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Appendix D-6
The Prospects for Immunizing Against Japanese Encephalitis Virus

DISEASE DESCRIPTION

Japanese encephalitis (JE) is an acute inflammatory disease of the brain, spinal cord, and meninges. Afflicted patients complain of fever and headache for 1 to 3 days, then typically present to medical facilities with signs of generalized impaired function of the nervous system, such as grand mal seizures or a depressed sensorium. Some patients exhibit focal neurologic signs, usually signifying upper motor neuron involvement. Lumbar puncture reveals a normal or slightly elevated pressure, a modest increase in the number of leukocytes, and little or no increase in the total protein concentration. Case fatality rates among all hospitalized patients in endemic countries typically range from 20 to 50 percent (Okuno, 1978); among patients in coma at the time of admission the fatality rate may be greater than 50 percent. A substantially lower case fatality ratio has been observed among U.S. servicemen in Asia (Dickerson et al., 1952; Ketel and Ognibene, 1971). Death probably results from compromise of brain stem respiratory control. Complete recovery takes weeks to months and occurs in 30 to 50 percent of patients. Persistent motor or psychological sequelae can be detected in 20 to 40 percent of surviving patients (Schneider et al., 1974).

An accurate and rapid diagnosis can be made by ELISA (enzyme-linked immunosorbent assay) detection of Japanese encephalitis virus (JEV) IgM antibodies in cerebrospinal fluid (CSF) at admission in 80 percent of cases; the remaining 20 percent develop antibodies within a few days (Burke et al., 1985a, 1985b). Virus can be isolated from the CSF in 10 to 15 percent of patients with acute disease and from postmortem brain tissue in almost all fatal cases (Burke et al., 1985c). A retrospective diagnosis can be made with any of a variety of conventional tests by demonstrating a rise in specific antibody titer in paired serum samples.

The committee gratefully acknowledges the efforts of D.S.Burke, who prepared major portions of this appendix, and the advice and assistance of R.E.Shope. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-6 The Prospects for Immunizing Against Japanese Encephalitis Virus DISEASE DESCRIPTION Japanese encephalitis (JE) is an acute inflammatory disease of the brain, spinal cord, and meninges. Afflicted patients complain of fever and headache for 1 to 3 days, then typically present to medical facilities with signs of generalized impaired function of the nervous system, such as grand mal seizures or a depressed sensorium. Some patients exhibit focal neurologic signs, usually signifying upper motor neuron involvement. Lumbar puncture reveals a normal or slightly elevated pressure, a modest increase in the number of leukocytes, and little or no increase in the total protein concentration. Case fatality rates among all hospitalized patients in endemic countries typically range from 20 to 50 percent (Okuno, 1978); among patients in coma at the time of admission the fatality rate may be greater than 50 percent. A substantially lower case fatality ratio has been observed among U.S. servicemen in Asia (Dickerson et al., 1952; Ketel and Ognibene, 1971). Death probably results from compromise of brain stem respiratory control. Complete recovery takes weeks to months and occurs in 30 to 50 percent of patients. Persistent motor or psychological sequelae can be detected in 20 to 40 percent of surviving patients (Schneider et al., 1974). An accurate and rapid diagnosis can be made by ELISA (enzyme-linked immunosorbent assay) detection of Japanese encephalitis virus (JEV) IgM antibodies in cerebrospinal fluid (CSF) at admission in 80 percent of cases; the remaining 20 percent develop antibodies within a few days (Burke et al., 1985a, 1985b). Virus can be isolated from the CSF in 10 to 15 percent of patients with acute disease and from postmortem brain tissue in almost all fatal cases (Burke et al., 1985c). A retrospective diagnosis can be made with any of a variety of conventional tests by demonstrating a rise in specific antibody titer in paired serum samples. The committee gratefully acknowledges the efforts of D.S.Burke, who prepared major portions of this appendix, and the advice and assistance of R.E.Shope. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Only a small fraction of persons infected with the virus develop acute encephalitis; the majority of infections are asymptomatic. Estimates of the ratio of apparent to inapparent infections range from 1:63 among American military personnel (Benenson et al., 1975; Halstead and Grosz, 1962) to 1:1,000 among Asian children (Grossman et al., 1974; Southam, 1956). Undifferentiated fever or aseptic meningitis also may result from infection with JEV. Existing Vaccines and Limitations An estimated 0.5 billion doses of various Japanese encephalitis vaccine preparations have been manufactured and administered to humans in Asia over the past 20 years, principally in the People’s Republic of China, Japan, and Korea. This enormous, sustained effort reflects the importance placed on JE control in countries stricken by the epidemic disease. However, none of the vaccines in use is ideal by current standards (see below), and none is licensed for use outside Asia. PATHOGEN DESCRIPTION Japanese encephalitis virus is a 45-nm enveloped, single (+) stranded RNA virus composed of three structural proteins (envelope, membrane, and core). The genome is 