Statement on prevention of 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.
Key Points/Messages
- Japanese encephalitis (JE) is a potentially fatal disease caused by a mosquito-transmitted virus. It is endemic through much of Asia and also occurs in parts of Oceania.
- Since 1973 there have been 66 cases of JE reported among Western travellers and expatriates including 2 cases among Canadian travellers. The overall risk of JE among travellers is estimated to be negligible, i.e. < 1 case/10,000,000 trips. Even allowing for 10-fold underreporting of JE cases, overall risk is estimated to be negligible, i.e. approximately 1 case/1,000,000 trips.
- The only JE vaccine (JEV) currently available in Canada is IXIARO, an inactivated Vero cell culture-derived vaccine licenced for individuals aged 2 months of age and older.
- Following a systematic review of the literature, recommendations for use of JEV were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Assessment focused on benefits and harms of JEV, use of an accelerated vaccination schedule, and use of JEV in children.
- No evidence on the values and preferences of travellers or health care providers related to use of JEV were found. However, there is evidence to indicate that some patients (including travellers) will choose and pay for vaccine-based protection against rare (e.g. a risk of 1/100,000), but serious diseases. Based partly on this evidence, CATMAT used a per trip risk for a case of JE of 1/100,000 as the threshold at which the majority of travellers would accept the harms, cost and inconvenience of JEV vaccination.
- Because the overall per trip JE risk estimate (< 1 case/10,000,000 or approximately 1 case/1,000,000 with 10-fold underreporting) is substantially less than this threshold, we suggest that JEV not be routinely used for travel to endemic areas.
- In some circumstances, based on factors that are thought to increase risk (e.g., rural exposure, repeated travel to risk areas, longer cumulative duration of travel (e.g., > 30 days), travel in areas suffering an outbreak), JEV will be of relatively greater absolute benefit and more travellers will likely choose to receive it.
GRADE Recommendations

# When to use JEV
- CATMAT suggests that JEV (IXIARO) not be routinely used for travel to endemic areas  
 (Conditional recommendation against ; moderate confidence in estimate of effect)
	+ For the large majority of travellers, the likelihood of developing clinical JE in endemic areas (see Table 1) is negligible (overall per trip attack rate estimated at approximately 1/10,000,000) as is the estimated absolute benefit of JEV (moderate confidence, intermediate risk of bias due to possibility of unreported clinical cases). Balanced against cost, inconvenience and the potential risk of adverse effects, most travellers would choose not to receive JEV in this situation.
	+ The relative likelihood of acquiring JE is likely elevated for some populations (e.g., long-term travel, exposure in rural areas, multiple trips to endemic areas and/or travel to an area suffering an outbreak) and more travellers would choose to receive vaccine in such circumstances (Risk factor evidence was not evaluated using GRADE, ).
	+ Because this recommendation is conditional, there is a need for providers to discuss with the traveller the anticipated benefits and harms (including financial costs) associated with JEV to help the traveller reach a decision that is consistent with their own values and preferences. The discussion should include potential alternative and/or complementary strategies (e.g., use of personal protective methods against mosquito bites) to vaccination.
	+ See Text Box 3 for a list factors that influence decision-making related to JE vaccine.
	+ For more information on how CATMAT arrived at this recommendation, see "".

# Vaccine administration
The licensed primary adult schedule for JEV in Canada is 2 doses spaced 28 days apart.
- CATMAT suggests use of an accelerated (0 and 7 days) schedule for adults aged 18-65 if there is insufficient time to immunize travellers with the normal primary schedule (0 and 28 days)  
(Conditional recommendation for; moderate confidence in estimate of effect)
	+ This accelerated schedule has been approved for use in Canada and Europe.
	+ The accelerated schedule elicited similar levels of seroconversion and adverse effects as the normal schedule.
- CATMAT suggests that JEV (normal schedule) can be used in children aged 2 months to <18 years  
(Conditional recommendation for; moderate confidence in estimate of effect)
	+ This normal schedule has been approved for use in children (2 months to <18 years) in Canada and is also approved in the United States.
	+ Seroconversion rates and rates of adverse effects were found to be similar in adults and children.
	+ Children aged 2 months to <3 years of age are recommended to receive a reduced dose of vaccine (0.25 ml) compared to older children and adults (0.5 ml).
	+ While a normal schedule is preferred, an accelerated schedule can be considered (off-label) for children where there is not sufficient time to complete the normal schedule.
Basis of GRADE Recommendation for Vaccine Use

