Japanese Encephalitis: Surveillance and Elimination Effort in Japan from 1982 to 2004

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1 Jpn. J. Infect. Dis., 61, , 2008 Review Japanese Encephalitis: Surveillance and Elimination Effort in Japan from 1982 to 2004 Satoru Arai, Yasuko Matsunaga, Tomohiko Takasaki 1, Keiko Tanaka-Taya, Kiyosu Taniguchi, Nobuhiko Okabe, Ichiro Kurane 1 * and Vaccine Preventable Diseases Surveillance Program of Japan** Infectious Disease Surveillance Center and 1 Department of Virology 1, National Institute of Infectious Diseases, Tokyo , Japan (Received May 21, Accepted July 28, 2008) CONTENTS: 1. Introduction 2. Surveillance of JE in Japan 3. Annual numbers of confirmed human JE cases 4. Sex and age distribution of the JE cases 5. Geographical distribution of JE in Japan 6. Monthly occurrence of JE 7. JE vaccination histories 8. Prognoses of the cases 9. Prevalence of JE antibody among general populations in Japan 10. JE virus infection of sentinel pigs 11. Discussion SUMMARY: Japanese encephalitis (JE) surveillance has been conducted since 1965 as a part of the National Epidemiological Surveillance of Vaccine Preventable Diseases in Japan. Over 1,000 JE cases were reported annually in the late 1960s. The number of JE cases has since markedly decreased, with less than 10 cases reported annually from 1992 to A total of 361 JE cases were reported between 1982 and Prognosis was available for 320 cases; 58 (18%) died, 160 (50%) recovered with neuropsychiatric sequelae, and 102 (32%) completely recovered. Seventy-eight percent of these cases were 40 years old or over with a peak age group of years old. JE predominantly occurred in unvaccinated populations. A high seroconversion rate among sentinel pigs was recorded every year. This suggests the presence of JE virus-infected mosquitoes during the summer in most areas of Japan, including the northern districts where no JE cases were reported from 1982 to Although JE cases have been reported in single figures since 1992, the risk of JE virus infection is still present. Thus, high immunization rates of JE vaccine should be maintained in Japan. Introduction Japanese encephalitis (JE) is a serious viral encephalitis with a high mortality rate and a high percentage of neuropsychiatric sequelae (1,2). JE occurs in annual epidemics in many Asian countries (3). Approximately 50,000 cases have been reported annually worldwide (4). However, the actual number of JE cases is considered to be significantly greater because JE surveillance systems are not effectively implemented in many developing countries. The epidemiological features of JE have dramatically changed over the past 3 decades in Japan, with a virtual elimination of clinical cases. In this paper, we analyze the records of JE surveillance in Japan from 1982 to 2004 and describe control measures taken in recent years. Surveillance of JE in Japan JE surveillance was first implemented in 1965 through the National Epidemiological Surveillance of Vaccine Preventable Diseases by the Ministry of Health and Welfare (currently the Ministry of Health, Labour and Welfare [MHLW]) *Corresponding author: Mailing address: Department of Virology 1, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo , Japan. Tel & Fax: , kurane@nih.go.jp **Members of the Vaccine Preventable Diseases Surveillance Program of Japan are listed in the Appendix. (5). The surveillance includes (i) confirmation of notified JE cases, (ii) prevalence of JE antibodies among general populations, and (iii) seroconversion rates of sentinel pigs nationwide. Laboratory confirmation of JE has been performed by hemmagglutination inhibition (HI) or complement fixation (CF) tests, according to the guidelines established in The cases were confirmed to be JE when HI or CF antibody titers were increased by 4 times or more in convalescent phase serum samples when compared to acute phase samples. In cases where only single patient samples were available, HI titers of 1:160 or greater and CF titers of 1:8 or greater were considered to be confirmatory laboratory data. Neutralization assay, polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) have also been used recently for laboratory confirmation. Annual numbers of confirmed human JE cases The annual numbers of confirmed JE cases from 1965 to 2004 are shown in Figure 1. More than 1,000 JE cases were reported annually in the late 1960s. Since then, the number of cases dramatically decreased, with 20 to 90 cases reported annually from 1978 to 1991, and less than 10 cases reported annually from 1992 to A total of 361 confirmed JE cases were reported between 1982 and Sex and age distribution of the JE cases Of 361 confirmed JE cases, 184 cases were male and

