selected travellers to Asia and should not be considered a routine immunization. Risk of acquiring JE during travel is extremely low (see above) and the vast majority of visitors to Asia on business or in tours are at low risk and need not be immunized. Because JE viral transmission is confined to certain seasons and occurs principally in rural areas, only visitors with such a travel itinerary have a high risk of acquiring the disease. Travellers and their physicians should consider what is known of JE risk in the areas and season of anticipated travel and evaluate individual risk factors and the potential for vaccine side effects in making the decision to seek immunization (Figure 1), (Table 4) and (Table 21) (170-172,225,274,275).Immunization is recommended for visitors to epidemic or endemic areas during the transmission season, especially when they have an extended period of exposure (>30 days) or they are at high risk of exposure to vectors because of the nature of activities or housing. For example bicyclists on tours, and workers and consultants on construction, agricultural or other field projects in rural areas may have greater outdoor exposure to vector mosquitoes. In addition, advanced age and pregnancy may affect risk and outcome of JE and these factors should be weighed in the decision to seek immunization. Repellents and other less specific protective measures always should be considered, because other vector-borne diseases may be transmitted in the same areas. These general approaches to protection may be especially important to travellers in whom vaccine is contraindicated, who are unable to complete immunization because of departures on short notice, or who do not choose to be immunized because their visits to high risk areas are brief or carry an equivocal risk.
Because allergic reactions to mouse brain-derived JE vaccine may be delayed for longer than a week after immunization, and to allow time for protective levels of antibody to develop, vaccinees ideally should defer travel until 10 days after receipt of the last vaccine dose. Travellers should remain in areas accessible to medical care for 10 days afterimmunization.
Research Laboratory Workers
JE virus has been transmitted in 22 laboratory-acquired cases, principally in research settings, where infectious JE virus was used (276). Infection can be transmitted by percutaneous or mucous membrane exposures and potentially by aerosols, especially from preparations containing high viral concentrations, as occur during viral purification. Presumably immunization protects against percutaneous exposures; however, it is unknown whether vaccine derived-immunity, especially from inactivated vaccine, protects against aerosol infection. Immunization is advised for all research laboratory personnel who potentially may be exposed to the virus (225,276).
Contraindications
Mouse brain-derived JE vaccine is contraindicated in persons who have had an allergic reaction to other rodent derived products, including previous doses of JE vaccine. Few biologics now are made in rodent tissue.The most widely distributed are vaccines against the hantaviral agents of hemorrhagic fever with renal syndrome, Hantaan and Seoul viruses. An experimental Hantaan virus vaccine is made in mouse brain and purified by methods similar to those used in JE vaccine manufacture. No allergic side effects have been reported among more than a million Korean vaccinees. Yellow fever vaccine made from the French neurotropic strain previously was produced in mouse brain but production was discontinued in 1982.
Hypersensitivity reactions to mouse-brain-derived JE vaccine are more common in persons with allergic conditions such as drug or hymenoptera venom sensitivity, food allergy, and urticaria following physical stimuli or unknown provocations (see above). When these persons are offered JE vaccine, they should be advised of their potential for vaccine-related angioedema and generalized urticaria. Hypersensitivity to a protein found in mouse urine is common in animal caretakers and certain laboratorians. It is unknown whether this allergy carries a specific risk in recipients of JE vaccine. The value of skin tests to identify persons who may be at risk for developing a vaccine-related allergic reaction is under investigation.
There are no specific contraindications for the use of PHK derived inactivated JE vaccine except history of allergic reaction to a previous dose.
JE vaccines pose a theoretical risk to the developing fetus. No adverse outcomes of pregnancy have been associated directly with JE vaccine. Travellers and their physicians must balance the theoretical risks of JE vaccine in pregnancy against the potential risks of acquiring JE and the adverse outcome of the disease.
There are few data on the safety and efficacy of inactivated JE vaccines in immunocompromised persons. A small study of children with various chronic diseases, including some oncology patients, disclosed no difference in immunogenicity or reactogenicity in recipients of mouse brain derived vaccine (249).