# Quality of the Evidence
Vaccine efficacy:
moderate confidence in estimate of effect
Vaccine harms:
moderate to high confidence in estimate of effect
Baseline risk of developing JE among travellers:
moderate confidence in estimate of risk
Risk factors for JE:
insufficient evidence to assess with GRADE
Values and Preference:
insufficient evidence to assess with GRADE

# Summary of Balance of Benefits and Harms
JEV (IXIARO) is expected to provide a high level of protection (>95%) against JE (Figure 1). Further, it is a well-tolerated vaccine. In the pivotal safety trial, JEV had a similar AE profile to placebo, though minor AE, e.g., pain at injection site, are common (Appendix 1; moderate to high confidence in the estimates of effect). The exception was itching, which occurred less often (RR 0.52; 95% Confidence Interval  0.29 to 0.92) with JEV than compared to placebo.
However, as with other vaccines, rare but serious AE are possible. This last point becomes increasingly important with decreasing JE risk in that it increases the possibility that rare but serious AE will be more prevalent than JE cases averted through immunization.
There were 42 AE following JEV immunization reported to the US Vaccine Adverse Event Reporting System (VAERS) for the period of 2009-2012. The majority of these (25/42) were reported after a patient had received several immunizations including JEV. Using an estimated 275,848 doses of vaccine distributed, the overall AE rate was 15.2/100,000 doses; and the serious AE rate was 1.8/100,000 doses. The most commonly reported serious AE were hypersensitivity reactions (0.7/100,000 doses). No cases of anaphylaxis or death were reported. Recently VAERS published an update on AE events reported during the period 2012-2016. There were 119 AE reported following JEV immunization. Using the estimated 802,229 doses of vaccine distributed, the overall AE rate during this time period was 14.8/100,000 doses. There were 9 serious AE reported for a rate of 1.1/100,000 doses. Serious AE included 1 report of anaphylaxis and 1 death (cardiac death due to ischemic heart disease). Importantly, reports to VAERS do not necessarily imply causal relationships.
For most travellers to endemic areas, the likelihood of acquiring JE is negligible (estimated at approximately 1 clinical case/10 million trips) (Table 1) and the number needed to vaccinate (NNV) to prevent a case is correspondingly high, e.g., > 10,000,000 (see Tables 2 and 3). The median trip duration for travel to endemic areas was estimated to be approximately 2 weeks (see Figure 2).
At the estimated overall JE attack rate among Canadians traveling to endemic areas of 1 clinical case/11,650,000 (95% CI ) person trips (median trip duration estimated to be 15 days), the number needed to vaccinate (NNV) to prevent 1 clinical case of JE, 1 severe sequelae from JE or 1 JE related death is approximately 12 million, 33 million and 49 million, respectively (see Tables 2 and 3). At this same risk of disease, approximately 5 million mild AEs would be expected to occur.
We did not identify JEV-specific evidence on traveller values and preferences. However, there is evidence to indicate that some patients (including travellers) will choose and pay for vaccine-based protection against rare (e.g. a risk of 1/100,000), but serious diseases.
The risk threshold should take into account patient values and preferences, risk of JE, the effectiveness and safety profile for JEV, and cost and inconvenience associated with the vaccine. In the absence of JEV-specific evidence on patient values and preferences, the committee judged that most travellers would be willing to accept the harms, cost (currently several hundred dollars) and inconvenience of vaccination if JEV risk was 1/100,000 or higher, but not at lower risks. This threshold for vaccine use is several orders of magnitude higher than the overall risk estimate for JE. Thus, we recommend against routine use of JEV for travel to endemic areas.
Certain populations, e.g., long term travellers (e.g., >30 days), travellers who make multiple trips to endemic areas, persons staying for extended periods in rural areas, persons visiting an area suffering a JE outbreak area, are likely at relatively higher risk for JE (). Due to the severity of potential consequences of JE, and the absence of specific treatments, it is plausible that individuals who are so affected would be more likely to choose to receive JEV.

