An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)*†
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The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.
Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.
Japanese encephalitis (JE) is caused by a fl avivirus transmitted by Culex mosquitoes. It is one of the most important causes of viral encephalitis worldwide, with an estimated 50,000 cases and 15,000 deaths annually(1,2) . JE is endemic throughout much of rural South-East Asia, where the risk to unvaccinated travellers has been estimated to be as high as 1/5,000 per month of exposure(3) . There is no specifi c treatment for JE(4) , although an effi cacious vaccine(5,6) and use of personal protective measures (PPM) will provide substantial protection against infection and disease.
In only a small proportion of humans infected with JE virus does symptomatic disease develop (reported range: 1/25 to 1/1,000)(1) . For persons admitted to hospital with symptomatic JE, about 10% to 25% die and approximately 50% of survivors have severe neurological sequelae (e.g. frank motor defi cits, cognitive and language impairment)(1). Of the remaining 20% of clinical cases, about half have mild neurological sequelae(1) . In endemic areas, disease occurs primarily in children(4) ; by adulthood, most persons have serologic evidence of previous JE infection.
JE is principally a threat in rural agricultural areas. The virus is maintained in an enzootic cycle that prototypically involves Culex mosquitoes and wild birds (e.g. Ardeids such as egrets and herons)(4) . Secondary epizootic cycles may lead to infection of incidental hosts, such as humans and horses, and often involve pigs as amplifying hosts.
The main vector of JE is Culex mosquitoes, of which one of the most important is Culex tritaeniorhynchus, a species that tends to bite primarily at dusk and dawn, outdoors more than indoors and non-human mammals preferentially. Larvae of this species and many other Culex develop in standing water habitats, of which rice fi elds can be an important site because they may support very high larval populations(4) .
Two epidemiologic patterns of JE occur. In temperate areas, JE is transmitted sporadically with periodic seasonal epidemics (July to September), whereas in subtropical areas JE is endemic and transmission occurs through much of the year, often without clearly defi ned seasonal epidemics(4,7) . See Table 1 for a country-by-country description of JE risk and Figure 1 for a map of JE risk areas.
Large-scale JE vaccine programs (targeted at children), changes in animal husbandry practices and increased urbanization have led to a substantial reduction in human cases of JE in some countries(4) , e.g. Japan and Korea. However, JE may still present a risk to non-immune persons (e.g. travellers) in these areas because transmission may persist in a zoonotic cycle.
Table 1. Risk of Japanese encephalitis, by country, region and season(8)
|Country||Affected areas||Transmission season||Comments|
|Australia||Islands of Torres Strait||Probably year-round transmission risk||Localized outbreak in Torres Strait in 1995, sporadic cases in 1998 in Torres Strait, and one case on mainland Australia at Cape York Peninsula|
|Bangladesh||Little data; probably widespread||Possibly July to December, as in northern India||Outbreak reported from Tangail District, Dhaka Division, in 1977; more recently, sporadic cases in Rajshahi Division|
|Bhutan||No data||No data||No comments|
|Brunei||Presumed to be sporadic-endemic, as in Malaysia||Presumed year-round transmission||No comments|
|Presumed to be endemic-hyperendemic countrywide||Presumed to be May to October||Repeated outbreaks in Shan State|
|Cambodia||Presumed to be endemic-hyperendemic countrywide||Presumed to be May to October||Cases reported from refugee camps on Thai border, and possibly in Phnom Penh|
|China||Cases in all provinces except Xizang (Tibet),
|Northern China: May to September
||Vaccine not routinely recommended for
travellers to urban areas only, including Hong
|Hyperendemic in southern China||Southern China: April to October (Guangxi,
Yunnan, Guangdong and Southern Fujian, Sichuan, Guizhou, Hunan and Jiangxi provinces)
|Endemic, periodically epidemic in temperate areas|
|Hong Kong: rare cases in new territories||Hong Kong: April to October|
|Taiwan: endemic, sporadic cases islandwide*||Taiwan: April to October, with a June peak*||Taiwan: cases reported in and around Taipei and the Kao-hsiung-Pingtung river basins|
|India||Reported cases from all states except Arunachal, Dadra, Daman, Diu, Gujarat, Himachal, Jammu, Kashmir, Lakshadweep, Meghalaya, Nagar Haveli, Orissa, Punjab, Rajasthan and Sikkim||South India: May to October in Goa;
October to January in Tamil Nadu; and
August to December in Karnataka Second
peak, April to June in Mandya District
Andhra Pradesh: September to December
North India: July to December
|Outbreaks in West Bengal, Bihar, Karnataka,
Tamil Nadu, Andhra radesh, Assam, Uttar Pradesh, Manipur, and Goa.
