japanese encephalitis for a reference to international travelers

259

© 2007 International Society of Travel Medicine, 1195-1982Journal of Travel Medicine, Volume 14, Issue 4, 2007, 259–268

Japanese encephalitis (JE) is an infl ammatory disease in the central nervous system including the cerebrum, the cerebellum, and the spinal cord. The disease is caused by the infection with a virus transmitted by mosquitoes. JE is an important disease in East, South-east, and South Asia, recording serious outcome. Mortality rate is high from 15% to 40%, and a high rate incidence of sequelae is recorded after the recov-ery. Complete cure is shown in only one third of the patients. The endemic regions have expanded re-cently to the South Pacifi c including Papua New Guinea and northern Australia. The JEV results in an inapparent infection in most cases, and 1 of 25 to 1,000 infections manifests neurological symptoms.

High morbidity is noted in children living in the endemic area, and adults usually acquire immunity. However, travelers visiting endemic regions from nonendemic countries have a risk of contracting the disease. Prevention of JE is possible by avoiding visits to the infested regions in epidemic season, avoiding mosquito bites during the epidemic season, and receiving vaccines. The effective and safe vac-cine is available in the endemic countries and for international travelers.

Disease

Clinical Features The main symptoms are fever, meningeal irritation, and encephalitis. 1 The incubation period was about 2 weeks. Most patients show sudden fever and head-ache. The body temperature rises to 39°C to 40°C or higher within a few days. Other early symptoms are vomiting, diarrhea, pains at different parts of the body, etc. From the second day of the illness, men-ingeal irritation becomes apparent, and then the ce-rebral symptoms rapidly develop, including cloudy consciousness ranging from a mild one such as apa-thy to a serious one such as coma or muscle spasm. Kernig ’ s sign also becomes marked. In around 1 week after the onset of fever, the illness reaches a peak and many patients die. However, death tended to be delayed recently. After this time, fever gradu-ally subsides and patients begin to recover from the symptoms.

The cerebrospinal fl uid (CSF) appears watery and transparent but rises in its pressure and in-creases in the number of cells and amount of pro-teins. The level of sugar in the CSF slightly increases. Computered tomography and magnetic resonance imaging (MRI) reveal high signal inten-sities in bilateral thalami, brain stem, hippocampi, and brain cortices in the early stage of illness. 2 – 5 MRI showed lesion even 2 months after the onset of the disease. 2 Generally prognosis is not good. The proportion of fatal cases and those recovering with

Japanese Encephalitis for a Reference to International Travelers

Akira Oya , MD and Ichiro Kurane , MD

National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan

DOI: 10.1111/j.1708-8305.2007.00134.x

Japanese encephalitis (JE) is an infl ammatory disease in the central nervous system caused by infection with Japanese encephalitis virus (JEV). JE is a disease with a high fatality rate and endemic and epidemic in East, Southeast, and South Asia. High morbidity is noted in children living in the endemic area. JEV is maintained mainly between vector mosqui-toes and pigs in nature. The risk of JE increases as the number of vector mosquitoes increases. The expansion of JEV-endemic area depends on irrigated rice fi eld and pig farming. These environments that are suitable for infectious cycle of JEV exist widely in Asia today. The effective and safe vaccine is available in endemic countries and for interna-tional travelers. JE vaccination is strongly recommended to those who visit the JEV-endemic regions, especially in the rainy season.

Corresponding Author: Ichiro Kurane, MD, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. E-mail: [email protected]

Dow

nloaded from https://academ

ic.oup.com/jtm

/article/14/4/259/1841315 by guest on 31 July 2022

260

J Travel Med 2007; 14: 259–268

Oya and Kurane

sequelae such as impaired intelligence and dyskine-sia due to the damaged central nervous system is high. Complete recovery were one third of the cases. Recently, the proportion of fatal cases tended to de-cline because of a progressed treatment, however, that of completely cured cases is still at the same level as before, one third. The mortality rate in the aged patients is high and sometimes over 40%.

Diagnosis Clinical diagnosis is prerequisite for early and proper treatment. However, the confi rmatory di-agnosis should rely on virus isolation, detection of the virus genomes, or serological examinations. Vi-rus isolation from blood or CSF of a patient could be successful at a very early stage of the illness but is very diffi cult. Hemagglutination inhibition (HI) test and enzyme-linked immunosorbent assay (ELISA) are commonly used for serodiagnosis. JEV HI antibody titer increases between acute and con-valescent stages. However, serodiagnosis is not simple in Southeast Asia where more than one fl avi-virus are endemic. Increase in antibody titers may be shown against multiple fl aviviruses. In such re-gions, detection of virus-specifi c immunoglobulin M (IgM) antibody is reliable for diagnosis. IgM-capture ELISA has been widely used recently for detection of specifi c IgM. 6,7

Pathogenesis The pathogenesis of JE is not completely under-stood. JEV transmitted to the human body by mos-quito bite may primarily proliferate in the local lymph nodes and enter the blood vessels causing vi-remia. The virus then spreads to the lymphatic tis-sues in the whole body and bone marrows. JEV proliferates secondarily in these organs and causes secondary viremia. The virus fi nally reaches neuro-nal cells in the central nervous system. It is generally believed that in most infections, JEV does not enter the central nervous system which is protected by the blood – brain barrier and results in inapparent infec-tion demonstrating that neutralizing antibody in-duced after infection. 8

