Canada Communicable Disease Report

Statement on Protection Against Japanese Encephalitis

Preamble

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.

Introduction

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.

Clinical picture

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.

Epidemiology

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⁾

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

Personal protective measures

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%.

JE vaccine

Availability and efficacy
The JE vaccine (JEVacc) available in Canada^1* 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) .

Adverse events
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

^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.

CATMAT recommendations

1. Properly used PPMs⁽²¹⁾ reduce the risk of JE and are recommended (BI² ). When the risk of JE infection is low, use of PPMs is expected to reduce the already small risk of JE to a level at which JEVacc provides little added benefi t, e.g. at a risk of 1/10,000 of JE without any protection, 90% effective PPMs reduce the residual risk that can be addressed by JEVacc to 1/100,000.
2. JEVacc is effi cacious in preventing JE (AI). JEVacc is recommended for travel to JE endemic/epidemic areas
   during the risk season:
   1. for all travellers who spend more than a cumulative total of 30 days in rural areas (or in urban areas known to be endemic or epidemic for JE); this might include longer term travellers or expatriates who, while based in urban areas, might be expected to make intermittent short trips to rural areas of risk (CIII);
   2. for travellers who will spend less than a cumulative total of 30 days in rural areas (or in urban areas known to be endemic or epidemic for JE) if they expect to have substantial cumulative activity outdoors (or indoors if the indoor area does not exclude mosquitoes), especially during the evening/ night (CIII).
3. JEVacc use is not recommended for JE endemic/ epidemic areas during the risk season:
   1. for travellers whose entire itinerary will be in urban areas (unless the urban areas are known to be endemic or epidemic for JE)(CIII);
   2. for travellers whose visits to rural areas (or urban areas known to be endemic or epidemic for JE) will be during the daytime only (CIII).
4. If there is insufficient time before entering a JE risk situation to allow for the usual dosing schedule (0, 7 and 30 days), then the use of the accelerated schedule (0, 7 and 14 days) or even the two-dose schedule (0 and 7 days) is reasonable (CIII).
5. While carefully collected data are lacking, it appears that the overall risk of DHR is quite low, and only a minority of DHRs occur beyond 3 days after vaccination. If the traveller’s situation does not allow for the usually recommended delay in travel of 10 days after the most recent dose and there is
   • no history of allergic diathesis
   • an anticipated risk period for JE exposure after vaccine-induced immunity develops and
   • no history of hypersensitivity reaction to a previous dose of JEVacc then use of JEVacc could be considered, regardless of whether the vaccinee can be close to medical care; in this case, the vaccinee needs to be aware of the possibility of a DHR and to seek medical assessment at the earliest opportunity should symptoms arise (CIII).

² Bracketed material refers to the strength and quality of the evidence for the recommendation.