Live attenuated JE vaccine potentially carries an additional risk in pregnancy and in immunocompromised patients. Although experimental data suggest that JE SA14-14-2 virus may not be neurotropic in immunosuppressed animals, there are no data on the safety of SA14-14-2 vaccine in immunocompromised persons. When JE vaccine must be given to pregnant women or to immunocompromised patients, available inactivated JE vaccines should be used in lieu of live vaccine.
Public Health Results of Vaccination
Although a secular trend towards declining JE incidence has been observed in Japan and Korea with widespread use of JE vaccine, the contribution of immunization to this reduction is unclear (1-3,277). Socioeconomic changes coincident with an increase in immunization also may have contributed to declining disease incidence (Figure 11). The most important of these factors have been improved agricultural productivity and increasing urbanization, resulting in fewer rural dwellers at risk, a decline in land area in rice cultivation, and increased use of agricultural pesticides which have reduced numbers of vector mosquitoes (Figure 12) and (Figure 13) (15,277,278). Although numbers of pigs have not declined in rural areas, changes in the patterns of pig husbandry, leading to centralization of pig rearing may have resulted in an overall reduction of risk to the general population. Improvements in the general standard of living, also may have led to a lower risk among remaining rural dwellers. Additional local reductions in viral transmission may have been achieved by specific vector control programs.Observations from the PRC, where development has been less extensive, are somewhat clearer in demonstrating the impact of immunization on disease reduction. JE incidence rates in Beijing, and in other areas of China where high immunization rates are maintained, have declined dramatically and have remained low (Figure 14) and (Table 22) (155).
JE remains a public health problem in Asia with the needless occurrence of tens of thousands of cases annually because of social and economic conditions that limit production and distribution of vaccine. The successful development of live and inactivated JE vaccines in China proves that safe and effective vaccines can be produced cheaply by countries with limited resources. Inclusion of JE vaccine in EPI programs throughout Asia should be supported as a means by which universal protection against JE can be achieved. The cost of live and inactivated JE vaccines produced in the PRC (3 cents/dose) is within an acceptable range for a mass immunization program of this scope and ambition.
Vaccines in Development
Several experimental JE vaccines, developed with molecular techniques are under investigation (279-284). Vaccinia recombinants expressing JE viral E and M proteins induce hemagglutinating and neutralizing antibodies and protect mice fully from 10(5) LD(50) after two doses. Constructs that encode preM and E proteins are optimal. These recombinants yield processed extracellular particles containing M and E that hemagglutinate and behave like empty viral envelopes. Cosynthesis of preM and E may be important to the production of particles with protective envelope antigenic determinants in correct conformations (62-65). Baculoviral E protein recombinants expressed in Spondoptera frugiperda also have induced neutralizing antibody and partial protection in mice (283). Recombinant E protein antigens have been expressed in Escherichia coli and in Saccharomyces cerevisiae as well (282,283). A canary pox construct expressing JE viral PrM, E NS(1) and NS(2a) proteins is under evaluation as a swine vaccine. An infectious clone of modified virulence, that does not cause illness or death in immunized mice, but protects fully against viral challenge, offers insight into the mechanisms of JE viral attenuation and promises the potential for more precise construction of attenuated JE vaccines. Complexes of flaviviral E protein polypeptides with lipopolysaccharide-free outer membrane meningococcus proteins have been highly immunogenic in mice, and offer a potential for combined vaccination with other antigens (285). Improved vaccine delivery systems have been investigated to simplify administration of the current inactivated mouse-brain-derived vaccine. Vaccine has been microencapsulated in glycolide and lactide polymer microspheres which have been designed to degrade at specific intervals. Biodegradation of a predetermined fraction of spheres at weekly intervals after a single injection mimics the spacing of a conventional immunization schedule (286).Attenuated SA14-14-2 vaccine currently is produced in PHK cells, a substrate which is not used conventionally in vaccine production. Attempts to adapt the virus to primary canine kidney cells and to fetal canine kidney cells show promise. A new chick embryo cell-derived inactivated JE vaccine has been produced by a procedure currently used to manufacture TBE vaccine. Infected cell culture fluid is purified and concentrated by continuous zonal ultracentrifugation, inactivated and administered with an alum adjuvant.
