Risk assessment for Japanese encephalitis vaccination

ABSTRACT

Japanese encephalitis (JE) is the most commonly diagnosed viral encephalitis in Asia. JE is caused by a virus called JE virus (JEV), a member of the genus Flavivirus, family Flaviviridae, and is transmitted by Culex mosquitoes. Neutralising antibody to JEV protects against JE, and can be induced by vaccination. JE is a potential threat to travellers to endemic areas, which are most of South and Southeast Asia and some Pacific Islands. The risk of JE can be expected to increase with increasing mosquito exposure and time spent in regions and seasons of active transmission. JE is very rare in travellers, but mortality is high, around 1 in 3, and there is a high rate of lasting neurological damage. JE can therefore be a profoundly life changing event for a traveller. Travellers and their healthcare providers need to balance the low risk of disease against the very high severity of disease if it does occur. In order to make an informed decision, the severity of JE disease should be carefully explained to travellers to Asia.

Introduction

Japanese encephalitis (JE) is a form of acute viral encephalitis caused by a member of the genus Flavivirus, family Flaviviridae, called JE virus (JEV).¹ JE is a relatively rare, but severe, disease. JE usually affects children in Asia, but travellers are ptentially at risk if they visit a JE endemic area (Fig. 1). Several other flaviviruses are related to JEV, such as West Nile virus, dengue virus (DENV), Zika virus (ZIKV) and yellow fever virus (YFV). Vaccines are in development for DENV and ZIKV, and a very effective vaccine has been available for YFV for many decades.

Figure 1.

JE endemic areas. The geographical area endemic for JE is shown. Within this area, the potential for transmission can vary widely, for example with distance from the equator, altitude, and season. As a general rule, further south, the more the tendency for low level, year-round, transmission (and hence risk to travellers). Further North, the risk becomes more seasonal. JE outbreaks, however, are recognised to occur at all latitudes. Image courtesy of CDC.

JE usually starts as an undifferentiated febrile illness, and this may be the only manifestation in some people.² Rigors, coryza or diarrhoea may occur, followed by the onset of clouding of consciousness, and maybe seizures or vomiting, after a few days.³ JE should be suspected in any person with these features with potential exposure to JEV in an endemic area (Fig. 1). A wide range of neurological abnormalities are described.⁴ There may be neutrophilia, hyponatraemia, raised liver enzymes and cerebrospinal fluid (CSF) pleocytosis.⁵ JE is most commonly diagnosed by testing for JEV IgM in the CSF, which is reliably positive if the CSF specimen is at least one week into illness.⁶ The case fatality rate for JE is high; approximately one third of patients in endemic areas admitted to hospital with JE die.³ A further 30% of survivors suffer permanent brain damage, so although JE is rare it has significant potential to be a severe life changing illness.

JE epidemiology

JEV is an arthopod-borne virus (arbovirus), and is transmitted by mosquitoes of the genus Culex, most commonly Culex tritaeniorhynchus.⁷ JEV naturally infects wading birds, and exists in an enzootic cycle between birds and mosquitoes;⁸ disease in humans occurs as a result of spill over from this cycle. JE is a disease of children, adult populations are typically immune as a result of exposure in childhood. Early epidemiological studies demonstrated an important role for pigs as amplifying hosts for JEV.⁹ Pigs get infected with JEV and become viraemic; this results in a reservoir of virus in closer proximity to humans than the natural bird hosts of JEV (Fig. 2). In endemic areas, JE is predominantly a rural disease of children,¹⁰ though peri-urban and urban transmission are also described.^11,12 Infection of man is a “dead-end” event for JEV, because in humans viraemia is too low and transient to be infectious to the mosquito vector. After natural JEV exposure only a small proportion of infections, estimated at approximately 0.1 to 1%, result in encephalitis — the vast majority are asymptomatic or result in a mild febrile illness only.¹³

Figure 2.

The enzootic cycle of JEV. The natural hosts of JEV in nature are wading birds (ardeids). JEV circulates in bird populations, transmitted by mosquitoes of the genus Culex. Mosquitoes infected with JEV after feeding on birds can bite, and infect, other birds, or other species such as pigs and humans. In some parts of Asia horses can also become infected. Pigs act as amplifying hosts because they exhibit sufficient viraemia to be onwardly infectious to the mosquito vectors and they live in close proximity to humans, resulting in a reservoir of JEV and increasing the risk of transmission to humans. Several studies have shown a wave of JEV infections in pigs before the emergence of human cases. Adapted with permission from: Tsai T, Yu Y. Japanese encephalitis vaccines. In: Plotkin S, Orenstein W, eds. Vaccines. 3rd Ed. Philadelphia, PA: WB Saunders, 1999: 672–710.

The risk to travellers

Multiple factors need to be weighed to assess the risk of JE to a traveler, typically an adult who is JE non-immune. Care providers giving pre-travel advice should ask about the location and duration of planned travel, and also about activities and behaviours that place travellers at increased risk of JEV acquisition.