Urban cases reported (e.g. in Lucknow)
|Indonesia||Kalimantan, Bali, Nusa, Tenggara, Sulawesi, Mollucas, Irian Jaya (Papua) and Lombok||Probably year-round risk; varies by island;
peak risks associated with rainfall, rice
cultivation and presence of pigs
Peak periods of risk: November to March; June and July in some years
|Endemic in Bali; sporadic cases recognized
Vaccine not recommended for travellers to urban areas only
|Japan*||Rare sporadic cases on all islands except Hokkaido||June to September, except April to
December on Ryuku Islands (Okinawa)
|Vaccine not routinely recommended for travel
to Tokyo and other major cities
Enzootic transmission without human cases observed on Hokkaido
|Korea||North Korea: no data
South Korea* : rare sporadic cases
|July to October||Last major outbreaks in 1982 and 1983
Vaccine not recommended for travellers to urban areas only
|Laos||Presumed to be endemic-hyperendemic countrywide||Presumed to be May to October||No comments|
|Malaysia||Sporadic-endemic in all states of the Peninsula,
Sarawak and probably Sabah
|Year-round transmission||Most cases from Penang, Perak, Salangor,
Johore and Sarawak
Vaccine not recommended for travellers to urban areas only
|Nepal||Hyperendemic in southern lowlands (Terai)
Sporadic cases now recognized in Kathmandu Valley
|July to December||Vaccine not recommended for travellers visiting only high-altitude areas|
|Pakistan||May be transmitted in central deltas||Presumed to be June to January||Cases reported near Karachi; endemic areas
overlap those for West Nile virus
Lower Indus Valley might be an endemic area
|Philippines||Presumed to be endemic on all islands||Uncertain; speculations based on locations
and agroecosystems. West Luzon, Mindoro, Negros, Palawan: April to November
Elsewhere: year-round, with greatest risk April to January
|Outbreaks described in Nueva Ecija, Luzon and Manila|
|Russia||Far Eastern maritime areas south of Khabarovsk||Peak period July to September||Rare human cases reported|
|Singapore||Rare cases||Year-round transmission, with April peak||Vaccine not routinely recommended|
|Sri Lanka||Endemic in all but mountainous areas
Periodically epidemic in northern and central provinces
|October to January; secondary peak of enzootic transmission May to June||Recent outbreaks in central (Anuradhapura) and northwestern provinces|
|Thailand||Hyperendemic in north; sporadic-endemic in south||May to October||Annual outbreaks in Chiang Mai Valley;
sporadic cases in Bangkok suburbs
|Vietnam||Endemic-hyperendemic in all provinces||May to October||Highest rates in and near Hanoi|
|Two epidemics reported in Guam and Saipan since
|Uncertain; possibly September to January||Enzootic cycle might not be sustainable; epidemics might follow introductions of virus|
*Local JE incidence rates may not accurately reflect risks to non-immune visitors because of high vaccination rates in local populations. Humans are incidental to the transmission cycle. High levels of viral transmission can occur in the absence of human disease.
Note: Assessments are based on publications, surveillance reports and personal correspondence. Extrapolations have been made from available data. The quality of surveillance data varies widely, and transmission patterns can change.
There have been very few cases of JE reported among Western travellers: from 1981 to 1992, the US Centers for Disease Control and Prevention reported 24 cases (11 in US citizens and 13 in expatriates/travellers from other Western nations)(3) ; a few additional cases have been reported in Western expatriates/travellers since 1992(9-14) . A possible case of JE was reported in a Canadian returning from Manchuria (northeastern China) in 1982(15) ; this may be the only Canadian case reported. Some travel-associated cases have involved minimal rural exposure, e.g. one night in a rural area(9) . A crude overall estimate of the risk of clinical JE among most short-term travellers to Asia may be 1 per million(3) , but in highly endemic areas during the transmission season risk may reach 1 per 5,000 per month(3) .
Figure 1 . Geographic distribution of Japanese encephalitis(8)
Risk areas for Japanese encephalitis
Insect repellents that contain DEET (N,N-diethyl-m-toluamide)(16,17) , permethrin-treated bed nets(18,19) and permethrin-treated clothing(20) have been shown to be effective in preventing the bites of Culex mosquitoes. Indeed, use of treated bed nets alone has been shown to achieve a substantial reduction in JE disease(19) . Overall, well-used PPMs are expected to substantially reduce the risk of exposure to JE(21) (and other arthropod-borne diseases, e.g. dengue); such reduction might be of the order of 90%.