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CAROL D SNAREY
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Table 1
Table 1 Fetal Outcome After Laboratory-Confirmed Japanese Encephalitis During Pregnancy Uttar Pradesh, 1978-80 ======================================================================================= Weeks of Gestation Outcome ----------- ------------ 8 Aborted - JE virus isolated from placenta, fetal brain 10 Aborted - No virus isolated from placenta, fetal brain 20 Aborted - cord blood, products of conception not tested 22 Aborted - JE virus isolated from placenta, fetal brain & liver 28 (2 cases) Normal full term delivery - cord blood not tested 30 (2 cases) Normal full term delivery - cord blood not tested 36 Normal full term delivery - cord blood not tested =======================================================================================
Table 2
TABLE 2 Japanese Encephalitis Cases in Expatriates and Travellers ======================================================================================================= Year Location Occupation Citizenship Age Sex Outcome ------------------------------------------------------------------------------------------------------- 1978 Beijing Diplomat Italy ? M Fatal 1981 Beijing Student U.S. 21 M Fatal 1981 ? ? Australia ? ? ? 1982 Beijing College Professor U.S. 62 M Fatal 1982 ? Soldier U.S. 32 M ? 1982 Manchuria ? Canada 36 F ? 1983 Thailand Nurse Holland 30 F Disabled 1983 ? Child U.S. 1 M ? 983 Hong Kong Unknown U.K, 35 F Fatal 1985 Thailand Oil Field Worker Germany 30 M ? Dead 1985 N. Vietnam Child E. Europe 9 M Fatal 1986 Philippines Soldier U.S. 55 M Disabled 1986 Philippines Soldier U.S. ? M Recovered 988 ? ? U.S. 64 M ? 1988 Indonesia Child Australia 10 F Hemiparesis 1989 Thailand Student Israel 22 F Recovered 1991 Thailand ? Austria ? ? ? ? Thailand ? Germany ? ? ? ? Thailand ? Denmark ? ? ? ? ? ? Australia ? ? ? 1991 Okinawa (Japan) Soldier U.S. 20 M Semi-vegetative state 1991 Okinawa (Japan) Soldier U.S. 35 M Disabled 1991 Okinawa (Japan) Soldier U.S. 28 M Recovered =======================================================================================================
Table 3
TABLE 3 Japanese Encephalitis in Unimmunized American and Other Western Military Personnel 1945-1991 ======================================================================================================== APPROXIMATE POPULATION RATE PER LOCATION YEAR CASES AT RISK 10,000 - WEEK REFERENCE -------------------------------------------------------------------------------------------------------- Okinawa 1991 3 19,000 0.1. 162 Thailand 1972 9 2,500 2.1# 20 Vietnam.. 1966-67 2 2,000 0.9@ 165 Korea 1958 3 860 1.6@ 16, 17 Korea& 1950 103 114,813 0.4@ 169 Korea 1946 3 1,500 0.9@ 168 Okinawa 1945 11 77,000+ 0.05. 195 -------------------------------------------------------------------------------------------------------- . Rate based on exposure during a 6 month transmission season # Rate based on exposure during 4 months .. Australian @ Rate based on exposure during a 5 month transmission season & American and British + Partially immunized population ========================================================================================================
Table 4
Table 4 Factors associated with risk for acquiring Japanese encephalitis during travel to Asia ========================================================================== RISK FACTORS Travel to developing country Travel during transmission season Travel to rural areas Extended period of travel/residence Outdoor activities, especially in twilight period and evenings Advanced age Pregnancy (to developing fetus) PROTECTIVE FACTORS Use of repellents Protective clothing Residence in air-conditioned or well screened areas ==========================================================================
Table 5