Epidemiology

Japanese Encephalitis Virus Japanese encephalitis virus (JEV) belongs to the family Flaviviridae, the genus Flavivirus ( Figure 1 ). The genome of JEV is a single and plus-stranded RNA nearly 11 kb in length. 9,10 JEV genome encodes an open reading frame fl anked by about 100- and 600-base untranslated regions at the 5 ′ and

3 ′ ends, respectively. The uninterrupted open read-ing frame codes for three structural proteins, the capsid (C), preM which is the precursor to the mem-brane (M) protein, and the envelope (E) protein, and seven nonstructural proteins, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. 9 JE virion has a spherical shape with 40 to 50 nm in diameter. 11 The envelope is a lipid bilayer containing two envelope-associated proteins: the E and M proteins. The nucleocapsid, which is about 30 nm in diameter and covered by envelope, is composed of RNA ge-nome and C protein.

The E protein is glycosylated and responsible for attachment to still-unidentifi ed cellular receptors and fusion with cell membrane. The E protein con-tains the main epitopes recognized by neutralizing antibodies. These epitopes include both JEV-specifi c ones and those cross-reactive for other fl aviviruses. The cross-reactivity is high among the JE serocom-plex group including JEV, West Nile virus, St Louis encephalitis virus, and Murray Valley encephalitis virus. It is generally accepted that neutralizing antibody plays a key role in protective immunity against JEV. Thus, the E protein plays the most im-portant role in induction of protective immunity. 12,13 Antibodies to the M protein do not possess strong neutralizing activity. The role of cellular immunity in the protection against JEV is not well under-stood, although the E protein includes multiple epitopes recognized by T lymphocytes.

JEV strains are grouped into fi ve genotypes, based on the nucleotide sequence of the E gene. 14 However, JEV strains comprise only one serotype. 15 Thus, JE vaccine induces protective immunity to JEV strains included in other genotypes as well as to those in the same genotype as the vaccine strain.

Global Distribution JE occurs in annual epidemics or endemically in many Asian countries including Japan, Korea,

Figure 1 Schematic presentation of Japanese encepha-litis virion. D

ownloaded from

https://academic.oup.com

/jtm/article/14/4/259/1841315 by guest on 31 July 2022

261

J Travel Med 2007; 14: 259–268

Japanese Encephalitis

Taiwan, China, Vietnam, Thailand, Malaysia, Myanmar, India, Nepal, and Sri Lanka ( Figures 2, 3 ). 16,17 The endemic regions are surrounded by Japan, China, and Korea in the north, Indonesia and Australia in the south, India and Pakistan in the west, and the Philippines in the east. 16 Nearly 3 billion peo-ple, approximately 60% of the world ’ s population, are believed to be at risk for JEV infection. The fi rst JE patient in Papua New Guinea was reported in 1995 and then in 1997. 18 – 20 In Australia, three JE pa-tients were fi rst reported in Badu Island in the Torres Strait in 1995. 21 In 1998, the patients were again re-ported in Badu Island and for the fi rst time in York Peninsula in Australian subcontinent. 22 Thus, the JEV-endemic area has been expanding. JE is no longer only endemic in Asia, but also in Oceania.

Approximately 20,000 JE cases with 6,000 deaths are reported annually in the world. 23 The actual number, however, is estimated to be a few times greater. There is a lack of common surveillance standards. Most Asian countries use a syndromic surveillance and do not include laboratory confi r-mation in their surveillance systems. Further, im-plementation of surveillance systems is incomplete in many Asian countries. The total number of re-ported JE cases has been recently decreased accord-ing to the report of World Health Organization (WHO). The decrease in China (People ’ s Republic of China) greatly contributes to this decrease. China accounted for the largest number of JE cases in the world. In the last decades, however, China achieved a signifi cant reduction in the number of JE cases be-cause of a nationwide implementation of JE vacci-nation. 24 In Japan, Korea, and Taiwan, the annual JE case number is less than 10 since the 1990s mainly due to a mass immunization campaign and in part to other ecological factors. 25,26

The age distribution of JE patients varies in countries. In the countries in JEV-hyperendemic zone, half of the patients are children under 4 years of age and most of the patients are children under 10 years of age. 27 However, in countries like Japan, Korea, and Taiwan where mass JE vaccination has been extensively implemented, JE occurs among adult populations rather than children, the majority of the patients being at over 50 years of age. 25,28

JE is a vaccine-preventable disease; however, the vaccines are not distributed to all at risk in all the JE-endemic or -epidemic countries. Enough doses are not produced, and it is expensive for use in de-veloping countries.

Ecology of JEV In endemic regions, JEV is maintained in nature among vector mosquitoes, susceptible wild birds, and pigs. 29 Pigs are also considered as an amplifi er for JEV in the temperate zone. 29 The virus is also carried by migrated viremic birds from endemic to nonendemic regions. Mosquitoes bite these viremic birds and become infected, these infected mosquitoes then bite pigs, and naïve pigs are infected and develop viremia. JEV is well amplifi ed in a pig – mosquito transmission cycle, and many mosquitoes acquire JEV. The infected mosquitoes transmit JEV to humans or horses. A small percentage of infected humans and horses develop illness. However, humans or horses do not transmit virus to biting mosquitoes because of low titers of viremia; thus, humans and horses are considered to be dead-end hosts. 30

Seasonal Prevalence JEV transmission season differs among endemic re-gions. It varies depending on the numbers and ac-tivities of vector mosquitoes. The climate, especially

Figure 2 Global distribution of Japanese encephalitis.