# Why is the recommendation a conditional recommendation?
The recommendation for use of JEV is conditional. This reflects, among other things, the poorly defined impact of risk factors such as destination, seasonality, travel itinerary and duration of stay on JE risk, and our belief that travellers could have divergent values and preferences (including willingness to pay) related to use of JEV. For a more detailed discussion of what a conditional recommendation means in the context of JE, see Text Box 2.
Interpretation of GRADE Recommendations
 Text Box 1: GRADE-based recommendation categories used by CATMAT (adapted from reference)
The GRADE working group specifies that if a recommendation is "strong", then it is expected that 90% or more of informed individuals would choose (or not choose) the recommended course of action.
The GRADE working group specified that if a recommendation is "conditional", then it is expected that less than 90% of informed individuals would choose (or not choose) the recommended course of action. The term "conditional" is used by CATMAT, and is considered as equivalent to "weak" as is articulated in much of the GRADE literature. For conditional recommendations the wording "suggests" rather than "recommends" will be used.

# Text Box 2: What does a conditional recommendation mean in the context of JEV?
GRADE-based recommendations for JEV are "conditional". This means that the majority of well-informed travellers to endemic areas would choose the recommended course of action and not use JEV. However, it also means that some travellers would choose to receive JEV. Reasons for making recommendations conditional include the very low overall risk of travel-associated JE, the poorly defined impact of risk factors such as destination, seasonality, travel itinerary and duration of stay, and our belief that travellers could have divergent values and preferences related to use of JEV.
Applied to individual travellers, our recommendations could result in the following types of joint (traveller and clinician) decisions:
- Persons staying in urban areas of endemic countries for relatively short periods (e.g., < 1 month) are estimated to have an extremely low risk for developing JE. In this situation and given the cost and inconvenience of vaccination, very few travellers would choose to receive JEV.
- Persons staying for longer periods in urban areas of endemic countries and/or who have short-term (e.g.,  1 week) exposure in rural areas are estimated to have a relatively higher, but still extremely low risk of developing JE. Very few travellers would choose to receive JEV in this situation.
- Persons staying for longer periods (e.g., > 30 days) in endemic areas with exposure in rural areas during the risk season are likely to have a relatively higher, but still very low risk of developing JE. However, there might be some individuals in this population for whom relative risk is substantially elevated, e.g., because they are staying in a highly endemic area for an extended period. In this situation, many more travellers would choose to receive JEV, but also that many, for example based on values and preferences, would choose not to receive the vaccine.

# Text Box 3: Points to consider when discussing JE vaccine (adapted from reference)

## Reasons that might increase likelihood that traveller would choose to be vaccinated
- analytic uncertainty, i.e. overall risk might be underestimated due to non-reporting of cases
- seriousness of disease, high case fatality rate and many survivors with serious sequelae
- relatively lower risk tolerance for "exotic" diseases
- travelling to known epidemic area
- longer duration stays, e.g., > 30 days in endemic areas with rural exposure
- extensive overnight exposure in rural environments
- repeated travel to risk areas (cumulative time)
- established safety profile for vaccine
- high level of vaccine efficacy