2 Fig. 1. Annual incidences of JE from 1965 to 2004 in Japan. Records of JE cases were collected using individual report cards by the Ministry of Health, Labour and Welfare, Japan. These reported cases included fatal cases and serologically and/or virologically confirmed survival cases. Fig. 2. Sex and age distribution of JE cases from 1982 to 2004 in Japan. A total of 361 JE cases are shown based on ages at the development of symptoms. Table 1. Number of confirmed cases of JE in Japan during from 1982 to 2004, by sex, prognosis, and history of vaccination Year Sex Prognosis History of vaccination No. of cases Complete Incomplete Male Female Sequelae Fatal Unknown Vaccinee Non-vaccinee Unknown recovery vaccinee Total Rate 51% 49% 28% 44% 16% 11% 1% 4% 51% 44% were female (Table 1). Seventy-eight percent of the total cases were 40 years old or older with a peak in the year age group (Figure 2). These data indicate that JE occurred mainly among elderly populations. The highest incidence rates were in the year age group among males and in the year age group among females. Although JE occurred mainly in elderly populations from 1982 to 2004, there were a small number of JE cases in individuals younger than 10 years old (Figure 2). These cases accounted for 12% of the total JE cases. Geographical distribution of JE in Japan Japan is geographically divided into 8 districts: Kyushu (the southernmost district including Okinawa Prefecture), Shikoku, Chugoku, Kinki, Chubu, Kanto, Tohoku, and the northernmost district of Hokkaido (Figure 3). Of 361 JE cases, 165 cases (46%) were reported in the Kyushu district, 40 cases (11%) in Shikoku, 40 cases (11%) in Chugoku, 64 cases (18%) in Kinki, 24 cases (7%) in Chubu, and 28 cases (8%) in Kanto (Figure 3). There were no confirmed JE cases in the northern districts of Tohoku and Hokkaido between 1982 and Therefore, JE occurred mainly in the southern districts of Japan. 334

3 Fig. 3. Geographical distribution of JE cases from 1982 to 2004 in Japan. Japan is geographically divided into 8 districts: from south to north, Kyushu (Fukuoka, Saga, Nagasaki, Kumamoto, Oita, Miyazaki, Kagoshima, and Okinawa Prefectures), Shikoku (Tokushima, Kagawa, Ehime, and Kochi Prefectures), Chugoku (Tottori, Shimane, Okayama, Hiroshima, and Yamaguchi Prefectures), Kinki (Osaka, Hyogo, Kyoto, Shiga, Nara, and Wakayama Prefectures), Chubu (Niigata, Toyama, Ishikawa, Fukui, Yamanashi, Nagano, Gifu, Shizuoka, Aichi, and Mie Prefectures), Kanto (Tokyo, Kanagawa, Saitama, Chiba, Ibaraki, Tochigi, and Gunma Prefectures), Tohoku (Aomori, Iwate, Miyagi, Akita, Yamagata, and Fukushima Prefectures), and Hokkaido. Records of 145 cases from 1982 to 1986, 163 cases from 1987 to 1991, 16 cases from 1992 to 1996, 23 cases from 1997 to 2001, and 14 cases from 2002 to 2004 were used for the analysis. Fig. 4. Date of the onset of JE cases from 1982 to A total of 361 JE cases were analyzed for the date of the onset of symptoms. The southern districts (Kyushu, Shikoku, Chugoku, and Kinki districts) and the northern districts (Chubu, Kanto, Tohoku, and Hokkaido districts) were separately analyzed. Monthly occurrence of JE All the JE cases were reported during a 5-month span, from July to November. The earliest onset of the disease was on July 12 in 2001 and the latest on November 1 in The majority of JE cases were reported in August and September with a peak in late August (Figure 4). When southern districts (Kyushu, Shikoku, Chugoku, and Kinki) and northern districts (Chubu and Kanto) are analyzed separately, a difference in monthly JE inception is observed. JE occurred from mid-july to early November with a peak in late August in the southern districts, while