12,000 nucleotides in length and codes for seven to nine poorly characterized nonstructural proteins, as well as the three structural proteins (Shapiro et al., 1971; Westaway, 1973). The virus is antigenically related to a large number of other arthropod-borne viruses recently placed in their own family, the Flaviviridae. The family includes yellow fever and dengue, as well as several viruses closely related to JEV that produce epidemic encephalitis in other parts of the globe (St. Louis encephalitis virus in the Americas, West Nile encephalitis virus in Southwest Asia and Africa, and Murray Valley encephalitis virus in Australia). Preliminary analysis of the nucleotide sequence of JEV (Fournier, personal communication, 1986) shows a genome organization similar to that of the more completely characterized yellow fever virus (Rice et al., 1985). JEV exists in nature as a mosquito-borne zoonosis, with birds and domestic mammals (principally pigs) serving as the vertebrate hosts (Buescher and Scherer, 1959). Infections in these vertebrate hosts are essentially asymptomatic, and the viremia is relatively short-lived but of high titer. Man is a nontransmitting host; the viremia in humans is probably too low to provide an efficient inoculum to biting mosquitoes. Principal vectors of JE are rice-field-breeding mosquitoes of the Culex vishnui group. Female mosquitoes usually become infected by feeding on a viremic animal and, after a temperature-dependent extrinsic incubation period of 3 days to 3 weeks, can transmit the virus during subsequent blood meals. Infected adult female mosquitoes can transmit JEV to their progeny through transovarial transmission (Rosen et al., 1978), but the epidemiologic significance of this mechanism is unknown.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries HOST IMMUNE RESPONSE The only known route of human infection with JEV is through the bite of an infected mosquito. Virus growing in the mosquito salivary glands (Takahashi and Suzuki, 1979) is inoculated into the skin and directly into capillaries; thousands of infectious particles are probably delivered. The initial site or sites of replication are unknown. The patient is asymptomatic while the virus multiplies and then viremia ensues. Circulating virus penetrates into the central nervous system, probably through defects in the endothelium, although infection through the cribriform plate or olfactory tract has been hypothesized (Albrecht, 1969). Symptoms begin 7 to 14 days after initial infection. JE is a diffuse encephalitis (Miyake, 1964); virus usually can be recovered from most if not all regions of the brain. Neurons containing JE antigens can be demonstrated throughout the brain, and the thalamus typically shows heavy involvement (Johnson et al., 1985). Glial elements are largely spared, and necrotic foci, when present, are of microscopic proportions. When brain tissues from fatal cases are examined by immunohisto-chemical techniques, the earliest detectable host response is extra-vascular migration of mononuclear phagocytes (Johnson et al., 1985). These cells, accompanied by T-lymphocytes, cluster around infected (antigen-bearing) neurons. Simultaneously, meningeal exudates and perivascular cuffs composed of monocytes, T-cells, and B-cells accumulate. The infected neurons undergo pyknosis and fragmentation, and traces of antigen appear within the mononuclear cells in the nodules. Antibody synthesis by cells within the central nervous system can be detected directly by culture of CSF leukocytes early in the course of infection (Burke et al., 1985a, 1985b). A low or slow antibody response is associated with cultivable virus in the CSF and portends a grave prognosis (Burke et al., 1985c). When JE occurs in a patient previously immune to another flavivirus (e.g., dengue), the IgG antibody response to JEV is brisk and strong, and an adverse outcome is less likely than in an individual experiencing JE as a first flavivirus infection (Edelman et al., 1975; Hammon, 1969; Sather and Hammon, 1970). The relative contributions of cellular and humoral immunity in these cross-flavivirus anamnestic responses in humans are unknown. Passively administered antibody has a protective effect in JE-challenged mice, even when administered 48 hours after virus challenge (Hammon and Sather, 1973; Ohyama et al., 1959). Inoculation with subimmunizing low doses of inactivated JE vaccine can prime nonhuman primates for an anamnestic antibody response to subsequent challenge, even in the absence of a detectable antibody response to the original immunization (Hoke and Burke, personal communication, 1985). There is no evidence that the immune response contributes to the pathology in JE. Cyclophosphamide immunosuppression shortens the survival time in JE animal models (Nathanson and Cole, 1970). Little data exist on the role of interferon or that of cell-mediated immunity in JE.