Dow


ic.oup.com/jtm


262

J Travel Med 2007; 14: 259–268

Oya and Kurane

temperature and rainfall, affects the number and activity of vector mosquitoes. The changes in agri-cultural procedures, especially rice cultivation, affect the mosquito density and eventually the size and frequency of the transmission cycle of JEV. Levels of immunity among pig population also in-fl uence the transmission cycle. Mosquito density is increased when rice cultivation is initiated in mid-year ( Figure 4 ). There is a year-round transmission of JEV in tropical countries. 29 In the Southeast Asian countries, JEV transmission mainly occurs between May and December and throughout year in limited

sites. However, the transmission pattern in the tem-perate area (eg, Japan, Korea, northern China) is rather well defi ned. 29 The epidemic season in these areas usually starts in May or June and ends in Sep-tember or October. The JE epidemic may fl uctuate from year to year depending on the climate.

Vectors The principal vector of JEV is Culex tritaeniorhyn-chus in the most endemic areas in Asia. 31 Culex tritae-niorhynchus reproduces in rice paddies and in the connecting canals. It prefers the blood of middle- to

Figure 3 Annual incidences of Japanese encephalitis (JE) in JE-endemic countries.

Dow


ic.oup.com/jtm


263

J Travel Med 2007; 14: 259–268


large-sized domestic or wild animals and that of hu-mans. It is active in twilight and bites outdoors. In addition to C tritaeniorhynchus , other mosquitoes also play a role as vectors. They include Culex vish-nui , Culex gelidus , Culex pseudovishnui , Culex bitae-niorhynchus , Culex fuscocephala , Culex annulus , and Culex whitmorei . 31 JEV has been isolated from Culex pipiens pallens and Culex quinquefasciatus . JEV has been also isolated from species of Aedes mosquitoes, but the epidemiologic role of Aedes mosquitoes has not been well evidenced. In the temperate areas, the vector mosquitoes were detected in May; then sero-conversion of pigs occurs and occurrence of human cases follows.

It was reported that there is a positive relation-ship between the number of mosquitoes and that of JE cases. 32 The study in Japan clearly demonstrated the decrease in the number of mosquitoes in 1970s compared to that in 1960s. 33 The decrease probably plays an important role in the decrease in the number of JE patients in addition to nationwide implementation of JE vaccination. In this area, the changes in rice cultivation procedures with occa-sional reduction in water in rice fi elds also contribute to the decrease. The results suggest that changes in the rice culture techniques contributed to the de-creased number of mosquitoes, resulting in a decrease in human JE cases ( Figure 4 ). 34

Although there seems to be a correlation be-tween abundance of vector mosquitoes and human cases, other factors such as human immunization status and preventive measures against mosquitoes contribute to the decrease in the number of JE cases. In some regions in Asia, deforestation and introduc-tion of race cultivation have introduced the condi-tion that favors the increase in vector mosquitoes, resulting in the expansion of JE-endemic areas.

Role of Pigs Pigs are the amplifi er of JEV in the transmission cycle of JEV in human residential areas. Naïve pigs are highly susceptible to JEV and easily infected with JEV by the bite of infected mosquitoes. Pigs develop high and sustained levels of viremia. Adult pigs are asymptomatic after infection with JEV, al-though infection of pregnant pigs frequently results in abortions and stillbirth. High body temperature and the large hairless skin area of pigs attract many mosquitoes. 24 As a result, one infected pig produces large numbers of infected mosquitoes, playing a role as an amplifi er. 31,32 In rural Asia, pigs are bred in close contact with humans in a backyard. The breeding condition makes the pig a central player in JEV transmission in these regions. Introduction of pig breeding and/or rice farming also contributes to the emergence of JE in some regions of Asia where there had been no or very few JE patients.

The seroconversion rate among sentinel seroneg-ative pigs refl ects the prevalence of JEV in the area. For example, in Japan, seroconversion rates of sentinel pigs are checked in most prefectures every year. Seroconversion usually starts in May in Okinawa Island and in July in other southern prefectures. The seroconversion-positive area goes up to the north. The seroconversion occurs in most of the attending prefectures by October ex-cept for the northern island, Hokkaido, refl ecting the risk for JEV infection in humans. Thus, the sentinel pig system is useful for estimating a JE risk in humans. 21

Because pigs play a role as an amplifi er in the JEV transmission cycle, the introduction of the pig-farming business may have introduced JE epidemics in some regions in Asia. In Japan, the number of pigs increased, but that of pig farms decreased in the last 40 years. There are more pigs bred in a modernized facility, and pig farms are segregated from residen-tial areas. As a result, the number of pigs interest-ingly demonstrates a converse relationship with the number of JE patients in Japan. On the contrary, decrease in the number of pig farms as infection source parallels with the decrease in JE patient num-bers. Thus, the pig farming can be maintained without increasing the transmission of JEV to humans ( Figure 5 ).

Control

Mosquito Control Culex tritaeniorhynchus , the main JEV vector mos-quito, emerges from rice paddy fi elds and irrigation

Figure 4 Changes of rice cultivation procedures and decrease in mosquito numbers between 1950 and 1970 (modifi ed from reference 34 ). Irrigation in the rice pads has been occasionally stopped during rice cultivation since 1970.