## Reasons that decrease likelihood that traveller would choose to be vaccinated
- very low overall risk for large majority of travellers
- relatively higher risk tolerance for "exotic" diseases
- relatively high cost of vaccine
- urban/short-term travel
- concern about adverse effects related to vaccination in general
- inconvenience of vaccination, including multiple doses
- availability of alternative interventions, e.g. bite prevention methods
Non-GRADE Recommendations
- For Canadians (adults and children) who remain at risk and desire vaccine-induced protection, CATMAT suggests that a single booster dose of JEV be administered 12-24 months after the primary series and that a second booster is not required for at least 10 years.
	+ After a primary series, 80-95% of fully immunized vaccine recipients maintained an adequate immune response after 6 months and 58-83% maintained it at 12-15 months.
	+ After receipt of a booster dose, there is evidence that an adequate immune response persists for an extended period among adults. CATMAT therefore suggests that additional booster doses are not necessary for at least 10 years after the initial booster in the situation where protection against JE is desired.
	+ Among children, evidence of long term seroprotection is limited but does suggest that antibody responses are at least as persistent in children as in adults. For this reason CATMAT suggests that it is reasonable to follow the same recommended second booster approach for children (off-label) as for adults.
- In adults 65 years or older CATMAT suggests that a single booster dose of JEV be considered earlier (before 12 months) following the primary series.
	+ JEV is generally well tolerated in older patients although seroconversion rates are lower than in younger adults.
	+ Assessment of the precise timing of vaccine administration should be done on a case-by-case basis if the traveller remains at risk for JE and wishes to receive protection.
- CATMAT recommends that, if an adult traveller wishes to receive JEV and if there is insufficient time to provide a normal or accelerated schedule, then an additional dose of vaccine can be provided with the first dose (on day 0).
	+ This is based on evidence showing that this approach achieves a seroconversion rate of approximately 60% by 10 days post-vaccination, compared to approximately 30% following a single dose. If this double dose approach is used, subsequent doses (if protection is still required) should be as per the normal schedule.
- CATMAT recommends that all travellers use personal protective measures (PPM) such as topical repellents, treated bed nets and/or treated clothing to prevent mosquitoes from biting.
	+ Recommendations related to PPM are provided in the CATMAT statement on .
Introduction
Japanese encephalitis (JE) is caused by a flavivirus transmitted by *Culex- mosquitoes. It is one of the most important causes of viral encephalitis in Asia, with an estimated 70,000 cases and up to 20,000 deaths annually . Appendix 2 shows areas where JE is endemic, and Appendix 3 provides country-specific information related to risk areas and seasonality. There is no specific treatment for JE but a JE vaccine (IXIARO) is licenced for adults in Canada. Immunization and/or use of personal protective measures (PPMs) against mosquito bites will provide substantial protection against disease   .
Background

# Clinical and Epidemiological features
The likelihood of developing clinical disease after infection with JE virus is low (approximately 1/250). If clinical disease develops (after an incubation period of 5 to 15 days), the prognosis is poor. Approximately 20-30% of patients die and, among survivors, about 50% will develop long term neurological and/or psychological sequelae . In endemic areas without a vaccination program, disease often occurs in children; whereas older adults, perhaps because of immune senescence, seem to be at greatest risk for disease in countries/areas with robust and long-standing immunization programs.
JE virus is maintained in a zoonotic cycle involving *Culex- mosquitoes and wild birds with pigs sometimes acting as amplification hosts. Risk is primarily in rural areas, and transmission can be year round with rainy season peaks (subtropical/tropical areas), or constrained to warmer periods of the year when the mosquito vectors are active (temperate areas) . Appendix 3 summarizes transmission patterns in JE-endemic countries.
JE vaccine programs, changes in animal husbandry practices and/or increased urbanization has led to a substantial reduction in human cases of JE in some countries like Japan and Korea . However, JE still presents a risk to non-immune persons (e.g., travellers) in these countries because zoonotic transmission persists.