The risk of exposure to JEV is very difficult to estimate. The geographic range of JEV reaches from Pakistan in the West, to Papua New Guinea in the Southeast, and Northern China, Korea and Japan in the Northeast (Fig. 1). China and India (with their very large populations) account for most current cases of JE. Most of China is JE endemic except Xinjiang province and Tibet in the West, in India the four southern states of peninsular India and the Northeast see the most cases. JE also occurs on the pacific islands of Guam and Saipan, and in the late 90s reached the Torres Strait and the Cape York Peninsula of Northern Australia,^14,15 although JEV did not become established in Australia. Within this geographic area, however, there is wide variety in the intensity of JEV transmission and also significant variation according to season.

The risk of JE varies with season and with distance from the equator, likely due to a multitude of factors that affect vector abundance and bird migration patterns. Historically, JE transmission patterns were divided into three areas of latitude: sub-tropical and temperate latitudes between 23°N and 43°N where transmission peaks with epidemics occurring in the late summer, latitudes between 13°N and 23°N where peaks of transmission occur with or after the rainy season; and latitudes between 1°N and 13°N where lower level year round transmission occurs.¹⁶ However, outbreaks can still occur in more southerly tropical regions, and JE may be under-reported.¹⁷ JE outbreaks also vary with the rainy season, for example in South Asia the Southwest monsoon usually occurs between May to July, whereas the Northeast monsoon is later, in September to November. As a general rule, travel in the latter half of the year, between June and November, will likely incur greater risk than travel outside this time.

Individual risk assessment

Essentially any travel to JE endemic areas can result in the potential for JEV acquisition. Further North (especially above 23°N), the risk of JEV acquisition outside the late summer transmission season is very low. The care provider should assess the type of accommodation the traveler will be using, and the potential for evening outdoor activities that will increase exposure to the mosquito vector. In general, low budget travel, travel to rural areas, longer duration of travel, and travel during the transmission season will increase the risk (Table 1). A pragmatic approach would be to discuss JE vaccination for any travel that is not either exclusively urban or coastal resort based in South/Southeast Asia, with the addition of travel during June – October in temperate Asia. For example, Northern Thailand has historically seen more JE than the South,¹⁸ which is more popular with tourists especially those on shorter trips. However, in a hospital surveillance study in 2003–2005 a higher proportion of acute encephalitis cases were positive for JEV in Southern Thailand than in Bangkok.¹⁹ Therefore, even what are considered to be lower risk itineraries will still carry some risk for acquisition of JE. Current recommendations emphasise travel for longer than one month, but in a series of JE cases occurring between 1973 and 2008, 16 of 37 cases (43%) with available data acquired JE within one month of travel. There are likely to be many more short-term than long term travellers to Asia, meaning the risk of disease in trips <1 month is still low; nevertheless, it is not unreasonable to discuss JE vaccination in short term travellers if other risk factors for transmission are present.

Table 1.

Risk factors for the acquisition of JEV. Factors which increase the risk of JEV acquisition are shown, with an explanation of their effects. Many of these are theoretical, but nevertheless represent factors which are reasonable to take into account when considering vaccination.

Risk factor	Impact
Factors associated with increased risk of acquisition
Duration	Longer travel associated with greater likelihood of JEV acquisition. Previous and existing, recommendations have used one month as a cut off though the risk below one month, may still be suficient to justify vaccination.
Latitude/altitude	Generally increasing risk further south; JEV transmission much more seasonal with increasing lattitude (further North). Higher altitude and cooler temperatures lead to lower mosquito populations and lower risk.
Rural versus urban	JEV is associated with a rural ecosystem where pigs (amplifying hosts) and mosquito, vectors are more abundant. The risk in urban areas is less but nevertheless is still present.
Budget accommodation	Lower quality accommodation is less likely to be sealed against mosquitoes increasing, mosquito exposure and the risk of JEV acquisition. Use of a mosquito net and repellant would be expected to lower the risk.
Level of evening outdoor activity	Increased time spent outdoors during the periods of peak mosquito activity (dawn & dusk) will increase mosquito exposure & hence the risk of JEV acquisition.
Factors associated with increased development of disease after JEV infection
Immunocompromise	Immunocomprmise may include extremes of age (<10 and >50 though these are not well defined), organ transplant use of immunosupressant drugs or other medical conditions such as chronic kidney disease or diabetes mellitus.
Breach of the blood-brain barrier	A defect in the blood-brain barrier may result in making the brain more susceptible to infection with JEV. History of CSF leak placement of a device that potentially crosses the blood-brain barrier previous neurosurgery or another condition such as intracranial haemorrhage could indicate a potential defect.

Additional risk factors that may increase the risk of disease after JEV infection should also be considered. Although the risk of disease arising from JEV infection is estimated to be low, approximately 1–3 per 1000 infections, there are some groups where the risk may be higher. These include extremes of age, immunocompromise, diabetes mellitus, and conditions where the blood brain barrier may be compromised, such as a history of CSF leak, or insertion of a device that may act as breach in the blood brain barrier, such as a ventriculo-peritoneal shunt (Table 1).