Availability and efficacy
The JE vaccine (JEVacc) available in Canada1* is produced by Biken (the Research Foundation for Microbial Diseases of Osaka University) and distributed through Sanofi Pasteur Limited (JE-VAX®, Japanese encephalitis virus vaccine inactivated). The vaccine uses the Nakayama-NIH strain of the vaccine virus and is prepared by inoculating mice intracerebrally with this strain. Field trials with the vaccine have indicated a protection level of 80% to 91%(5,6). The vaccine is for immunization of persons ≥ 1 years of age.
The recommended vaccination schedule for travellers is three doses at 0, 7 and 30 days(22,23) . The use of a 0, 7 and 14 day schedule provides seroconversion rates similar to those associated with the longer schedule, but the serologic titres are lower and may decline more quickly. No definitive recommendation can be made regarding the timing of booster doses of JEVacc in travellers, but a 3 year booster interval is generally suggested in Canada(22) . Among travellers from nonendemic areas, two doses of vaccine at 0 and 7 days will seroconvert about 70% to 80% of vaccinees(24) with seroconversion occurring within 10 or so days after the second dose; seroconversion rates after two doses may be higher among persons from JE endemic areas, presumably because of exposure to JE and other fl aviviruses(5) .
Mild adverse events occur in about 20% of vaccinees(23) . However, in the late 1980s and early 1990s concerns were raised in Canada(25) and elsewhere regarding delayed hypersensitivity reactions (DHRs) to JEVacc, principally urticaria and angioedema; such reactions are not considered“immediate or Type 1 allergic reactions” (and, hence, are not associated with anaphylaxis). There is no accepted specific etiology for these DHRs. No deaths have been reported as a result of a DHR to JEVacc, though some patients have required hospitalization. A previous allergic reaction (e.g. urticaria, rhinitis, asthma) has been documented as a risk factor for JEVacc-associated DHRs(26,27) . The occurrence of mild adverse events does not predict the occurrence of DHRs. The estimated risk of a DHR after receipt of JEVacc has varied markedly from 0.0008% to 0.27% (Table 2). Since the early 1990s the rate of JEVacc-associated DHRs has noticeably decreased(28,29) . The risk of DHRs also may vary by dose(29) , i.e. the second dose (about 60% of all DHRs) more than the fi rst dose (about 30% of all DHRs) more than the third dose/revaccination (about 10% of DHRs).
There has not been a demonstrated causal link between “acute disseminated encephalomyelitis” and receipt of JEVacc (such concern led to the discontinuation of the routine childhood use of mouse-derived inactivated JEVacc in Japan in 2005)(32) .
Table 2. Reported rates of delayed hypersensitivity reactions (DHRs) after Japanese encephalitis vaccination from various published studies
|Country||Years||Doses given||DHR rate (percentage)||Reference no.|
|US military in Okinawa||Early 1990s||36,850||0.1||26|
|Australia||Jan. 1990-May 1992||4,500†||0.27||30|
|United Kingdom||Early 1990s‡||Not stated||0.6
(95% CI: 0.1-2.3)
*Distributed doses (assumed to approximate number of doses administered)
‡Not specifi cally stated in the reference but inferred by the date of publication
CI = confi dence interval
1* The manufacturer of JE-VAX® has ceased production of this vaccine. The distributor in Canada, Sanofi Pasteur Limited, has announced that the remaining JE-VAX® stockpile in Canada will be allocated to travel clinics based on previous usage rates of vaccine until the remaining stock is depleted. In light of this situation, the Public Health Agency of Canada is actively exploring alternatives for continued access to an effective JE vaccine.
Adverse events: precautions
Concern about DHRs has led to the recommendation that vaccinees remain close to medical care for the 10 days after each dose of JE vaccine(22) . The delay between immunization and onset of the DHR is < 6 days in 80% to 90% of DHRs (median: 2 days). However, in a small minority of DHRs delays between 10 and 14 days have been reported. Delays are longer for the second than for the fi rst dose.
*Members: Dr. P.J. Plourde (Chair); Dr. D. Werker (Executive Secretary); Dr. C. Beallor; Dr. K. Gamble; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean; Dr. J.R. Salzman; Dr. J.D. MacLean
Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. P. Teitelbaum; Dr. Anita Pozgay
Ex-Officio Representatives: Dr. J. Given, Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. N. Marano; Dr. P. Arguin; Dr. P. Charlebois; Dr. A. Duggan; Dr. M. Tepper
Member Emeritus: Dr. C.W.L. Jeanes.
† This statement was prepared by S. Schofield, PhD, an entomologist consultant for CATMAT and M. Tepper, MD. This statement was approved by CATMAT.