Dow


ic.oup.com/jtm


264

J Travel Med 2007; 14: 259–268

Oya and Kurane

canals that connect them and bites animals, includ-ing humans, at night. Aerial applications from fi xed-wing aircraft or helicopters provided an effective mass control of mosquitoes than ground-based applications. Vector control by application of in-secticide aerosol was reported to be successful in Japan 37 and Korea. 38 Residual house spraying of in-secticides is not likely to be effective since most of C tritaeniorhynchus do not stay on house walls. Ultra – low volume techniques, which apply a small volume of insecticides, have been used effectively for JE in Korea. Malathion, fenitrothion, fenithion, primiphos-methyl, pyrethroides, etc are used as insecticide compounds.

For personal protection, a mosquito net is commonly used against night-biting JEV vector mosquitoes. Application of insect repellents is rec-ommended to use for personal temporal protection against mosquito bites. Benzyl benzoate, butyl ethyl propanediol, DEET (N,N-diethyl-3-methyl ben-zamide, formerly N,N-diethyl metha-toluamide), etc are used as the most effective compounds. DEET is more preferable because of its long-term effectiveness for 6 to 13 hours. 39

Vaccines JE vaccines are used for different purposes. Those are (1) vaccine for protection of humans, 40 (2) vac-cine for protection of horses, and (3) vaccine for protection of stillbirth of sows. Three types of JE vaccines are produced and used for humans in the world: (1) inactivated vaccine employing mouse brain, (2) inactivated vaccine employing primary hamster kidney cell culture, and (3) live vaccine em-ploying primary hamster kidney cell culture. Among them, WHO recommends at present only mouse brain – derived, inactivated vaccine. Live and inacti-vated vaccines from primary hamster kidney cells

are used in China. Expansion of JE-endemic region attracts attention of many countries. The Thai gov-ernment decided to include JE in EPI program in 1990. Immunization is now recommended for travelers to visit JE-endemic regions for more than 1 month in wet season, particularly for those engaging in considerable outdoor activity.

Mechanism of Protection Against JEV Infection The mouse is susceptible to JEV and shows a similar infection pattern to the humans after peripheral in-fection with JEV. In cases of adult mice, JEV infec-tion results in different outcomes: fatal encephalitis in some mice and inapparent infection and survival in others. However, 2-week-old weanling mice demonstrate fatal outcome, and virus titration is possible by peripheral inoculation to the weanling mice. Passive transfer of serum antibody against JEV inhibited viremia and protected mice against disease when given before virus inoculation. The challenge doses which were resisted by mice were linearly re-lated to serum antibody titers in challenged mice. This observation provided strong evidence that an-tibodies play a critical role in immunity to JEV. 8

Inactivated Vaccine Prepared From Infected Mouse Brain Purifi ed inactivated mouse brain vaccine of current use was licensed in Japan in 1965. It is produced in Japan, Korea, Taiwan, Thailand, India, and Vietnam. In Japan, two forms of vaccine, liquid and freeze-dried ones, are produced by fi ve manufacturers. Freeze-dried JE vaccine is exported for use outside of Japan because of its higher stability and longer expiring period, 5 years. Either Nakayama-NIH strain or Beijing-1 strain is used as a seed virus. The vaccines are produced by a series of purifi cation procedures from JEV-infected mouse brain in-cluding protamine sulfate precipitation, ultracen-trifugation, and virus inactivation by formalin. According to the minimum requirement of Japan, the potency of JE vaccine is measured by the titer of JEV neutralizing antibody induced in mice immu-nized with a tested vaccine. The antibody titer of a tested vaccine should be equal to or higher than that of the reference vaccine. The reference vaccine pos-sesses a potency equal to or higher than that which demonstrated over 80% effi cacy in the double-blind fi eld trial conducted in Taiwan in 1965. 41 The purity of vaccines is regulated so that total content of protein should not exceed 80 � g/mL. The freeze-dried JE vaccine is supplied by a 10 mL or 1 mL vial with a solvent.

Figure 5 Converse relationship between the numbers of pigs and patients with Japanese encephalitis in Japan.

Dow


ic.oup.com/jtm


265

J Travel Med 2007; 14: 259–268


Immunization Schedule. As a traveler ’ s vaccine, JE vaccination is recommended for those from 1 year to all ages. Three doses in primary vaccina-tion at days 0, 7, and 28 or two doses given at 1 to 4 weeks apart are recommended. At least a two-dose regimen is recommended before departure. Booster immunization is made at 1 year after and then every 3 years. 8 High levels of antibody are maintained for at least 3 years after booster vaccination. 42 Hyper-sensitivity to the previous vaccination is contraindi-cation. Local pain and tenderness at injection sites are seen in approximately 20% of vaccines. Fever and malaise are reported in 1%. Severe adverse re-action is rare. Effi cacy of Vaccination. Mouse brain – derived, in-activated JE vaccines demonstrated 80% to 90% effi cacy in fi eld trials. 34,43 Since JEV-specifi c neu-tralizing antibody was shown to be the essential immune mechanism to protect JEV infection, sero-conversion by the vaccine indicates the effective-ness of vaccine. 8 It was reported that JE vaccination induced no particular side reaction in human im-munodefi ciency virus – infected children but less potent antibody response to JEV. 43 Either Na-kayama strain or Beijing-1 strain induced antibody high enough to assure the protection against the current wild JEV strains. 44 After booster immuniza-tion, neutralizing antibody was shown to continue for at least 3 years. 8,44 Adverse Reactions of Inactivated Mouse Brain Vaccine. Since JE vaccine used infected mouse brain as a source, concern existed regarding the possible inci-dence of severe adverse reaction in nervous systems of vaccinees. Extensive survey of adverse events with a special reference to the incidence of neuro-logical symptoms was conducted in Japan in 1965 and 1966. 8 Some mild symptoms including fever, general malaise, and abdominal symptoms were noted in 1.2% of the vaccinees. No evidence was demonstrated to confi rm the etiologic relationship between systemic neurological syndromes and JE vaccination.