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries DISTRIBUTION OF DISEASE Geographic Distribution Japanese encephalitis was first recognized in Japan in 1871, and epidemics recurred every few years until the late 1960s (Ishii, 1983; Okuno, 1978). All parts of the country were affected except Hokkaido, the northern most island. The worst epidemics occurred in the years immediately following World War II, with 3,000 to 5,000 cases per year and 1,000 to 2,000 deaths (representing an attack rate of 4 to 6 per 100,000). Children were predominantly affected. In the immediate postwar period, major annual epidemics also were recorded in Korea (2,000 to 6,000 cases per year) (Okuno, 1978; Paik, 1983). The maritime provinces of mainland China were also affected. In these latter two countries, the disease was confined largely to children under the age of 15. Between 1967 and 1970 the geographic distribution of JE shifted dramatically. Annual morbidity rates in Japan dropped from 2–4 to 0.1–0.2 per 100,000, and the peak age-specific attack rate shifted to adults over age 50 (Ishii, 1983). Simultaneously, rates in Korea dropped from 5–30 to 1–2 per 100,000 (Okuno, 1978). This regional decline has been attributed to a combination of increased distribution of vaccine, altered agricultural practices and insecticide use, and improved housing standards. Rates have remained low in Japan, but in 1982 the southwestern provinces of Korea were struck by the first major epidemic there in 12 years, involving almost 3,000 children (attack rates 5 to 10 per 100,000 in affected provinces) (Paik, 1983). During the same 4-year period between 1967 and 1970, epidemic JE was recognized for the first time in northern Vietnam, where annual morbidity rates for acute encephalitis jumped from 2–4 to 9–22 per 100,000 (Okuno, 1978). Simultaneously, rates in Thailand increased from less than 0.1 to 3–4 per 100,000 total population (Jatanesen, personal communication, 1985; Okuno, 1978). In Thailand, epidemic JE was confined to the northern parts of the country, where rates reached 10 to 30 per 100,000; among children in northern Thailand, annual rates in excess of 100 per 100,000 have been recorded. Epidemics continue to recur in these countries. Three-fourths of all cases are among children less than 15 years old. In China, reported cases of JE, relatively stable at 2,000–9,000 cases per year, dramatically increased during the late 1960s, to 20,000–40,000 cases per year. Since 1975 the incidence of cases has declined to a relatively stable 10,000–15,000 cases per year (Quan, 1983). All provinces except the two most western, Xinjiang and Xizong, have the disease (Huang, 1982). JEV has been known (by virus isolation) to exist in southern India and Sri Lanka for decades (Carey, 1969), but the proportion of the total number of acute encephalitis cases attributable to JE is uncertain; it may be less than 30 percent (Vitarana, 1982). In 1978, a major epidemic of JE was recorded in the northern India states of Bihar and Uttar Pradesh, with 7,600 recorded cases (Mathur et al., 1982; Rodrigues, 1982). Since then, smaller epidemics have recurred annually. Concurrently with the north Indian epidemics, JE appeared in the nearby

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries lowland regions of Nepal: between 1978 and 1982, more than 2,000 cases were recognized (Joshi, 1983). In north India and Nepal, adults and children are affected equally. Sporadic, well-documented cases of human JE have occurred in southern Thailand, Malaysia, Indonesia, and the Philippines, but attack rates in these regions are low (less than 0.1 per 100,000) and epidemic disease has never been observed (Okuno, 1978). One puzzling feature of the epidemiology of JE is that the virus can be isolated with relative ease from mosquitoes or sentinel animals in these regions, but human disease is rare (Burke et al., 1985d; Simpson et al., 1970; Trosper et al., 1980; Van Peenan et al., 1974). Foreign visitors to epidemic regions in Asia also are at risk. Sporadic cases have occurred among tourists and within expatriate diplomatic and business communities. Epidemics of JE, involving hundreds of U.S. troops, have occurred during every recent military conflict in Asia (World War II and the Korean and Vietnam wars). Disease Burden Estimates Special difficulties impede efforts to determine the total disease burden of Japanese encephalitis. Incidence rates and age distribution patterns may vary dramatically within a single country. Table D-6.1 shows the incidence rates used to determine total numbers of cases and deaths due to Japanese encephalitis in endemic regions. The proportion of cases in each age group is shown in Table D-6.2. For countries for which incidence rates and age distributions were not available, estimates were based on the epidemiology of disease in surrounding countries. The proportion of cases in each morbidity category is assumed to be the same for each age group. All cases require hospitalization. Twenty-five percent of patients die about 1 week after hospitalization, and another 25 percent develop chronic sequelae (10 percent fall into each of categories D and E, and the remaining 5 percent in category F). Total disease burden estimates are shown in Table D-6.3. PROBABLE VACCINE TARGET POPULATION In most areas JE occurs in children, although as discussed above, epidemics in some regions have shown a peak incidence among adults. The target population for an improved vaccine probably would be all infants in areas of potential JE occurrence; but immediately after introduction it is likely that the vaccine also would be administered to susceptible older children and adults. Potential target areas include Japan, China, Thailand, Korea, Vietnam, Kampuchea, Laos, Malaysia, Indonesia, the Philippines, Nepal, northern India, and Sri Lanka. To simplify the calculations, the potential target population is considered to be the entire birth cohort of all countries in affected regions (see Table D-6.4).