The above recommendation will lead to many travellers potentially being offered JE vaccine. This approach has been advocated by some authors,²⁰ citing a potential annual attack rate of 1 in 10,000, derived from studies in closed populations of US service personnel.²¹ However, other authors have criticised this,²² based on more recent studies of non-resident travellers, where the attack rate is estimated to 1.3 per year in 7 million visits to Asia.²³ The most comprehensive recent estimate of the annual incidence of JE suggests an overall annual incidence of approximately 1.8 cases per 100,000 population.²⁴ However, the incidence in children aged 0–14, which may more accurately reflect the incidence in a non-immune population newly exposed to JEV, was estimated to be 5.4 per 100.000. Many cases of JE go undiagnosed or unreported, so these figures are likely to be under-estimates.

Clearly, the individual risk to any given traveler will be low, and difficult to estimate accurately. What is most important in the discussion around vaccination in order to make an informed choice, is an emphasis on the severity of JE. The mortality of JE in travellers is approximately 20%²⁵ and many survivors of JE are left with significant sequelae.^1,26 From our anecdotal experience, those clinicians who have seen cases of JE are keenly aware of the severity of JE and the possibility of life changing events, such as living with permanent, severe disability.

Available JE vaccines

Although many different JE vaccines have been available historically, or are being developed (Table 2),²⁷ the majority of travellers from non-endemic countries will have access either to IXIARO® (inactivated, adjuvanted, SA14–14-2) or IMOJEV® (formerly Chimerivax™-JE; SA14–14–2 envelope protein in a yellow fever vaccine background). IXIARO is available in Europe and North America, IMOJEV is mostly used in Australasia. Both vaccines produce antibody responses in most people and are very safe,^28,29 for example the side effects of IXIARO are no greater than those of adjuvant alone.³⁰ IMOJEV has the advantage that, being a live vaccine, only a single dose is required; whereas IXIARO requires two doses to ensure protection before travel. IXIARO is usually given with a dose interval of one month, however this can be shortened to one week if needed.³¹ The long-term duration of protection of JE vaccines is not yet clear, but immunity is likely to wane faster in the absence of boosting by natural exposure to JEV such as might result from long term residence in an endemic area. In the majority of cases only one vaccine will be available — outside rare instances of intolerance or allergy the decision as to which vaccine to use is relatively unimportant compared with the decision whether to vaccinate or not. Up to date information on administration and dosing intervals can be found in immunisation against infectious disease, chapter 20 (https://www.gov.uk/government/publications/japanese-encephalitis-the-green-book-chapter-20).

Table 2.

Vaccines for Japanese encephalitis. Several different vaccines have been used to prevent JE. Older as well as currently available vaccines are shown. Before 2005, predominantly mouse brain derived vaccines were used, the source of virus for each vaccine is indicated. Vero cells are an African green monkey derived kidney cell line that have a defective interferon response, they are widely used for propagation of viruses of many types. Although several different JE vaccines are available, for travellers from non-endemic countries, it is likely that only IXIARO or IMOJEV will be available. In Asia the live attenuated vaccine SA14–14–2 (RS.JEV™, CD.JEVAX™) is widely used, recently a new inactivated vaccine (JENVAC) has been developed in India.³²

Description	Type	Common name	Manufacturer/developer
Older vaccines, no longer in use:
Mouse brain	Inactivated	BIKEN	Japan, BIKEN
Mouse brain	Inactivated	Green Cross	Korea, Green Cross
Mouse brain	Inactivated		Japan
Primary hamster kidney	Inactivated		China
Vaccines currently available:
Vero cell	Inactivated		China
Primary hamster kidney (SA14–14–2)	Live attenuated	RS.JEV™, CD.JEVAX™	Chengdu Biological Products, China
Vero cell	Inactivated	JEBIK®V	Japan, BIKEN
Vero cell	Inactivated	ENCEVAC®	Japan, Kaketsuken
Vero cell	Inactivated	IC51, IXIARO®*	Intercell, Valneva
Vero cell	Inactivated	JENVAC	Bharat Biotech Int. ltd, India
Yellow fever 17D recombinant vectored	Live attenuated	IMOJEV, Chimerivax JE*	Acambis, Sanofi Pasteur

Conclusion

The assessment for JE vaccination presents something of a conundrum for primary care providers. They must balance the very small risk of disease, the potentially devastating consequences of disease, the potential side effects of the vaccine, and the cost of vaccination. The final choice for vaccination rests with the traveler, but they should be aware of all the arguments for and against vaccination, including the rare but devastating effects of JE.

Funding Statement

Lance Turtle is supported by Wellcome Trust clinical research career development fellowship, grant no. 205228/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England.

Abbreviations

CSF

cerebrospinal fluid

DENV

dengue virus

JE

Japanese encephalitis

JEV

Japanese encephalitis virus

YFV

yellow fever virus

ZIKV

Zika virus.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.