it occurred from early August to late October with a peak in early September in the northern districts. JE vaccination histories Records of JE vaccinations were available for 203 cases Fig. 5. Prevalence of the JE antibody among general populations in Percent anti-je virus antibody positive rates are shown based on the ages. Populations with neutralizing antibody titers equal to or greater than 1:10, equal to or greater than 1:40, and equal to or greater than 1:160 are separately shown. (Table 1). One hundred and eighty-three of the 203 cases were unvaccinated, and only 20 cases were vaccinated in full (5 times) or on partial vaccination schedules. The data suggest that JE predominantly occurred in the unvaccinated populations. Prognoses of the cases Prognoses were available for 320 of the 361 cases. Of the 320 cases, 58 (18%) died, 160 (50%) recovered with neuropsychiatric sequelae, and 102 (32%) completely recovered (Table 1). Prognosis was analyzed in 2 groups: cases younger than 40 years old and cases 40 years old or older. The percentages of JE cases with fatal outcomes and complete recoveries were 9% (7/78) and 38% (38/78), respectively, in the younger group, and 18% (51/283) and 29% (72/283), respectively, in the older group. 335

4 Fig. 6. The seroconversion rate among sentinel pigs in each prefecture. Serum samples were collected from 6- to 8-month-old pigs every 10 days. HI antibody was tested, and percent positive rates were calculated. The results are presented in each attending prefecture at the end of July, August, and October in 1982, 1986, 1990, 1994, 1998, 2001, and Prevalence of JE antibody among general populations in Japan JE antibody prevalence was surveyed among general populations in the National Epidemiological Surveillance of Vaccine Preventable Diseases. The data for 2004 are shown in Figure 5. Neutralizing antibody titers equal to or greater than 1:10 were considered to be positive in the analysis. Antibody prevalence differed between age groups. The JE antibodypositive population was less than 50% for ages 3 years and younger, greater than 70% for ages 4-24 and 65-69, and between 20 and 70% for ages and 70 years or more. It should be noted that the JE antibody-positive rate was also low in the population aged JE virus infection of sentinel pigs The seroconversion rates among sentinel seronegative pigs were checked annually in most prefectures. Swine are known to be an amplifier of JE virus, and it is generally accepted that the seroconversion rates of sentinel pigs reflect the prevalence of JE virus in the area. Local public health institutes in most of the 47 prefectures surveyed pigs, which were brought to slaughterhouses, for positive rates of HI antibodies. Data in the representative 7 years including 1982, 1986, 1990, 1994, 1998, 2001, and 2004 are presented in Figure 6. Seroconversion usually began in May in Okinawa Prefecture and in July in other southern prefectures (data not shown). Seroconversion in the sentinel pigs moved to the north and occurred in all the prefectures by October with the exception of Hokkaido in some years. Seroconversion rates were somewhat lower in the northern prefectures. Discussion JE is an acute viral encephalitis transmitted by infected mosquitoes. Culex tritaeniorhynchus is the main vector in Japan. The ratio of asymptomatic to symptomatic infections is estimated to be 100:1-1,000:1 (3). Mouse-brain-derived, inactivated JE vaccine is available and internationally accepted (6,7). JE is, therefore, a vaccine preventable disease; however, this vaccine has not been used regularly in all the JE epidemic or endemic countries in Asia, mainly due to its high cost and to limitations in production capacity. The epidemic and endemic areas are located in East Asia, South Asia, and Southeast Asia (3,8). Approximately 1 billion children are believed to be at risk for JE virus infection in these areas. Additionally, JE cases have been reported in Papua New Guinea and Australia (9-12). JE is therefore no longer restricted to only Asian countries. JE was a serious cause of morbidity and mortality in Japan for many years. There were more than 1,000 JE cases reported annually in the late 1960s. The number of JE cases has