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-6.1 Disease Estimates: Cases and Deaths Country Population (millions) Annual Incidence per 100,000a Cases per Year Deathsb Southeast Asia         Burma 38.9 1.0 389 97 Indonesia 161.6 0.1 162 40 Kampuchea 6.1 1.0 61 15 Laos 3.7 5.0 185 46 Malaysia 15.3 0.1 15 4 Philippines 54.5 1.0 545 136 Thailand 51.7 5.0 2,585 646 Vietnam 58.3 5.0 2,915 729 East Asia         China 1,034.5 1.5 15,518 3,880 Japan 119.9 0.2 240 60 North Korea 19.6 2.4 490 122 South Korea 42.0 2.4 1,000 250 Taiwan 19.2 1.0 192 48 Mid-South Asia         India 746.4 0.4 2,986 746 Nepal 16.6 3.4 564 141 Sri Lanka 16.1 3.2 515 129 Total     28,852 7,213 aBurma—Fukunaga, 1983; Khin, 1982; Okuno, 1978. Indonesia—Okuno, 1978; Thaib, 1982. Kampuchea—Assumes rates similar to northeast Thailand. Laos—Assumes rates similar to northern Thailand. Malaysia—Lam, personal communication, 1985; Okuno, 1978. Philippines—Chan, 1982; Okuno, 1978. Thailand—Jatanesen, personal communication, 1985; Okuno, 1978; Sangkawibha, 1982. Vietnam—Assumes rates similar to Thailand. China—Chu, 1982; Quan, 1983. Japan—Ishii, 1983; Okuno, 1978. North Korea—Assumes rates similar to South Korea. South Korea—Okuno, 1978; Paik, 1983. Taiwan—Assumes rates intermediate between Japan and China. India—Mathur et al., 1982; Pavri and Rodrigues, 1982; Rodrigues, 1982. Nepal—Joshi, 1983. Sri Lanka—Vitarana, 1982.. bAssuming a 25 percent case-fatality rate.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-6.2 Distribution of Cases by Age Group     Age Group (years)     Under 5 5–14 15–59 60 and Over Distribution Pattern Total Number of Cases Cases Percent Cases Percent Cases Percent Cases Percent Distribution 1a 6,135 1,841 30 3,681 60 614 10 — — Distribution 2b 722 101 14 181 25 390 54 50 7 Distribution 3c 17,498 1,750 10 12,249 70 3,500 20 — — Distribution 4d 432 43 10 43 10 130 30 216 50 Distribution 5e 3,501 525 15 1,400 40 1,225 35 350 10 Distribution 6f 564 113 20 226 40 226 40 — — Total 28,852 4,373   17,780   6,085   616   aIncludes Burma (Fukunaga, 1983; Khin, 1982; Okuno, 1978), Kampuchea (assumes rates similar to northeast Thailand), Thailand (Jatanesen, personal communication, 1985; Okuno, 1978; Sangkawibha, 1982), Laos (assumes rates similar to northern Thailand) , Vietnam (assumes rates similar to Thailand) . bIncludes Indonesia (Okuno, 1978; Thaib, 1982), the Philippines (Chan, 1982; Okuno, 1978), Malaysia (Lam, personal communication, 1985; Okuno, 1978). cIncludes North Korea (assumes rates similar to South Korea), South Korea (Okuno, 1978; Paik, 1983), China (Chu, 1982; Quan, 1983). dIncludes Japan (Ishii, 1983; Okuno, 1978) and Taiwan (assumes rates intermediate between Japan and China). eIncludes India (Mathur et al., 1982; Pavri and Rodrigues, 1982; Rodrigues, 1982) and Sri Lanka (Vitarana, 1982); distributions speculative because India has two very different patterns. fIncludes Nepal (Joshi, 1983).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-6.3 Disease Burden: Japanese Encephalitis     Under 5 Years 5–14 Years 15–59 Years 60 Years and Years Morbidity Category Description Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity                 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work                 C Severe pain, severe short-term impairment, or hospitalization 4,373 11 17,780 11 6,085 11 616 11 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work) 437 n.a. 1,778 n.a. 609 n.a. 62 n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work) 437 n.a. 1,778 n.a. 609 n.a. 62 n.a. F Total impairment 219 n.a. 889 n.a. 304 n.a. 31 n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death 1,093 n.a. 4,445 n.a. 1,521 n.a. 154 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-6.4 Estimates of Vaccine Target Population Country Population (millions) Birth Ratea Birth Cohort Southeast Asia       Burma 38.9 38 1,478,200 Indonesia 161.6 34 5,494,400 Kampuchea 6.1 38 231,800 Laos 3.7 42 155,400 Malaysia 15.3 31 474,300 Philippines 54.5 32 1,744,000 Thailand 51.7 26 1,344,200 Vietnam 58.3 34 1,982,200 East Asia       China 1,034.5 21 21,724,500 Japan 119.9 13 1,558,700 North Korea 19.6 32 627,200 South Korea 42.0 23 966,000 Taiwan 19.2 23 441,600 Mid-South Asia       India 746.4 34 25,377,600 Nepal 16.6 43 713,800 Sri Lanka 16.1 28 450,800 Total     64,764,700 aNumber of births per 1,000 population. Foreign visitors also might avail themselves of a new vaccine, but their numbers are considered negligible compared with the main target population. Because the virus is transmitted in a zoonotic cycle, with man as an incidental host, a vaccination program would not provide herd immunity. Thus, disease reduction would be directly proportional to vaccine coverage of the population. With this approach, vaccination would have to be continued indefinitely. A safe and effective vaccine that could confer immunity in a single or limited number of doses probably could be incorporated into the World Health Organization Expanded Program on Immunization (WHO-EPI) for delivery to infants or young children. Vaccine Preventable Illness* Although some cases of JE may occur in young infants, the disease occurs primarily in children and, in some areas, adults (see above). *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries For the calculations conducted here, it is assumed that all JE is potentially preventable by administration of a hypothetical, totally efficacious vaccine administered to the entire target population. SUITABILITY FOR VACCINE CONTROL Alternative Control Measures and Treatments JEV exists in nature as an arthropod-borne zoonosis; man becomes infected only incidentally. In theory, preventive measures could be directed toward control of the