# Vaccine
The only JE vaccine currently available in Canada is IXIARO, an inactivated Vero cell culture-derived vaccine marketed in Canada by Valneva Canada and licenced for individuals aged 2 months of age and older. It is important that the product monograph for IXIARO be read by those who prescribe and/or inoculate this vaccine. Information regarding important features of IXIAROis also summarized in the Canadian Immunization Guide.
Methods

# General
This statement was developed by a CATMAT working group (WG) of volunteers, none of whom declared a relevant conflict of interest. The WG, with support from the secretariat, was responsible for: literature retrieval, evidence synthesis and analysis; development of key questions and draft recommendations and writing of the statement. The final statement and recommendations were approved by CATMAT.
The GRADE process was used to formulate some of the recommendations in this statement. Other recommendations in this statement did not use GRADE, for example those related to boostering or use of personal protective measures to prevent mosquito bites. This did not reflect an absence of evidence on these topics, but rather a decision on the part of the WG and broader committee to focus resources on clinical questions that were judged most likely to benefit by a GRADE-based evidence appraisal. For non-GRADE recommendations, advice was based on a narrative review of the relevant literature evidence and expert opinion. For more information on the CATMAT approach to developing recommendations and guidelines, see the statement on .
The following summarizes the process used to develop this statement and recommendations:

# GRADE Recommendations
1. An analytic framework identifying clinical preventive actions (interventions) and risk factors for JE was developed (Appendix 4).
2. From the analytic framework, the working group framed key concepts in the form of a PICO question (Population of interest, Intervention, Comparison, and Outcome) in order to develop focused GRADE-based recommendations. Evidence on efficacy and harms of JEV was considered for each PICO question.
The following PICO questions were identified:
	1. Among adult Canadian travellers, does use of JEV (normal schedule) decrease the risk of acquiring JE compared to no vaccine (placebo)?
	2. Among adult Canadian travellers, does use of an accelerated (0, 7 days) JEV schedule achieve levels of protection similar to or greater than a normal JEV schedule (0, 28 days)?
	3. Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers, and is use of JEV associated with similar harms to adults?
3. Other concepts from the analytical framework were identified to support the GRADE assessment but were framed as non-PICO questions. The following contextual questions were identified:
	1. What is the risk of clinical JE among Canadian travellers?
	2. What are the important risk factors for JE among Canadian travellers (e.g., destination, duration of travel)?
	3. What are the values and preferences of Canadian travellers regarding the magnitude of risk reduction in JE that would make use of JEV worthwhile given associated costs and inconvenience?
4. Evidence was retrieved by performing searches in electronic databases (Ovid MEDLINE, Embase, Global Health, and Scopus) and by manually searching in Google for grey literature. Time period for the search was from earliest available to June 2015. There were 2 literature searches: 1. JE vaccine (efficacy and harms) and travellers and 2. Baseline risk of and risk factors for developing JE among travellers. Details on search strategies and dates are provided in Appendix 5. The inclusion and exclusion criteria were applied by 2 WG members to the identified studies, based on an initial screening of titles and abstracts. Studies were excluded if they appeared to be irrelevant, were not published in English or French, or were duplicates.
5. From these searches, relevant literature was identified. If evidence specific to Canadian travellers was not available, then evidence derived from other Western populations or from other populations, in that order of preference, was extracted.
6. Quality assessments were performed for: vaccine efficacy and adverse events (AE); and, risk of developing JE among travellers. Results were collated into summary of findings tables (see Appendices 5-7 and 9). We decided that there was insufficient evidence to subject the other questions to the GRADE process.
7. Recommendations were developed taking into consideration:
	1. CATMAT's confidence in the estimates of effect for efficacy and JEV-associated AE;
	2. the balance of harms and benefits; and,
	3. CATMAT's judgement on the likely values and preferences of travellers and health care providers related to use of JEV.