References

1. Solomon T, Dung NM, Kneen Ret al. Neurological aspects of tropical disease: Japanese encephalitis. J Neurol Neurosurg Psychiatry 2000;68:405-15.
2. World Health Organization. WHO Position Paper: Japanese encephalitis vaccines. Wkly Epidemiol Record 2006;81:331-40.
3. Centers for Disease Control and Prevention. Inactivated Japanese encephalitis virus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993;42(RR-01).
4. Vaughn DW, Hoke CH. The epidemiology of Japanese encephalitis: Prospects for prevention. Epidemiol Rev> 1992;14:197-221.
5. Hoke CH, Nisalak A, Sangawhipa N et al. Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med 1988;319:608-14.
6. Halstead SB, Tsai TF. Japanese encephalitis vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines, 4th ed. Saunders, 2004:919-58.
7. Mandell GL, Bennett JE, Dolin R, eds. Mandell’s principles and practice of infectious diseases, 6th ed. Elsevier, 2005.
8. Centers for Disease Control and Prevention. Chapter 4. Prevention of specifi c infectious diseases. In: Traveler’s health: yellow book. URL: <http://www2.ncid.cdc.gov/ travel/yb/utils/ybGet.asp?section=dis&obj=jenceph. htm&cssNav=browseoyb>. Accessed 27 July, 2007.
9. Centers for Disease Control and Prevention. Japanese encephalitis in a US traveler returning from Thailand, 2004. MMWR 2005;54(5):123-25.
10. Wittesjo B, Eitrem R, Niklasson B et al. Japanese encephalitis after a 10-day holiday in Bali. Lancet 1995;345:856.
11. Pro-MED mail. Japanese encephalitis – Belgium Ex China: Request for information. Pro-MED mail 2005; 20050413.1070. URL: <http://www.promedmail.org>. Accessed 8 March, 2007.
12. Buhl MR, Black FT, Anderson PL et al. Fatal Japanese encephalitis in a Danish tourist visiting Bali for 12 days. Scand J Infect Dis 1996;28:189.
13. Östlund MR, Kan B, Karlsson M et al. Japanese encephalitis in a Swedish tourist after travelling to Java and Bali. Scand J Infect Dis 2004;36:512-13.
14. Pro-MED mail. Japanese encephalitis – Italy Ex Viet Nam. Pro-MED mail 2006; 19 October: #20061019.2995. URL: <http://www.promedmail.org>. Accessed 8 March, 2007.
15. Artsob H, Spence L. Imported arbovirus infections in Canada, 1974-89. Can J Infect Dis 1991;2:95-100.
16. Frances SP, Eamsila C, Pilakasiri C et al. Effectiveness of repellent formulations containing DEET against mosquitoes in northeastern Thailand. J Am Mosq Control Assoc 1996;12:331-33.
17. Thavara U, Tawatsin A, Chompoosri J et al. Laboratory and fi eld evaluations of the insect repellent 3535 (ethyl butylacetylaminopriopionate) and DEET against mosquito vectors in Thailand. J Am Mosq Control Assoc 2001;17:190-95.
18. Jinjiang X, Meiluan Z, Xinfu L et al. Evaluation of permethrin-impregnated mosquito-nets against mosquitoes in China. Med Vet Entomol 1988;2:247-51.
19. Dapeng L, Konghua Z, Jinduo S et al. The protective effect of bed nets impregnated with pyrethroid insecticides and vaccination against Japanese encephalitis. Trans R Soc Trop Med Hyg 1994;88:632-34.
20. Harbach RE, Tang DB, Wirtz RA et al. Relative repellency of two formulations of N,N-diethyl-3-methylbenzamide (DEET) and permethrin-treated clothing against Culex sitiens and Aedes vigilax in Thailand. J Am Mosq Control Assoc 1990;6:641-44.
21. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on personal protective measures to prevent arthropod bites. CCDR 2005;31(ACS-4).
22. Public Health Agency of Canada. Canadian immunization guide, 7th ed., 2006.
23. Sanofi Pasteur Limited. JE-VAX : Japanese encephalitis vaccine inactivated (product monograph), 2006.
24. Poland JD, Cropp B, Craven RB et al. Evaluation of the potency and safety of inactivated Japanese encephalitis vaccine in US inhabitants. J Infect Dis 1990;161:878-82.
25. Robinson HC, Russell ML, Csokonay WM. Japanese encephalitis vaccine B and adverse effects among travellers. CDWR 1991;17(32):173-77.
26. Berg SW, Mitchell BS, Hanson RK et al. Systemic reactions in US Marine Corps personnel who received Japanese encephalitis vaccine. Clin Infect Dis 1997;24:265-66.
27. Plesner A-M, Ronne T, Wachmann H. Case-control study of allergic reactions to Japanese encephalitis vaccine. Vaccine 2000;18:1830-36.
28. Takahashi H, Pool V, Tsai TF et al. Adverse events after Japanese encephalitis vaccination: Review of postmarketing surveillance data from Japan and the United States. Vaccine 2000;18:2963-69.
29. Plesner A-M, Ronne T. Allergic mucocutaneous reactions to Japanese encephalitis vaccine. Vaccine 1997;15:1239-43.
30. Robinson P, Ruff T, Kass R. Australian case-control study of adverse reactions to Japanese encephalitis vaccine. J Travel Med 1995;2:159-64.
31. Nazareth B, Lenin J, Johnson H et al. Systemic allergic reactions to Japanese encephalitis vaccine. Vaccine 1994;12(7):666.
32. World Health Organization. Global Advisory Committee on Vaccine Safety, 9-10 June 2005. Wkly Epidemiol Record 2005;80:242-43.

*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.