Table 5 Japanese Encephalitis Vaccines ========================================================================================= VACCINE DESCRIPTION SUBSTRATE STRAIN(S) MANUFACTURER(S) inactivated mouse brain Nakayama, India: Central Beijing-1 (Pl) Research Institute Japan: Biken, Chiba, Denka, Katetsu-ken, Kitasato, Saika-ken, Takeda Korea: Green Cross Taiwan: National Institute of Preventive Medicine Thailand: Government Pharmaceutical Organization Viemain: National Institute of Hygiene inactivated primary hamster P3 People's Republic of China: Beiiing, kidney ceils Shanghai, Wuhan, and Changchun Institutes of Biological Products live, attenuated primary hamster SA14-14-2 People's Republic of kidney ceils China: Chengdu Institute of Biological Products =========================================================================================
Table 6
Table 6 Recommended Immunization Schedule for Inactivated Japanese Encephalitis Vaccine ==================================================================================== Primary * Booster * ------------------------------------------------------------------------------------ Adults & children >= 1.0 ml given on days 1.0 ml given at 1 year 3 years O, 7, 30** and thereafter at intervals of 3 years or as determined by serologic testing Children > 6 months 0.5 ml in schedule 0.5 ml in schedule and < 3 years as above as above ------------------------------------------------------------------------------------ * All doses given subcutaneously ** An abbreviated schedule of immunization of days O, 7, and 14 can be used when the recommended schedule cannot be followed ====================================================================================
Table 7
TABLE 7 Passage History of Japanese Encephalitis SA 14-14-12 Virus ========================================================================================= . SA14 virus isolated from Culex tritaeniorhynchus parent . 100 serial passages in primary hamster kidney (PHK) cells; 3 plaque clone 12-7-1 purifications in primary chick embryo (CE)cells . 2 x plaque purification in CE cells clone 17-4 . 1 mouse i.p. passage; spleen harvested for further CE cell passage clone 2 . 3 x plaque purification in CE cells clone 9 . 1 mouse s.c. passage; skin harvested for 1 CE cell plaque passage clone 9-7 . 6 hamster p.o. passages; spleens harvested for 2 x plaque clone 5-3 purification in PHK cells . 5 suckling mouse s.c. passages; skin used in 2 x PHK cell plaque clone 14-2 purifications =========================================================================================
Table 8
TABLE 8 EFFICACY OF SA14-5-3 ATTENUATED JAPANESE ENCEPHALITIS VACCINE GUANGTONG, PEOPLES REPUBLIC OF CHINA ===================================================================== EFFICACY YEARS VACCINATED JE CASES CONTROL JE CASES (95% C.I.) --------------------------------------------------------------------- 1973 205,359 58 26, 180 63 88 (85-92) 1974 205,301 12 26, 117 22 93 (90-97) 1975 205,289 8 26,095 7 85 (70-95) 1976 205,281 7 26,088 13 93 (88-97) 1977 205,274 3 26,075 9 96 (92-99) =====================================================================
Table 9
Table 9 Immunogenicity of inactivated Japanese encephalitis vaccine (Two doses of Nakayama strain mouse-brain-derived vaccine) =================================================================================================== Country (vaccine) n Seroconversion GMT Year Reference --------------------------------------------------------------------------------------------------- Thailand (BIKEN) 320 99% 126 1989 241 Thailand (GPO)@ 329 97% 63 1989 241 India (CRI)& 42 100% 1778 1988 242 India {Liquid - BIKEN) 13 17%+ 1986 243 India (lyophilized - BIKEN) 6 33%+ 1986 243 Japan (BIKEN) 20 95% 72 1986 248 Japan (BIKEN) 75 100%* 741-832 1986 249 --------------------------------------------------------------------------------------------------- @ Government Pharmaceutical Organization & Central Research Institute + mouse neutralization test * 20% of vaccinees had pre-existing JE antibody ===================================================================================================
Table 10