mosquito vector, or toward immunization of the nonhuman vertebrate hosts. In fact, neither of these approaches is feasible. The principal vector species of JE are common rice-field-breeding mosquitoes present in huge numbers throughout Asia; no practical vector control measures are available or are likely to be available in the near future. Because these species feed largely at night, window screens and mosquito nets probably are useful devices for limiting, but not eliminating, exposure. Immunization of pigs, the major amplifying host, has been seriously considered. However, the domestic pig population in many of the affected countries is roughly equal to that of the human population. Further, the average life span of a pig raised for slaughter is only 1 to 2 years. A pig immunization program that would require distribution of a quantity of vaccine equal to the human population every year is unacceptably expensive. Elimination or immunization of the wild bird hosts is equally impractical. There are no known specific therapeutic agents for the treatment of acute JE in humans; treatment is entirely supportive (World Health Organization, 1979, 1983). PROSPECTS FOR VACCINE DEVELOPMENT Status of Existing Vaccines JEV was first isolated more than 50 years ago, in 1934. Ten years later, toward the end of World War II, the first large-scale JEV immunization program was conducted: 77,000 U.S. troops, stationed on Okinawa in preparation for the invasion of mainland Japan, received an inactivated mouse brain JEV vaccine. No attempt was made to study protective efficacy. Since then, an estimated 0.5 billion doses of various JE vaccine preparations have been manufactured and administered to humans in Asia. Regrettably, there are still no published studies presenting the details of a field trial of vaccine efficacy. Three main types of JE vaccine have been used extensively in humans.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Formalin-Inactivated Mouse Brain Vaccine This is the major vaccine currently used in Japan, Korea, and Taiwan. Over the past 20 years, about 8.2 million doses of vaccine have been distributed by the major Japanese commercial producer, The Research Foundation of Osaka University (logo=“Biken”). The vaccine is administered to children starting at school age; an initial two doses are administered 1 week apart, followed by a booster at 1 year and then every 3 years thereafter. Coverage is nearly universal in southern Japan. Preparation of the vaccine involves purification of virions from a mouse brain suspension by ultracentrifugation (Fukai, 1983; Takaku et al., 1971). Biken research workers are unable to detect myelin basic protein in the final product, and Biken officials state that, to the best of their knowledge, no case of neurologic complications of vaccination has been reported. Minor side effects of fever or local tenderness are encountered in a few percent of vaccinees. The vaccine has never been evaluated completely in a controlled field efficacy trial (two trials were begun, but neither was completed). Boosters are required to maintain serum neutralizing titers at detectable levels. The vaccine is prepared from a strain of the prototype Nakayama virus that was isolated in 1935 (Mitamura et al., 1936). In tests in mice, vaccine prepared from this strain induced antibody that neutralized the homologous virus well but that neutralized less well several other strains isolated from more western parts of Asia. A bivalent vaccine, consisting of equal parts of the Nakayama strain and the Beijing strain, was shown to induce satisfactory levels of neutralizing antibodies to all known JEV strains (Fukai, 1983). This bivalent Biken inactivated mouse brain vaccine is currently undergoing controlled field testing in northern Thailand. Formalin-Inactivated Cell Culture Vaccine Since 1967, JE vaccines have been produced in China on a large scale by infecting roller bottle cultures of primary hamster kidney cells with the P3 (Beijing, 1949) strain. Six Institutes of Biological Products around the country produce a total of about 100 million doses of vaccine per year. Vaccine is administered to children under the age of 10 years: two doses separated by a 1-week interval, followed by boosters at 1 year and every 3 years thereafter. Low-grade fever and local reactions are encountered occasionally, but neurological complications have not been reported. Controlled field trials involving 360,000 children are said to have been conducted between 1967 and 1969 (He Shi-min, 1983). Efficacy rates of 85 percent, 76 percent, and 87 percent were reported for three trials, but details are not available.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Live Attenuated Vaccine Three different live attenuated JE vaccines have been tested in humans in China. All three vaccine strains derive from a single parent virus, the SA14 mosquito field isolate, which was passed 100 times in hamster kidney cells to yield the avirulent 12–1–7 strain. The 2–8 vaccine strain was developed from the 12–1–7 strain by ultraviolet irradiation and passage in adult mice. The resultant live vaccine was shown to have a protective efficacy of 87 percent in a trial involving 500,000 horses, but only 50 percent of 8,000 children inoculated with this vaccine developed neutralizing antibody. No further trials were conducted. The 5–3 vaccine strain was derived from the 12–1–7 strain by 12 sequential plaque clonal selection passages. Detailed characteristics of this vaccine virus, such as the actual dose used for human