# Non-GRADE Recommendations
1. Additional questions were identified that were not selected for GRADE review by the working group. They were:
	1. What is the appropriate boostering interval for JEV?
	2. Among older (aged > 65 years) Canadian travellers, does use of JEV achieve levels of protection similar to adult travellers?
	3. Does an additional dose of vaccine on day 0 achieve a higher seroconversion rate than a single dose?
	4. Do personal protective measures provide protection against bites from the type(s) of mosquitoes that transmit JE?
2. Evidence relevant to these questions was identified through the previously-described literature search, or was extracted from existing CATMAT statements. Recommendations are based on a narrative review of the evidence and expert opinion.
Results

# General
The literature search on JE vaccine and travellers identified 423 studies of which 310 were excluded. The risk factors for JE search identified 131 studies of which 127 were excluded. The remaining 117 relevant articles addressed vaccine harms and/or benefits (N= 36), booster dose (N=10), accelerated schedule (N= 4), pediatric use (N=6) and risk factors (N=4). As well, 57 studies addressing burden of disease (incidence, morbidity, mortality, hospitalizations) among travellers, population-specific risk factors (e.g., age), itinerary-specific risk factors (e.g., destination, duration of travel), efficacy of preventive measures (e.g., personal protective measures), and/or disease treatment/management were retained. After the literature review was completed, an additional study on values and preferences was identified and included. In addition, in 2018 an updated IXIAROproduct monograph was released with expanded recommendations for use in Canada, and was used as a reference.

# GRADE questions

## PICO questions
Among adult Canadian travellers, does use of JEV (normal schedule) decrease the risk of acquiring JE as compared to no vaccine (placebo)?
We did not identify evidence showing JEV reduces the incidence of JE (and associated harms) among travellers to endemic areas. Rather, efficacy is inferred from studies using serological correlates of protection. Efficacy of JEV (IXIARO) was initially established through a non-inferiority comparison to inactivated mouse brain-derived JE vaccine (MBV), trade name JEVAX, which is no longer licenced in Canada. Protection was defined using seroconversion rate (SCR) as an endpoint, i.e. a PRNT50 titre  95% of recipients) (moderate confidence in the estimates of effect, downgraded for indirectness given seroconversion is a surrogate of protection). The vaccines were associated with similar rates of systemic adverse effects; however, local reactions were more common with MBV (high confidence in estimate of effect).
Additional studies, without a comparator, have consistently shown that 2 doses of JEV (days 0, 28) achieve high SCR      . Results from these studies are summarized in Figure 1.
Data extracted from 9 studies        .
Among adult Canadian travellers, does use of an accelerated (0, 7 days) JEV schedule achieve levels of protection similar to or greater than a normal JEV schedule (0, 28 days)?
In adults, an accelerated JEV schedule (first dose on day 0 and second dose on day 7) yielded similar SCR to the normal schedule (1 dose on each of days 0 and 28) (moderate confidence in the estimate of effect) (Appendix 7). Compared at a similar time point (10-14 days) after the initial dose, the accelerated schedule was associated with a significantly higher SCR (RR 3.95; 95% CI 3.16 to 4.92) than the normal schedule (low confidence in the estimate of effect). Safety profiles (Appendix 7) for the accelerated and normal schedule were similar (moderate to high confidence in the estimates of effect). This accelerated schedule has recently been approved for use in Canada for adults aged 18-65 years.
Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers and is JEV use associated with similar harms to adults?
Through the literature review, GRADE assessments published in 2013 by the United States Advisory Committee on Immunization Practices (ACIP) were identified. This work specifically addressed the question "Should inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) be recommended for use in children 2 months through 16 years of age at increased risk of travel-related exposure to Japanese encephalitis virus". Adults were included in the analyses as a comparator. We judged that the ACIP GRADE could be used to address our PICO question: "Among Canadian children, does use of JEV achieve levels of protection similar to that observed in adult travellers?" We did not identify additional and relevant evidence published since this review in our literature search.
The ACIP concluded that SCR (moderate confidence in the estimate of effect) and rates of serious (low confidence in the estimate of effect) or systemic (moderate confidence in estimate of effect) adverse effects were similar in adults and children (see Appendix 8). A complete explanation of the assessment of quality of evidence is available elsewhere. Briefly, downgrading of the quality of evidence was done because of indirectness (e.g., because efficacy was not directly measured and/or the evidence was primarily developed with adults) and potential sources of bias (e.g., lack of blinding). Use of JEV in children aged 2 months to <18 years has recently been approved in Canada.
Evidence supporting the use of an accelerated schedule in children was not identified and use of an accelerated schedule in children is not approved in Canada. Hence, the normal schedule for JEV should be used for children when possible. However, it appears reasonable to use an off-label accelerated schedule for children in the circumstance where time does not allow for the normal schedule to be used, especially in older children.