TABLE 10 Homologous and heterologous neutralization antibody responses in humans immunized with mouse-brain-derived inactivated Japanese encephalitis vaccines Beijing and Nakayama strains ====================================================================================================================================== VACCINE VACCINATION CHALLENGE POST 2ND POST 3RD ONE YEAR POST POST SCHEDULE (DAY) VIRUS DOSE DOSE IMMUNIZATION BOOSTER REF -------------------------------------------------------------------------------------------------------------------------------------- Seroconversion (GMT) Seroconversion (GMT) Seroconversion (GMT) GMT -------------------------------------------------------------------------------------------------------------------------------------- Beijing n=54 O, 14 Beijing 94% (79) N.D. 92% (63) 241 n=59 Nayakama 80% (20) N.D. 55% (13) Beijing n=124 O, 10, 17 Beijing 98% (708) 100% (3981) 11,481** 219 n=124 Nayakama 86% (245) 95% (323) 1,065 Beijing n=36 O, 1O, 35 Beijing N.D. 100% (4,365) 221 n=35 Nayakama N.D. 97% (251) Nakayama 250 n=70 O, 30 Nakayama 100% (776) n=70 E=50. JaGAr-01 97-99% (56-74) Nakayama 248 n=20 O, 30 Nakayama 95% (72) 83% (311) 1,288 n=20 Beijing 90% (~48) 75% (~26) ~479 Nakayama 221 n=62 O, 10 Nakayama 92% (617) n=62 Beijing 55% (81) Nakayama n=31 O, 10,20 Nakayama N.D. 100% (1,622) 221 n=37 Beijing N.D. 84% (123) Nakayama n=38 O, 1O, 20 Nakayama N.D. 95% (955) 221 n=38 Beijing N.D. 79% (65) -------------------------------------------------------------------------------------------------------------------------------------- * n = 6 ** n = 7
Table 11
TABLE 11 Immunogenicity of Inactivated Japanese Encephalitis Virus Mouse-Brain-Derived Vaccine (Nakayama Strain) in Western Subjects After 2 or 3 Doses =========================================================================================================== Two Dose Series Three Dose Series STUDY n Seroconversion n Seroconversion Rate GMT+ Rate GMT ----------------------------------------------------------------------------------------------------------- United (1984-1987) 118 77% 28 72 99% 141 British (1983) 27 33% 31-61 94 88% 146-214 United States (1990) 20 80% 25 100%* United States (1990) 526 100% 104-692** ----------------------------------------------------------------------------------------------------------- + geometric mean titer * dose 3 at week 26 ** day 60 serum; short and long 3 dose schedules p < .0001. ===========================================================================================================
Table 12
TABLE 12 Efficacy of Inactivated Japanese Encephalitis Vaccine (two doses of Nakayama or bivalent NakaYama/Beijing mouse-brain-derived vaccines) ============================================================================================== STUDY NUMBER CASE RATE % EFFICACY GROUP AT RISK PER 100,000 (95 % CI) ------------------------------------------------------------------------------- Taiwan, 1965 Total Vaccinated 133,943 4.48 76 (63-90) (references 1 dose 22,194 9.01 50 (26-88) 253-255) 2 doses 111,749 3.58 80 (71-93) placebo 131,865 18.20 --- Unvaccinated 140,514 24.91 --- Thailand, Total Vaccinated 43,708 4.60 91 (70-97) 1984-1985 Monovalent 21,628 4.60 91 (54-98) (reference Bivalent 22,080 4.50 91 (54-98) 222) Placebo 21,516 51.10 --- ==============================================================================================
Table 13
TABLE 13 Efficacy of Inactivated Japanese Encephalitis (JE) Vaccine Produced in Primary Hamster Kidney Cells People's Republic of China ============================================================================================ STUDY NUMBER OF INCIDENCE RATE EFFICACY YEAR REGION GROUP SUBJECTS JE CASES per (100,000) (95% C I.) -------------------------------------------------------------------------------------------- 1967 Wuxi Vaccinated* 38,482 3 7.8 84 Control 34,182 17 52.8 (75 - 95) 1968 Nanjing Vaccinated 52,004 3 5.8 87 Control 18,584 8 43.0 (73 - 96) 1968 Hunan Vaccinated 75,083 7 9.3 76 Control 48,543 19 39.1 (63 - 90) 1969 Beijing Vaccinated 86,847 3 3.5 87 Control 76,260 21 27.5 (81 96) 1973 Guangxi Vaccinated 58,211 2 3.4 95 Control 1O,165 7 68.9 (90 - 100) -------------------------------------------------------------------------------------------- * 2 doses with an interval of one week. ============================================================================================
Table 14