On the other hand, some severe allergic or neu-rological symptoms have been reported recently, particularly outside of Japan. 45 – 47 The incidence of systemic reactions characterized by generalized ul-ticaria, respiratory symptoms, and cardiovascular symptoms has been noted since 1998. 43,48 – 52 Some of them showed serum immunoglobulin E against gelatin; 53 however, many remained obscure in etiology. Such claims were reported in Denmark, Australia and Canada. Thus, recommendation to receive JE vaccine for travelers is on argument in some countries.

Severe neurological disorders including acute disseminated encephalomyelitis (ADEM) were re-ported in relation to JE vaccination. 54 – 57 Patients in-cluded children at 1 to 7 years of age and young adults. The ADEM symptoms appeared 1 day to 1 month after vaccination.

Live Attenuated JE Vaccine An attenuated strain of JEV was developed in China through serial passages of JEV on primary hamster kidney cells. The attenuated strain was named SA14-14-2. The live attenuated vaccine was pre-pared from JEV; SA14-14-2 strain has been used as an effective and safe vaccine since 1989 in China. 58 It has been reported that more than 100 million children received the SA14-14-2 vaccine with no serious adverse events. Neuroattenuation was evi-denced in intracerebral and intraperitoneal inocu-lation into weanling mice and intrathalamic or intraspinal inoculation into monkeys. It is not con-fi rmed yet whether it grows in JEV vector mosquito, C tritaeniorhynchus . 58 Two-dose immunization at 1 week apart is recommended as a routine immuni-zation although a single dose immunization also showed a comparable effi cacy. 59 The SA14-14-2 vaccine is produced only in China and used in a lim-ited number of countries including China. Clinical studies were performed in Nepal and Korea, and the studies showed an excellent effi cacy. 59,60

Primary Hamster Kidney – Derived, Inactivated Vaccine Inactivated JE vaccine produced in primary ham-ster kidney cells has been used in China. 58 However, it is now being substituted by the live attenuated SA14-14-2 vaccine because of its limited effi cacy and limited production scale.

JE Vaccines in Research and Development An inactivated JE vaccine deprived of mouse brain component is now under development. Vero cell – derived, inactivated JE vaccine produced with the Beijing-1 strain has completed phase III study and was submitted for licensure in Japan by two manufac-turers, Biken 61 and Kaketsuken, 62 in early 2005. The potency of Vero cell – derived vaccine was comparable to the current inactivated mouse brain – derived vac-cine. The Vero cell – derived vaccine was also reported to fulfi ll WHO minimum requirement for vaccine produced in animal cell cultures: cell-derived protein <1 ppm and cell-derived DNA <100 ng/dose. Vero cell – derived JE vaccine was also developed using SA14-14-2 strain with successful immunogenicity. 63

Dow


ic.oup.com/jtm


266

J Travel Med 2007; 14: 259–268

Oya and Kurane

Genetically Engineered Vaccines Chambers and colleagues developed a chimera virus by replacing prM and E genes of yellow fever virus, 17D strain, with those of JEV, SA14-14-2 strain. 64 The chimera virus as a candidate vaccine thus constructed induced JEV-specifi c antibodies in the vaccinees. The chimera vaccine was taken well in yellow fever – immune individuals and in-duced antibodies not only to JEV but also to the re-lated fl aviviruses. The vaccinees showed viremia for 4 to 7 days after inoculation, and some developed fever and malaise as those who had received yellow fever 17D vaccination. The yellow fever – JE chime-ric vaccine is expected to be as potent as yellow fever vaccine in the duration of specifi c antibody for years even after a single injection. 65,66 Development pro-gram of yellow fever – JE chimeric vaccine has fi n-ished the phase II study.

Another type of genetically engineered attenu-ated vaccine was reported. JEV envelope gene was inserted to vaccinia virus gene to produce recombi-nant vaccinia – JE vaccine. Inoculation with a candi-date vaccinia – JE recombinant vaccine elicited JE neutralizing antibody in individuals naïve to vaccinia virus. 67

Inoculation of plasmid DNA encoding JEV PrM – E protein induced JEV neutralizing antibody in mice, and these mice survived from otherwise le-thal JEV challenge, showing effectiveness of DNA vaccine. 68,69 JEV E protein and pseudoparticles including M and E protein were also prepared from transformed cells and were successfully used as candidate JE vaccines in mice. 70,71

Conclusions

JE is the most important viral encephalitis in Asia, especially in Southeast Asia and South Asia. Those who visit these regions should recognize the risk of JEV infection. An effective and safe vaccine is avail-able. JE vaccination is strongly recommended to those who visit the JEV-endemic regions, especially in the rainy season.