decreased dramatically, and less than 10 cases have been reported annually since 1992 (Figure 1). The majority of the cases were in the elderly population with a peak in the year age group. The JE antibody-positive percentage, however, is not lower in the elderly population than in the younger population. We assume that the high incidence of JE among the elderly population is mainly due to impaired immune responses. However, it should be noted that the age distribution of JE patients in Table 1 is a sum from 1982 to 2004, and the antibody positive rate in Figure 5 is that observed in Thus, a direct comparison between these two data may not be appropriate. Although the percentage was low, there were 336

5 JE cases among children younger than 10 years old. In Japan, primary JE vaccination is to be given twice at 1-4 week intervals between 6 and 90 months of age, and the current standard schedule usually starts at 3 years old. The first booster immunization is given 1 year after the primary vaccination (usually at the age of 4 years), and the 2nd and 3rd booster immunizations are given at ages 9-13 years and years, respectively. (The 3rd booster immunization was terminated as of July 29, 2005.) The small cluster of cases between the ages of 0 and 4 years most likely reflects lower levels of antibody prevalence among this age population. Thus, immunization at ages younger than 3 years old should be considered in order to prevent JE in children aged 3 years old and younger. The JE antibody-positive rate was also low in the population years of age. It is possible that this population was not vaccinated with JE vaccine at a high rate and was not naturally infected at a high rate as in the elderly populations. There have been reports of acute disseminated encephalomyelitis (ADEM) after immunization with mouse brainderived JE vaccine. The MHLW of Japan halted the recommendation of JE vaccination as of May 30, 2005, because of the occurrence of severe ADEM. However, the JE vaccination system has not been changed, and JE vaccine is available for those who request the vaccination. The incidence of ADEM is estimated to be less than one case per 1 million doses ([13] and data not shown), and this rate is not higher than those induced by other vaccines. Further investigation is needed to define the relationship between JE vaccine and ADEM. The development of Vero cell-derived JE vaccine is underway (14). Extensive vaccination with mouse brain-derived, inactivated vaccine is considered to be the main factor in the significant decrease in the number of JE cases in Japan. The JE virus Nakayama strain was originally used for vaccine production in Japan, but since 1989 the Beijing-1 strain has been used instead. The protective efficacy of the vaccine was evaluated in placebo-controlled studies. The efficacy was estimated to be 80% in Taiwan in 1965 (15) and 91% in Thailand in 1988 (16). Neutralizing antibody titers of 1:10 or greater, which are generally considered to be protective levels, were maintained for at least 3-4 years after the first booster immunization (17-20). It is believed that in addition to extensive JE vaccination, there are other multiple factors which also contributed to the decrease in the number of JE cases in Japan. These factors include a decrease in the areas of the irrigation fields where Cx. tritaeniorhynchus breed and changes in rice cultivation methods. These changes decreased the population of Cx. tritaeniorhynchus (21). Other factors also include the segregation of pigs, which are amplifiers of JE virus, from residential areas (21) and fewer pig farms (22). Due to these factors, JE virus-infected mosquitoes have fewer chances to bite humans. A high seroconversion rate among sentinel pigs is consistent with the occurrence of JE cases in southern districts (Figure 4). It should, however, be noted that sentinel pigs are seroconverted even in northern districts with the exception of Hokkaido in some years. The data suggest that JE virusinfected mosquitoes are present during the summer in most areas of Japan, including the northern districts where no JE cases were reported from 1982 to Therefore, caution is still necessary with respect to JE in Japan. It was