TABLE 14 Inactivated Japanese Encephalitis Vaccine Produced in Primary Hamster Kidney Cells- Efficacy of 2 Doses and Booster Guangdong Province, Peoples Republic of China ============================================================================================== STUDY NUMBER OF INCIDENCE RATE EFFICACY YEAR GROUP SUBJECTS JE CASES (per 100,000) (95% C.I.) ---------------------------------------------------------------------------------------------- 1973 Vaccinated 72,309* 4 5.5 96 Unvaccinated 3,526 5 141.8 (91 - 99) 1974 Vaccinated 71,070** 4 5.6 90 Unvaccinated 3,521 2 56.7 (60 - 9) 1975 Vaccinated 71,066 1 1.4 --- Unvaccinated 3,519 0 0 1976 Vaccinated 71.065 3 4.2 95 Unvaccinated 3,519 3 85.3 (85 - 99) 1977 Vaccinated 71,062 1 1.4 95 Unvaccinated 3,516 1 28.4 (65 - 99) ---------------------------------------------------------------------------------------------- * 2 dose primary series ** booster given ==============================================================================================
Table 15
TABLE 15 Immune Response to SA14-14-2 Attenuated Japanese Encephalitis Vaccine ================================================================ VACCINE % TITER * SUBJECTS SEROCONVERSION GMT REFERENCE >=6.3 23 100 >32 187 6.3 39 85 23 273 6.0 13 92 29 186 5.0 17 71 10 186 4.0 16 62 10 186 ---------------------------------------------------------------- * log(10) TCID(60)/0.2 ================================================================
Table 16
TABLE 16 Protective Efficacy of SA 14-14-2 Attenuated Japanese Encephalitis Vaccine in Children (1-10 years of age) People's Republic of China ====================================================================================== STUDY INCIDENCE EFFICACY YEAR PROVINCE GROUPS NUMBER JE CASES (PER/100,000) (95% C.I.) 1988 Guizhou Vaccinated 86,132 1 1.16 98.0 Unvaccinated 21,149 12 56.7 (96-100) 1989 Guizhou Vaccinated 86,933# 0 2.30 100 Unvaccinated 16,869 12 71.1 1989 Jiang-xi Vaccinated 64,027 2 3.12 98.4 Unvaccinated 4,546 9 198 (97-100) -------------------------------------------------------------------------------------- . Children immunized with single primary dose and booster 1 year later. # Second year of observation ======================================================================================
Table 17
TABLE 17 Reported Side Effects of Inactivated Mouse-Brain Derived Japanese Encephalitis Vaccine ============================================================================ STUDY SITE SUBJECTS LOCAL* SYSTEMIC** REFERENCE ---------------------------------------------------------------------------- Thailand 490 < 1% 1.7-2.9% 222 U.S. 59 18% 9% 159 1328 12% 2% U.S. 526 1st dose 20% 5% 226 2nd dose 12% 2% 3rd dose 11% 1% U.S. 3573 23% 10-13% 224 Canada 96 31% 21% 262 India 42 29% 0% 242 Thailand 448 2% 1.3-1.8% 241 ---------------------------------------------------------------------------- * local tenderness, redness, swelling, itching, numbness ** chiefly fever, headache, malaise, rash; also chills, dizziness, myalgia, nausea, vomiting,abdominal pain, diarrhea, sore throat, blurred vision, increased salivation and taste, difficulty concentrating, emotional instability ============================================================================
Table 18
TABLE 18 Reported Neurological Manifestations Temporally Associated with Japanese Encephalitis Vaccination Japan, 1965-1980 (Inactivated Mouse-Brain-Derived Vaccine) ========================================================================== NUMBER OF NUMBER OF NUMBER OF NUMBER OF ESTIMATED YEARS YEARS CASES CASES/YEAR RATE -------------------------------------------------------------------------- 1965 - 1970 6 75 12.5 1/10(6) 1971 1978 8 ? ? 2.3/10(6). 1979 - 1980 2 6 3 - 1981 - 1982 2 3 1.5 - 1983 - 1986 4 ? ? - 1987 - 1989 3 2 0.7 - -------------------------------------------------------------------------- * 1971-1973 data from Tokyo only; 2 cases/883,373 vaccinees ==========================================================================
Table 19
TABLE 19 Reported Neurological Manifestations Temporally Associated with Japanese Encephalitis Vaccination Japan 1965-1970 (inactivated mouse-brain-derived vaccine) ==================================================================================== ENCEPHALITIS/ MYELITIS PERIPHERAL TOTAL YEAR ENCEPHALOPATHY MENINGITIS CONVULSIONS NEUROPATHY OTHER CASES ------------------------------------------------------------------------------------ 1966 4 2 3 2 - 11 1965 2 - - 1 - 3 1967 5 - 3 1 1 10 1968 14 1 3 2 - 20 1969 6 - - 1 - 7 1970 13 - 4 5 2 24 TOTAL 44 3 13 12 3 75 ====================================================================================