Declaration of Interests

The authors state that they have no confl icts of interest.

References

1. Researchers Associates National Institute of Health , ed . Vaccine handbook . Vol 103 . Tokyo, Japan : Maruzen , 1996 .

2. Nakashima A , Horichi Y , Takagi Y , et al . A case of Jap-anese encephalitis: CT and MRI fi ndings in acute and convalescent stages . Radiat Med 1999 ; 17 : 369 – 371 .

3. Ayukawa R , Fujimoto H , Ayabe M , et al . An unex-pected outbreak of Japanese encephalitis in the Chu-goku District of Japan , 2002 . Jpn J Infect Dis 2004 ; 57 : 63 – 66 .

4. Kalita J , Misra UK . Neurophysiological changes in Japanese encephalitis . Neurol India 2002 ; 50 : 262 – 266 .

5. Nalini A , Arunodaya GR , Tali AB , et al . Hemiplegia: an initial manifestation of Japanese encephalitis . Neurol India 2003 ; 51 : 397 – 398 .

6. Martin DA , Muth DA , Brown T , et al . Standardiza-tion of immunoglobulin M capture enzyme-linked immunosorbent assays for routine diagnosis of arbo-viral infections . J Clin Microbiol 2000 ; 38 : 1823 – 1826 .

7. Martin DA , Biggerstaff BJ , Allen B , et al . Use of im-munoglobulin M cross-reactions in differential diag-nosis of human fl aviviral encephalitis infections in the United States . Clin Diagn Lab Immunol 2002 ; 9 : 544 – 549 .

8. Oya A . Japanese encephalitis vaccine . Acta Paediat-rica Japonica 1988 ; 30 : 175 – 184 .

9. Sumiyoshi H , Mori C , Fuke I , et al . Complete nucle-otide sequence of the Japanese encephalitis virus ge-nome RNA . Virology 1987 ; 161 : 497 – 510 .

10. Ni H , Barrett AD . Nucleotide and deduced amino acid sequence of the structural protein genes of Japanese encephalitis viruses from different geo-graphical locations . J Gen Virol 1995 ; 76 : 401 – 417 .

11. Murphy FA . Togavirus morphology and morpho-genesis . In : Schlesinger RW , ed . The togaviruses: biology, structure and replication . New York, NY : Academic press , 1980 : 241 – 316 .

12. Yasuda A , Kimura-Kuroda J , Ogimoto M , et al . In-duction of protective immunity in animals vaccinated with recombinant vaccinia viruses that express PreM and E glycoproteins of Japanese encephalitis virus . J Virol 1990 ; 64 : 2788 – 2795 .

13. Konishi E , Yamaoka M , Khin-Sane-Win , et al . The anamnestic neutralizing antibody response is critical for protection of mice from challenge following vaccination with a plasmid encoding the Japanese encephalitis virus premembrane and envelope genes . J Virol 1999 ; 73 : 5527 – 5534 .

14. Solomon T , Ni Haoli , Beasley DWC , et al . Origin and evolution of Japanese encephalitis virus in South-east Asia . J Virol 2003 ; 77 : 3091 – 3098 .

15. Tsarev SA , Sanders ML , Vaughn DW , et al . Phylo-genetic analysis suggests only one serotype of Japa-nese encephalitis virus . Vaccine 2000 ; 18 ( Suppl 2 ): 36 – 43 .

16. Vaughn DW , Hoke CH Jr . The epidemiology of Japanese encephalitis: prospects for prevention . Epi-demiol Rev 1992 ; 14 : 197 – 221 .

Dow


ic.oup.com/jtm


267

J Travel Med 2007; 14: 259–268


17. Basnyat B , Zimmerman MD , Shrestha Y , et al . Per-sistent Japanese encephalitis in Kathmandu: the need for immunization . J Travel Med 2001 ; 8 : 270 – 271 .

18. Mackenzie JS . The ecology of Japanese encephalitis virus in the Australian region . Clin Virol 1999 ; 27 : 1 – 17 .

19. Hanson JP , Taylor CT , Richards AR , et al . Japanese encephalitis acquired near Port Moresby: implica-tions for residents and travellers to Papua New Guinea . Med J Aust 2004 ; 181 : 282 – 283 .

20. Rubin G , Baird J . New recommendations on Japa-nese encephalitis vaccination for travelers to Papua New Guinea . Med J Aust 2004 ; 181 : 283 .

21. Hanna JN , Ritchie SA , Phillips DA , et al . An out-break of Japanese encephalitis in the Torres Strait, Australia , 1995 . Med J Aust 1996 ; 165 : 256 – 260 .

22. Hanna JN , Ritchie SA , Phillips DA , et al . Japanese encephalitis in north Queensland, Australia , 1998 . Med J Aust 1999 ; 170 ( 11 ): 533 – 536 .

23. Halstead SB , Tsai TF . Japanese encephalitis vaccine . In : Plotin S , Orenstein WA , eds . Vaccine . 5th Ed . Philadelphia, PA : W.B. Saunders Co ., 2004 : 919 – 957 .

24. Yu YX . Japanese encephalitis in China . Southeast Asian J Trop Med Hyg 1995 ; 26 ( Suppl 3 ): 17 – 21 .

25. Matsunaga Y , Yabe S , Taniguchi K , et al . Current status of Japanese encephalitis in Japan . J Jap Assoc Infect Dis 1999 ; 73 : 97 – 103 .