## Contextual questions
What is the risk of clinical JE among Canadian travellers?
Likelihood estimates for travel-related clinical JE are shown in Table 1. For calculations, the numerator reflects the number of published cases over a 10 year period (2006-2015). We used cases identified in data from a previous review published in 2010 and identified more recent reports        by applying the same search strategy as is described in the review. To be included, published cases must have been for a traveller returning to Canada, the United States (US) or Europe. For the denominator, we used outbound travel statistics for Canada, the United States and Europe   .
We estimate the likelihood of clinical JE as approximately 1/10,000,000 trips (moderate confidence in the estimate of effect) for Canada, the United States and Europe (Table 1). The quality of the body of evidence was downgraded due to risk of bias (Appendix 9), i.e. not all cases in travellers may have been reported in the literature. In this respect, while we cannot be certain of the degree to which cases are under-reported, it has been suggested that the majority are identified in the literature. Moreover, even if it was assumed that only 1 in 10 cases of JE disease in travellers were reported, the overall risk of JE would remain very low, i.e. approximately 1 case/1,000,000 trips.
Previous estimates for US and European travellers   have also suggested a very low overall risk for JE.
What are the important risk factors for JE among Canadian travellers (e.g., destination, duration of travel)?
For the period of 2006-2015, we identified 18 published reports of JE, of which 17 were in travellers returning to Canada (1 case), the United States (5 cases) or Europe (11 cases). Including reports published before 2006 increased the total to 67 cases. Only 1 case identified was not in a traveller from the Western hemisphere and hence was excluded from the analysis. Overall, the case fatality rate was 20% (12/60) (outcome was unknown in 6 cases); most cases were in males (59%); the average age of cases was 39 years; and the mean duration of travel was 35 days (Figure 2). The countries to which exposure was most often ascribed were: were Thailand, Indonesia, China and the Philippines (Figure 3).
We estimate that travel-associated JE is rare, consistent with previous estimates. However, it also is widely accepted that certain subpopulations of travellers are at relatively higher risk for JE; examples include those travelling for an extended period and/or those spending substantial amounts of time in rural areas where vectors are more prevalent       . We did not identify evidence (observational or randomized trials) that would allow robust estimates of the incremental impact of these factors on risk to be made, and for this reason did not assess this evidence with GRADE. Based on identified travel-related cases (N=66, see above) we nevertheless make the following observations:
- Among cases where age is available (N=57), there is not an obvious age associated trend, e.g., children aged 10 years or younger (5 cases) accounted for 9% of the total and adults aged 60 years or older (12 cases) accounted for 21% of the total.
- There is a trend towards increased likelihood of JE with longer duration travel. Specifically, median duration of travel for cases at 35 days (Figure 2) is approximately double the median duration (15 days) for all travel to endemic areas . There is not, however, a clear cut-off for travel duration below which risk is absent (cases have been reported in short-term travellers) or for a travel duration at which disease likelihood crosses a "threshold" that would prompt use of JEV.
- Itineraries that include rural exposure are often reported in association with published cases. However, rural activity is not a universal risk factor nor, in the situation where time is spent in rural and urban areas, can the rural component of travel be definitively ascribed as the exposing activity. Hence, while there is consensus that activities in rural areas are "riskier", the absolute magnitude of the risk increase is unknown.