Table 20
TABLE 20 ALLERGIC! REACTIONS FOLLOWING IMMUNIZATION WITH INACTIVATED JAPANESE ENCEPHALITIS VIRUS VACCINE (Biken) ================================================================================================================== ESTIMATED # ESTIMATED RATE 95% OF per 10,000 CONFIDENCE COUNTRY LOT # CASES VACCINEES VACCINEES INTERVAL Denmark 16 13& 17,500 7 4 - 13 32 2@ 7,500 3 0.3-9.6 33 2 10,000 2 0 2 - 7.2 12 4 6,500 6 1.7-16 Sweden+ 30 1 15,000 0.7 .02 -3.7 United Kingdom 13 1 1,950 5 0.13-29 Australia Nationwide (9?),17,42 4++ 3,400 12++ 3 - 30 Fairfield Hospital 17/42 3 601 50 10-140 Canada Nationwide 32, 54 3 - - - Univ. of Calgary 32 1 96 104 2.6- 567 United States Travellers (CDC) 2* 1328 15 1.8-54 Active Duty Army 29,30,31 1** 526 19 0.5-105 Active Duty Military 49,55 25 14293 17 11 -26 (Okinawa) Military Dependents 49,55 17 2077 82 48-131 (Okinawa) ------------------------------------------------------------------------------------------------------------------ ! generalized urticaris and or angioedema & one additional case of erythema multiforme @ one additional case of erythema nodosum + two case, lots unknown ++ lots unknown for 4 cases; estimatedk rate is bases on total number of vaccines * puffy eyes reported; not documented to have article ** 1 case diagnosed as exercised induced enaphylaxis; 1case of generalized anaphylaxis ==================================================================================================================
Table 21
TABLE 21 RISK OF JAPANESE ENCEPHALITIS BY COUNTRY, REGION, AND SEASON =============================================================================================================================================================== AFFECTED AREAS/ TRANSMISSION COUNTRY JURISDICTIONS SEASON COMMENTS --------------------------------------------------------------------------------------------------------------------------------------------------------------- Bangladesh Few data, probably widespread Possibly July - December as in northern Outbreak reported from Tangall India near Dacca Bhutan no data no data Brunei Presumed to be sporadic - endemic as to; Presumed year round transmission Malaysia Burma Presumed to be endemic - Presumed to be May - October Repeated outbreaks in Shan hyperendemic country wide State in Chiang Mai Valley Cambodia Presumed to be endemic - Presumed to be May - Oclober Refugee camp cases reported hyperendemic country wide from Thai border Hong Kong Rare cases in New Territories April - October Vaccine not routinely recommended. India Reported cases from all states, South India: May - October in Goa Outbreaks in West Bengal, Bihar, except Arunachal, Dadra, Daman, Diu October - January in Tamil Nadu Karnataka, TamilNadu, Andrha Gujarat, Himachal, Jammu, Kashmir, August - December in Karnataka; second peak Pradesh, Assam, Uttar Kerala, Lakshadweep, Meghalaya, Nagar (April - June in Mandya district) Pradesh, Manipure and Goa Haveli, Orissa, Punjab, Rajasthan and Andrha Pradesh: September - December Urban cases reported e.g. Sikkim North India: July -December Lucknow Indonesia Kalimantan, Bali, Nusa Tenggara, Probably year-round risk; varies by island; Human cases recognized on Bali Sulawesi, Mollucas, West Irian, peak risks associated with rainfall, rice cultivation and Java only Java, Lombok and presence of pigs; November - March peak period of risk; June - July in some years Japan Rare-sporadic cases on all islands, June - September except Ryukyu Vaccine not routinely except Hokkaido islands (Okinawa) April - October recommended for travel to Tokyo and other major cities, Enzootic transmission without human cases observed on Hokkaido Korea No data from North Korea July - October Last major outbreaks in South Korea -Rare in Kangwon 1982-1983 province; sporadic - endemic with occasional outbreaks elsewhere Laos Presumed to be endemic- Presumed