reported that anti-je virus NS1 antibody was detected in 10 and 5% of the residents in rural and urban areas, respectively, in Hyogo Prefecture (23). It was also reported that anti-je virus NS1 antibody was detected in 0.2 to 3.4% of the residents in 8 prefectures (24). Additionally, anti-je virus NS1 antibody was detected among racehorses nationwide (25). Anti-JE virus NS1 antibody is induced only by JE virus infection, not by immunization with inactivated JE vaccine. These results indicate that humans and horses are naturally infected with JE virus at low but significant levels today. Therefore, JE vaccination is still recommended throughout Japan. For many countries that have been suffering from serious JE epidemics, the Japanese experience is a good example of successfully fighting the battle against this devastating disease. ACKNOWLEDGMENTS We wish to thank Dr. Isao Arita of the Agency for Cooperation in International Health, Kumamoto, Japan for critical reading of the manuscript. This study was supported by the vaccine preventable diseases surveillance program of the Ministry of Health, Labour and Welfare, Japan. APPENDIX The member of Vaccine Preventable Diseases Surveillance Program of Japan (VPDSJ) have been constructed with researchers from the Hokkaido Institute of Public Health, Aomori Prefectural Institute of Public Health and Environment, Research Institute for Environmental Sciences and Public Health of Iwate Prefecture, Miyagi Prefectural Institute of Public Health and Environment, Akita Prefectural Institute of Public Health, Yamagata Prefectural Institute of Public Health, Fukushima Institute for Public Health, Ibaraki Prefectural Institute of Public Health, Tochigi Prefectural Institute of Public Health and Environmental Science, Gunma Prefectural Institute of Public Health and Environmental Sciences, Saitama Institute of Public Health, Chiba Prefectural Institute of Public Health, Tokyo Metropolitan Institute of Public Health, Kanagawa Prefectural Institute of Public Health, Niigata Prefectural Institute of Public Health and Environmental Sciences, Toyama Institute of Health, Ishikawa Prefectural Institute of Public Health and Environmental Science, Fukui Prefectural Institute of Public Health and Environmental Science, Yamanashi Institute for Public Health, Nagano Environmental Conservation Research Institute, Gifu Prefectural Institute of Health and Environmental Sciences, Shizuoka Institute of Environment and Hygiene, Aichi Prefectural Institute of Public Health, Mie Prefectural Science and Technology Promotion Center, Shiga Prefectural Institute of Public Health and Environmental Science, Kyoto Prefectural Institute of Hygienic and Environmental Sciences, Osaka Prefectural Institute of Public Health, Hyogo Prefectural Institute of Public Health and Environmental Sciences, Nara Prefectural Institute for Hygiene and Environment, Wakayama Prefectural Research Center of Environment and Public Health, Tottori Prefectural Institute of Public Health and Environmental Science, Shimane Prefectural Institute of Public Health and Environment Science, Okayama Prefectural Institute for Environmental Science and Public Health, Hiroshima Prefectural Health Environment Center, Yamaguchi Prefectural Research Institute of Public Health, Tokushima Prefectural Institute of Public Health and Environmental Sciences, Kagawa Prefectural Research Institute for Environmental Sciences and Public Health, Ehime Prefectural Institute of Public Health and Environmental Science, The Public Health Institute of Kochi Prefecture, Fukuoka Institute of Health and Environmental Sciences, Saga Prefectural Institute of Public Health and Pharmaceutical Research, Nagasaki Prefectural Institute of Public Health and Environmental Sciences, Kumamoto Prefectural Institute of Public Health and Environmental Science, The Oita Prefectural Institute of Health and Environment, The Miyazaki Prefectural Institute for Public Health and Environment, Kagoshima Prefectural Institute for Environmental Research and Public Health, Okinawa Prefectural Institute of Health and Environment and National Institute of Infectious Diseases since REFERENCES 1. 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