immunization, are not available. After one dose of the vaccine, 80 percent of children developed neutralizing antibodies (Li Ho-mia, 1983). In a brief report of a controlled trial involving more than 200,000 children, a protective efficacy of 85 percent was reported (Li Ho-min, 1983). More than 5 million children have been immunized with the 5–3 vaccine. The 14–2 strain was derived from the 5–3 strain by serial passage in murine subcutaneous tissues and subsequent cloning. This was done to increase the infectivity and immunogenicity. Compared to the 5–3 strain, about 100-fold less of the infectious virus is required to infect humans. Only a few dozen children have been inoculated with this strain; seroconversion rates and mean titers are higher following 14–2 vaccination than following 5–3 vaccination (Li Ho-min, 1983). Potential for New Vaccines Fatal encephalitis can be induced in essentially any rodent and primate species when the challenge virus is inoculated directly into the brain. However, animal models based on direct intra-cranial inoculation are at best a poor reflection of the pathogenesis of JE in man, where the virus multiplies for several days in peripheral tissues before the brain is invaded. Aerosol challenge (Larson et al., 1980) or intra-nasal inoculation (Harrington et al., 1977) of primates or rodents can lead to fatal encephalitis, probably by passage of virus through the cribiform plate, but the relevance of this route of challenge to natural human infections is also questionable. Peripheral challenge of sub-human primates regularly results in a sub-clinical infection with viremia but without evidence of viral replication in the brain (Morris et al., 1955; Nathanson and Harrington, 1966). In rodents, the response to peripheral JEV challenge is strikingly age dependent; suckling mice are regularly susceptible, while adult mice are usually resistant (Taylor et al., 1980). Genetically determined resistance of mice to lethal flavivirus encephalitis has been determined to be inherited as a simple, autosomal dominant trait (Bang, 1978). However, peripheral inoculation of older weanling or

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries adult mice of susceptible strains with virulent JEV does not always reliably produce encephalitis; titration end-points are not sharp. Other less well defined host factors are also important in susceptibility (Huang, 1957; Huang and Wong, 1963). As noted in previous sections, several different types of reportedly efficacious JE vaccines have been developed and administered to large numbers of humans; feasibility of vaccine construction is not an issue. However, none of the existing vaccines is ideal; significant problems still exist regarding vaccine safety, cost, and the requirement for booster immunizations. Life-threatening adverse effects may be associated with currently available vaccines: although no cases of vaccine-related allergic encephalomyelitis have been attributed to the inactivated mouse brain vaccines, it is possible that some cases have occurred and were missed. The same is possible for cases of acute viral encephalitis, which could result from growth of the live attenuated vaccine virus within the central nervous system. The frequencies of these complications presumably are very low, but finite. The third major type of existing JE vaccine, the inactivated hamster kidney cell culture product, would appear theoretically to be relatively free from encephalitic complications. However, the possibility of a disaster resulting from inadvertent incomplete virus inactivation always exists. The inactivated mouse brain vaccine is expensive: production costs are about $2.30 per dose or $4.60 per primary immunization (U.S. dollars). Information is not available on the costs of the two vaccines prepared in China. Both are probably less expensive than the mouse brain vaccine. The yield of JE virus in cell cultures is considerably lower than that of other viruses for which inactivated cell culture vaccines are practical (e.g., poliovirus), so it is likely that the cost per dose is proportionally much greater for the inactivated hamster kidney JE vaccine than for polio. Cost per dose of the live attenuated 5–3 strain vaccine is unknown. Periodic booster immunizations are required for all three of the existing vaccines; none induces solid lifelong immunity with a single inoculation. Induction of humoral immunity (neutralizing antibody) appears to be a good predictor of vaccine efficacy (Hammon and Sather, 1973; Morris et al., 1955). Because neutralizing antibodies are directed against the virion surface, a subunit vaccine prepared from the JE virus envelope glycoprotein (E protein) appears to be the safest alternative. However, available methods for separation of the E protein from virions or infected cells are too laborious for commercial application. Research on the molecular biology of the flaviviruses using recombinant DNA techniques is proceeding rapidly, and the gene coding for the E protein of JEV probably will be cloned and sequenced in the near future. The ideal JE vaccine would induce sustained (lifelong) antibody production to the E protein. To achieve this goal, novel E protein delivery systems must be developed, such as sustained release “depot” vaccine carriers, or self-replicating avirulent vectors into which the E protein