to be May - October No data available hyperendemic country wide Malaysia Sporadic - endemic in all states No seasonal pattern; year round Most cases from Penang. of Peninsula, Sarawak and transmission Perak, Selangor, Johore probably Sabah and Safawak Nepal Hyperendemic in southern July - December Vaccine no recommended for lowlands (Terai) travellers visiting hgh altitude areas only Peoples Republic of Cases in all provinces except Northern China: May - September Vaccine not roultiely recommended China Xizang (Tibet). Xinjiang. Southern China: April- October for travellers 10 urban areas Qinghai (Guangshi, Yunnan, Gwangdong and Southern only Hyperendemic in southern Fujian. Szechuan, Guizhou. China; endemic - periodically Hunan, Jiangsi provinces) epidemic in temperate areas Pakistan May be transmitted in central Presumed to be June - January Cases reported deltas Karachi Endemic areas overlap those for West Nile virus Philippines Presumed to be endemic on all Uncertain, speculations based on Outbreaks described n islands locations and agroecosystems: Nueva Ecija, Luzon, and in West Luzon, Mindoro, Negro Palowan: April- Manila November Elsewhere: Year round - greatest risk April- January Russia Far eastern maritime areas south of Peak period July - September First human cases in 30 years Khabarousk recently reported Singapore Rare cases Year round transmission - ? April peak Vaccine not routinely recommended Sri Lanka Endemic in all but mountainous October - January; secondary peak of Recent outbreaks in areas; periodically epidemic in enzootic tansmission May - June central (Anuradhapura) northern and central provinces and northwestern provinces Taiwan Endermic - hyperendemic April - October Numerous cases in and Chungyang Shanmo around Taipei Thailand Hyperendemic in north; May - October sporadic - endermnic in south Annual outbreaks in Chiang Mai Valley; sporadic cases in Bangkok suburbs Vietnam Endemic - hyperendemic in all May - October Highest rates in and near provinces Hanoi Western Pacific Two epidemics reported on Uncertain, possibly September - Enzootic cycle may not be Guam, Saipan (Northern January sustainable; epidemic Mariana Islands) since 1947. may follow introductions of virus --------------------------------------------------------------------------------------------------------------------------------------------------------------- * Reported human cases may not accurately reflect risks to non-immune visitors because of high immunization rates in local populations. Humans are incidental to the transmission cycle. High levels of viral transmission may occur in the absence of human disease. N.B. Assessments are based on publications, surveillance reports, and personal correspondence. Extrapolations have been made from available data, Transmission patterns may change. Consult CDC [(303) 221-6400] or other public health authorities for latest trends. ===============================================================================================================================================================
Table 22
Table 22 Japanese Encephalitis Immunization Coverage and Incidence Liaoning, Peoples Republic of China, 1974* ================================================================================== Population of # of children Percentage Incidence in District 1-10 year olds immunized immunized 1-10 year olds ---------------------------------------------------------------------------------- Zhuang Ho 237,457 33,637 14.2 35.0 Fu Hsien 187,414 161,491 86.7 6.5 Xin Chin 135,754 120,839 89.0 3.6 ---------------------------------------------------------------------------------- * From Zhang (1978) cited in reference 188.
Figure 1
Reported Japanese Encephalitis Cases By Country, 1986 - 1990
Figure 2
Transmission Cycle Of JE Virus
Figure 4
Reported Cases Of Encephalitis By Age
Figure 6
History Of Development Of Inactivated JE Vaccine
Figure 10
Antibody Response After JE Vaccination
Figure 11
JE Incidence In Relationaship To Vaccine Distribution
Figure 12
JE Incidence In Relationship To Pesticide Consumption
Figure 13
Relationship Declining Land Area Rice Paddies/Cx.Tritaeniorhynchus
Figure 14
JE Incidence, Beijing 1950-1985