26. Petersen LR , Marfi n AA . Shifting epidemiology of fl aviviridae . J Travel Med 2005 ; ( Suppl 1 ): S3 – S11 .

27. Gajanana A , Thenmozi V , Samuel P , et al . A community-based study of subclinical fl avivirus in-fections in children in an area of Tamil Nadu, India, where Japanese encephalitis is endemic . Bull World Health Organ 1995 ; 73 : 237 – 244 .

28. Wu YC , Huang YS , Chien LJ , et al . The epidemiol-ogy of Japanese encephalitis ion Taiwan during 1966-1997 . Am J Trop Med Hyg 1999 ; 61 : 78 – 84 .

29. Monath TP , Tsai TF. Flaviviruses . In : Richman DD , Whitley RJ , Hayden FG , eds . Clinical virology . Washington, DC : ASM Press , 2002 : 1097 – 1151 .

30. Gould DJ , Byrne RJ , Hayes DE . Experimental In-fection of horses with Japanese encephalitis virus by mosquito bite . Am J Trop Med Hyg 1964 ; 13 : 742 – 746 .

31. Rosen L . The natural history of Japanese encephali-tis virus . Annu Rev Microbiol 1986 ; 40 : 76 – 79 .

32. Maeda O , Karaki T , Kuroda A , et al . Epidemio-logical studies of Japanese encephalitis in Kyoto city area, Japan. II. Annual patterns of virus dis-semination on virus recoveries from unfed Culex tritaeniorhynchus summorosus . Jap J Med Sci Biol 1978 ; 31 : 39 – 51 .

33. Maeda O , Takenokuma K , Karoji Y , et al . Epidemio-logical studies on Japanese encephalitis in Kyoto city area, Japan. I. Evidence for decrease of vector mos-quitoes . Jap J Med Sci Biol 1978 ; 31 : 27 – 37 .

34. Kamimura K , Watanabe M . Some aspects of great diminution of Culex tritaeniorhynchus summo-

rosus, the principal vector of Japanese encephalitis: with special reference to the recent advance in agricul-tural methods . Botyu Kagaku 1973 ; 38 : 245 – 253 .

35. Maeda O , Karaki T , Kuroda A , et al . Epidemiologi-cal studies on Japanese encephalitis in Kyoto city area, Japan. III. Seasonal prevalence of virus infec-tions in several pig populations shown by virus re-covery from engorged Culex tritaeniorhynchus summorosus . Jap J Med Sci Biol 1978 ; 31 : 277 – 290 .

36. Maeda O , Takenouchi K , Karoji Y , et al . Epidemio-logical studies on Japanese encephalitis in Kyoto city area, Japan. IV. Natural infection in sentinel pigs . Jap J Med Sci Biol 1978 ; 31 : 317 – 324 .

37. Maeda O , Uemoto K , Nakazawa T , et al . Mosquito control project by aircraft application of larvicidal granules on rice fi elds . Jap J Sanit Zool 1981 ; 32 : 193 – 202 .

38. Self LS , Ree HI , Lofgren CS , et al . Aerial applica-tions of ultra-low-volume insecticides to control the vector of Japanese encephalitis in Korea . Bull World Health Organ 1973 ; 49 : 353 – 357 .

39. Lane RP , Crosskey RW ., eds . Medical insects and arachnids . Vol 214 . London, England : Chapman & Hill , 1993 .

40. Shlim DR , Tolomon T . Japanese encephalitis vac-cine for travelers: exploring the limits of risk . Clin Infect Dis 2002 ; 35 : 183 – 188 .

41. Hsu TC , Chow LP , Wei HY , et al . A completed fi eld trial for an evaluation of the effectiveness of mouse-brain Japanese encephalitis vaccine . In : Hammon WMcD , Kitaoka M , Downs WG , eds . Immuniza-tion for Japanese encephalitis . Tokyo, Japan : Igakushoin , 1971 : 258 – 265 .

42. Gambel JM , DeFraites R , Hoke C , et al . Japanese en-cephalitis vaccine: persistence of antibody up to 3 years after a three dose primary series . J Infect Dis 1995 ; 171 : 1074 .

43. Hoke CH , Nisalak A , Sangawhipa N , et al . Protec-tion against Japanese encephalitis by inactivated vac-cines . N Engl J Med 1988 ; 319 : 608 – 614 .

44. Rojanasuphot S , Shaffer N , Chotpitayasunondh T , et al . Response to the vaccine among HIV-infected children, Bangkok, Thailand . Southeast Asian J Trop Med Public Health 1998 ; 29 : 443 – 450 .

45. Nimmannitya S , Hutamai S , Kalayanarooj S , et al . A fi eld study on Nakayama and Beijing strains of Japa-nese encephalitis vaccines . Southeast Asian J Trop Med Public Health 1995 ; 26 : 689 – 693 .

46. Plesner A , Ronne T , Wachmann H . Case-control study of allergic reactions to Japanese encephalitis vaccine . Vaccine 2000 ; 18 : 1830 – 1836 .

47. Takahashi H , Pool V , Tsai T , et al . Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States . Vaccine 2000 ; 18 : 2963 – 2969 .

48. Marfi n AA , Eidex RS , Kozarsky PE , et al . Yellow fe-ver and Japanese encephalitis vaccines: indications and complications . Infect Dis Clin North Am 2005 ; 19 : 151 – 168 .