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries gene has been inserted, for example, vaccinia. The practicality of producing a safe E protein subunit vaccine through recombinant DNA technology remains to be determined. Adequate field testing of a new JE vaccine will be difficult. The relatively low clinical attack rate of JE (maximum 100 to 200 per 100,000 in an epidemic in a highly selected population) will necessitate an extremely large study to document vaccine efficacy. To test a new vaccine with a predicted efficacy of 80 percent in a placebo-controlled trial, a study population in excess of 100,000 subjects would be required in most affected regions. The need exists for an inexpensive JE vaccine of proven safety and efficacy. Although there are several apparently promising approaches to achieve such a vaccine, there are also a number of problems to be overcome, including ethical questions concerning the testing of a new vaccine against a product of presumed (but not proven) efficacy. REFERENCES Albrecht, P. 1969. Pathogenesis of neurotropic arbovirus infections. Curr. Top. Microbiol. Immunol. 43:44–91. Bang, F.B. 1978. Genetics of resistance of animals to viruses. I. Introduction and studies in mice. Adv. Virus Res. 23:270–343. Benenson, M.W., F.H. Top, Jr., W.Gresso, C.W.Ames, and L.B.Altstatt. 1975. The virulence to man of Japanese encephalitis virus in Thailand. Am. J. Trop. Med. Hyg. 24:974–980. Buescher, E.L., and W.F.Scherer. 1959. Ecologic studies of Japanese encephalitis virus in Japan. IX. Epidemiologic correlations and conclusions. Am. J. Trop. Med. Hyg. 8:719–722. Burke, D.S., A.Nisalak, M.A.Ussery, T.Laorakpongse, and S. Chantavibul. 1985a. Kinetics of Japanese encephalitis virus immunoglobulin M and G antibodies in human serum and cerebrospinal fluid. J. Infect. Dis. 151:1093–1099. Burke, D.S., A.Nisalak, W.Lorsomrudee, M.Ussery, and T.Laorpongse. 1985b. Virus-specific antibody-producing cells in blood andcerebrospinal fluid in acute Japanese encephalitis. J. Med. Virol. 17:283–292. Burke, D.S., W.Lorsomrudee, C.J.Leake, C.H.Hoke, A.Nisalak, V. Chongswasdi, and T.Laorakpongse. 1985c. Fatal outcome in Japanese encephalitis. Am. J. Trop. Med. Hyg. 34:1203–1210. Burke, D.S., M.Tingpalapong, G.S.Ward, R.Andre, and C.J.Leake. 1985d. Intense transmission of Japanese encephalitis virus to pigs in a region free of epidemic encephalitis. Southeast Asian J. Trop. Med. Public Health 16:199–206. Carey, D.E. 1969. Japanese encephalitis in South India, a summary of recent knowledge. J.Indian Med. Assoc. 52:10–15. Chan, V.F. 1982. Viral diseases in the Philippines: An overview. Pp. 256–260 in Viral Diseases in South-East Asia and the Western Pacific, J.S.MacKenzie, ed. New York: Academic.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Chu, Chi-Ming. 1982. Viral diseases in China. Pp. 243–248 in Viral Diseases in South-East Asia and the Western Pacific, J.S.MacKenzie, ed. New York: Academic. Dickerson, R.B., J.R.Newton, and J.E.Hansen. 1952. Diagnosis and immediate prognosis of Japanese encephalitis. Am. J. Med. 12:277–288. Edelman, R., R.J.Schneider, and P.Chieowanich. 1975. The effect of dengue virus infection on the clinical sequelae of Japanese encephalitis: A one year follow-up study in Thailand. Southeast Asian J.Trop. Med. Public Health 6:308–315. Fournier, M. 1986. Personal communication, University of Massachusetts, Boston. Fukai, K. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983. Fukunaga, T. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983. Grossman, R.A., R.Edelman, and D.J.Gould. 1974. Study of Japanese encephalitis in Chiangmai Valley, Thailand. VI. Summary and conclusions. Am. J.Epidemiol. 100:69–76. Halstead, S.B., and C.R.Grosz. 1962. Subclinical Japanese encephalitis. I. Infection of Americans with limited residence in Korea. Am. J. Hyg. 75:190–201. Hammon, W.McD. 1969. Observations on dengue fever, benign protector and killer; a Dr. Jekyll and Mr. Hyde. Am. J.Trop. Med. Hyg. 18:159–165. Hammon, W.McD., and G.E.Sather. 1973. Passive immunity for arbovirus infection. I. Artifically induced prophylaxis in man and mouse for Japanese encephalitis. Am. J. Trop. Med. Hyg. 22:524–534. Harrington, D.G., D.E.Hilmas, M.R.Elwell, R.E.Whitmire, and E.L. Stephen. 1977. Intranasal infection of monkeys with Japanese encephalitis virus: Clinical response and treatment with a nuclease-resistant derivative of poly (I)-poly (c). Am. J.Trop. Med. Hyg. 26:1191–1198. He Shi-min. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983. Hoke, C.H., and D.S.Burke. 1985. Personal communication, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Walter Reed Army Institute of Research, Washington, D.C. Huang, C.H. 1957. Studies on host factors in inapparent infection with Japanese B encephalitis. Acta Virol. 1:83–91. Huang, C.H. 1982. Studies of Japanese encephalitis in China. Adv. Virus Res. 27:71–101. Huang, C.H., and C.Wong. 1963. Relation of the peripheral multiplication of Japanese B encephalitis virus to the pathogenesis of the infection in man. Acta Virol. 7:322–334. Ishii, K. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Jatanesen, S. 1985. Personal communication, Ministry of Health, Bangkok, Thailand. Johnson, R.T., D.S.Burke, M.Eluell, C.J.Leake, A.Nisalak, C.H. Hoke, and W.Lorsomrudee. 1985. Japanese encephalitis: Immunocytochemical studies of viral antigen and inflamatory cells in fatal cases. Ann. Neurol. 18:567–573. Joshi, D.D. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983. Ketel, W.B., and A.J.Ognibene. 1971. Japanese B encephalitis in Vietnam. Am. J. Med. Sci. 261:271–279. Khin, M.M. Viral diseases in Burma. 