Dow


ic.oup.com/jtm


268

J Travel Med 2007; 14: 259–268

Oya and Kurane

49. Sakaguchi M , Inouye S . Two patterns of systemic immediate-type reactions to Japanese encephalitis vaccines . Vaccine 1998 ; 16 : 68 – 69 .

50. Nothdurft HD , Jelinek T , Marschang A , et al . Ad-verse reactions to Japanese encephalitis vaccine in travellers . J Infect 1996 ; 32 : 119 – 122 .

51. Ruff T , Eisen D , Fuller A , et al . Adverse reactions to Japanese encephalitis vaccine . Lancet 1991 ; 338 : 881 – 882 .

52. Andersen MM , Ronne T . Side-effects with Japanese encephalitis vaccine . Lancet 1991 ; 337 : 1044 .

53. Plesner A , Ronne T . Allergic mucocutaneous reac-tions to Japanese encephalitis vaccine . Vaccine 1997 ; 15 : 1239 – 1243 .

54. Ohtaki E , Murakami Y , Komori H , et al . Acute disseminated encephalomyelitis after Japanese B encephalitis vaccination . Pediatr Neurol 1992 ; 8 : 137 – 139 .

55. Ohtaki E , Matsuishi T , Hirano Y , et al . Acute dis-seminated encephalomyelitis after treatment with Japanese B encephalitis vaccine (Nakayama-Yoken and Beijing strains) . J Neurol Neurosurg Psychiatry 1995 , 59 : 316 – 317 .

56. Fukuda H , Umehara F , Kawahigashi N , et al . Acute disseminated myelitis after Japanese B encephalitis vaccination . J Neurol Sci 1997 ; 148 : 113 – 115 .

57. Plesner A , Arlien-Soborg P , Herning M , et al . Neu-rological complications and Japanese encephalitis vaccination . Lancet 1996 ; 348 : 202 – 203 .

58. Tsai TF . New initiatives for the control of Japanese encephalitis by vaccination. Minutes of a WHO/CVI meeting in Bangkok, Thailand, 13-15 October 1998 . Vaccine 2000 ; 18 : 1 – 25 .

59. Bista MB , Banerjee MK , Shin SH , et al . Effi cacy of single-dose SA 14-14-2 vaccine against Japanese en-cephalitis: a case control study . Lancet 2001 ; 358 : 791 – 795 .

60. Sohn YM , Park MS , Rho HO , et al . Primary and booster immune responses to SA14-14-2 Japanese encephalitis vaccine in Korean infants . Vaccine 1999 ; 17 : 2259 – 2264 .

61. Ishikawa T , Yoshii H , Onishi T , et al . An inactivated Japanese encephalitis vaccine manufactured from the virus-infected microcarrier-attached Vero cells;

III Manufacture of three consecutive lots of vaccines for clinical trial. WHO meeting of the Steering Committee on Dengue/JE Vaccines , Chieng Mai, Thailand , 2000 .

62. Sugawara K , Nishiyama K , Ishikawa Y , et al . Devel-opment of Vero cell-derived inactivated Japanese encephalitis vaccine . Biologicals 2002 ; 30 : 303 – 314 .

63. Srivastava AK , Putnak JR , Lee SH , et al . A purifi ed inactivated Japanese encephalitis virus vaccine made in vero cells . Vaccine 2001 ; 19 : 4557 – 4565 .

64. Chambers TJ , Nestorowicz A , Mason PW , et al . Yel-low fever/Japanese encephalitis chimaeric viruses; construction and biological properties . J Virol 1997 ; 73 : 3095 – 3101 .

65. Monath TP , McCarthy K , Bedford P , et al . Clinical proof of principle for ChimeriVax ™ : recombinant live, attenuated vaccines against fl avivirus infections . Vaccine 2002 ; 20 : 1004 – 1018 .

66. Kirkpatrick BD , Alston WK . Current immuniza-tions for travel . Curr Opin Infect Dis 2003 ; 16 : 369 – 374 .

67. Kanesa-thasan N , Smucny JJ , Hoke CH Jr , et al . Safety and immunogenicity of NYVAC-JEV and ALVAC-JEV attenuated recombinant Japanese encephalitis virus — poxvirus vaccines in vaccinia-nonimmune and vaccinia-immune humans . Vaccine 2001 ; 19 : 483 – 491 .

68. Zhao Z , Wakita T , Yasui K . Inoculation of plasmids encoding Japanese encephalitis virus PrM-E pro-teins with colloidal gold elicits a protective immune response in BALB/c mice . J Virol 2003 ; 77 : 4248 – 4260 .

69. Wu Y , Zhang F , Ma W , et al . A plasmid encoding Japanese encephalitis virus PrM and E proteins elic-its protective immunity in suckling mice . Microbiol Immunol 2004 ; 48 : 585 – 590 .

70. Kojima A , Yasuda A , Asanuma H , et al . Stable high-producer cell clone expressing virus-like par-ticles of the Japanese encephalitis virus E protein for a second-generation subunit vaccine . J Virol 2003 ; 77 : 8745 – 8755 .

71. Yang D , Kweon C , Kim B , et al . Immunogenicity to baculovirus expressed recombinant proteins of Japanese encephalitis virus in mice . J Vet Sci 2005 ; 6 : 125 – 133 .

Dow


ic.oup.com/jtm


japanese encephalitis for a reference to international travelers

Documents