1982. Pp. 210–216 in Viral Diseases in South-East Asia and the Western Pacific, J.S. MacKenzie, ed. New York: Academic. Lam, S.K. 1985. Personal communication, University of Malaysia, Kuala Lumpur. Larson, E.W., J.W.Dominik, and T.W.Slone. 1980. Aerosol stability and respiratory infectivity of Japanese B encephalitis virus. Infect. Immun. 30:397–401. Li Ho-min. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983. Mathur, A., U.C.Chaturvedi, H.O.Tandon, A.K.Agarual, G.P.Mathur, D.Nag, A.Prasad, and U.P.Mittal. 1982. Japanese encephalitis epidemic in Uttar Pradesh, India during 1978. Indian J. Med. Res. 75:161–169. Mitamura, T., M.Kitaoka, S.Wutanabe, K.Okubo, S.Tenjin, S.Yamada, K.Mori, and J.Asada. 1936. Study on Japanese encephalitis virus, animal experiments and mosquito transmission experiments. Kansai Iji 1:260–261. Miyake, M. 1964. The pathology of Japanese encephalitis: A review. Bull. WHO 30:153–160. Morris, J.A., J.R.O’Connor, and J.E.Smadel. 1955. Infection and immunity patterns in monkeys injected with viruses of Russian Spring-Summer and Japanese encephalitis. Am. J. Hyg. 62:327–341. Nathanson, N., and G.A.Cole. 1970. Fatal Japanese encephalitis virus infection in immunosuppressed spider monkeys. Clin. Exp. Immunol. 6:161–166. Nathanson, N., and B.Harrington. 1966. Experimental infection of monkeys with Langat virus. I. Comparison of viremia following peripheral inoculation of Langat and Japanese encephalitis viruses. Am. J. Epidemiol. 84:54–566. Ohyama, A., A.Ishiga, and N.Fujita. 1959. Effect of human gamma globulin upon encephalitis viruses. Jpn. J. Microbiol. 3:159–169. Okuno, T. 1978. An epidemiological review of Japanese encephalitis. World Health Stat. Rep. 31:120–133. Paik, S.B. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Pavri, K., and J.Rodrigues. 1982. Viral diseases in India—a national overview. Pp. 191–197 in Viral Diseases in South-East Asia and the Western Pacific, J.S.MacKenzie, ed. New York: Academic. Quan, C.B. 1983. Paper presented at a World Health Organization Working Group on the Prevention and Control of Japanese Encephalitis, Tokyo, Japan, December 19–21, 1983. Rice, C.R., E.M.Lenches, S.R.Eddy, S.J.Shin, R.L.Sheets, and J.H. Strauss. 1985. Nucleotide sequence of yellow fever virus: Implications for flavivirus gene expression and evolution. Science 229:726–733. Rodrigues, F.M. 1982. Paper presented at a Conference on Japanese Encephalitis, Indian Council on Medical Research, New Delhi, India, Nov. 3–4, 1982. Rosen, L., R.B.Tesh, J.H.Lien, and J.H.Cross. 1978. Transovarial transmission of Japanese encephalitis virus by mosquitoes. Science 199:909–911. Sangkawibha, N. 1982. Viral diseases in Thailand—a national overview. Pp. 217–223 in Viral Diseases in South-East Asia and the Western Pacific, J.S.MacKenzie, ed. New York: Academic. Sather, G.E., and W.McD.Hammon. 1970. Protection against Saint Louis encephalitis and West Nile arboviruses by previous dengue virus (type 1–4) infection. Proc. Soc. Exp. Biol. Med. 135:573–578. Schneider, R.J., M.H.Firestone, R.Edelman, P.Chieowanich, and R.V. Pornpibul. 1974. Clinical sequelae after Japanese encephalitis: A one year follow-up study in Thailand. Southeast Asian J.Trop. Med. Public Health 5:560–568. Shapiro, D., W.E.Brandt, R.O.Cardiff, and P.K.Russell. 1971. The proteins of Japanese encephalitis virus. Virology 44:108–124. Simpson, D.I.H., E.T.W Bowen, G.S.Platt, H.Way, C.E.G.Smith, S. Peto, Sumitra Kamath, Lim Boo Liat, Lim Teong Wah. 1970. Japanese encephalitis in Sarawak: Virus isolation and serology in a land Dyak village. Trans. Roy. Soc. Trop. Med. Hyg. 64:503–510. Southam, C.M. 1956. Serologic studies of encephalitis in Japan. II. Inapparent infections by Japanese B encephalitis virus. J. Infect. Dis. 99:163–169. Takahashi, M., and K.Suzuki. 1979. Japanese encephalitis virus in mosquito salivary glands. Am. J. Trop. Med. Hyg. 28:122–135. Takaku, K., T.Yamashita, T.Osanai, I.Yoshida, M.Kato, H.Goda, M.Takagi, T.Amano, K.Fukai, N.Kunita, K.Inoue, K.Shoji, A. Igarashi, and T. Ito. 1971. Inactivated vaccine from Japanese encephalitis infected mouse brains (ultracentrifuge-purified vaccine). Pp. 59–64 in Immunization for Japanese Encephalitis, W.McD.Hammon, M.Kitaoka, and W.G.Downs, eds. Tokyo: Igaku Shoin Ltd. Taylor, J.L., C.Schoenherr, and S.E.Grossberg. 1980. Protection against Japanese encephalitis virus in mice and hamsters by treatment with carboxymethylacridanone, a potent interferon inducer. J. Infect. Dis. 142:394–399.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Thaib, S. 1982. Viral diseases in Indonesia. Pp. 236–242 in Viral Diseases in South-East Asia and the Western Pacific, J.S. MacKenzie, ed. New York: Academic. Trosper, J.H., T.G.Ksiazek, J.H.Cross, and V.Basaca-Sevilla. 1980. Isolation of Japanese encephalitis virus from the Republic of the Philippines. Trans. Roy. Soc. Trop. Med. Hyg. 74:292–295. Van Peenan, P.F.D., R.Irsiana, J.S.Saroso, S.W.Joseph, R.E.Shope, and P.L.Joseph. 1974. First isolation of Japanese encephalitis virus from Java. Mil. Med. 139:821–823. Vitarana, T. 1982. Viral diseases in Sri Lanka: A national overview. Pp. 198–204 in Viral Diseases in South-East Asia and the Western Pacific, J.S.MacKenzie, ed. New York: Academic. Westaway, E.G. 1973. Proteins specified by group B togaviruses in mammalian cells during productive infections. Virology 51:454–465. World Health Organization. 1979. WHO technical guidelines on Japanese encephalitis. WHO Regional Office for Southeast Asia, New Delhi. World Health Organization. 1983. Working group on the prevention and control of Japanese encephalitis. WHO Regional Office for the Western Pacific.