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ACIP Evidence to Recommendations Framework – Japanese Encephalitis Vaccine

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Question: Should inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) be recommended for use in persons aged ≥2 

months at risk of travel-related exposure to Japanese encephalitis (JE) virus?

Population: Persons aged ≥2 months traveling to JE risk areas

Intervention: JE-VC administered as a 2-dose primary series

Comparison: No JE vaccination 

Outcomes: The benefits considered critical outcomes for which there were data available included short and long-term seroprotection 

using the established immunologic correlate of protection (JE virus neutralizing antibodies at a PRNT50 titer ≥10). The harms 

considered critical outcomes were serious adverse events and adverse events of special interest (i.e., fever, rash, 

hypersensitivity/urticaria, neurologic adverse events, and medically attended adverse events).

Background: JE is a mosquito-borne disease that occurs throughout most of Asia and parts of the western Pacific. JE virus is transmitted 

in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds. JE virus is transmitted to 

humans by infected mosquitoes. Humans usually do not develop a level or duration of viremia sufficient to infect mosquitoes, and 

therefore are considered dead-end hosts. JE virus transmission occurs primarily in rural agricultural areas. 

 JE-VC (manufactured as IXIARO) is the only JE vaccine licensed and available in the United States. JE-VC is manufactured by Valneva 

Austria GmbH. In March 2009, the US Food and Drug Administration (FDA) licensed JE-VC for use in adults aged ≥17 years. In June 2009, 

the ACIP approved recommendations for use of JE-VC in adults. In September 2010, FDA approved a JE-VC booster dose for adults and, in 

February 2011, adult booster dose recommendations were approved. In May 2013, FDA approval for use of JE-VC was extended to 

include children aged ≥2 months. A GRADE for use of JE-VC in children was presented to ACIP and recommendations for pediatric use of 

JE-VC were approved in June 2013. In April 2018, FDA approved the pediatric booster dose.

 There are no efficacy data for JE-VC. However, a JE virus 50% plaque reduction neutralization test (PRNT50) titer of ≥10 is an 

established immunologic correlate of protection. JE-VC was licensed based on its ability to induce neutralizing antibodies and a noninferiority comparison to a licensed inactivated mouse brain-derived JE vaccine (JE-MB [manufactured as JE-VAX]). JE-MB is no longer 

available in the United States. At the time of licensure, JE-VC had been studied in <5,000 adults. 

 Since JE-VC’s licensure, more than 1 million doses have been distributed in the United States. Since the 2013 GRADE, additional 

immunogenicity and safety data from clinical trials and surveillance activities have become available. The ACIP JE Vaccine Work Group 

used GRADE methods to review and evaluate these newly available data. Additional factors also were assessed in considering the JE 

vaccine recommendations, as outlined in the Evidence to Recommendations (EtR) framework. The results of the work group’s

deliberations and the JE vaccine recommendations are presented below. 

 Additional information supporting the ACIP recommendations on the use of JE vaccine can be found here. 

https://www.cdc.gov/vaccines/acip/recs/grade/JE-etr-framework.pdf
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ACIP Evidence to Recommendations Framework – Japanese Encephalitis Vaccine

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CRITERIA JUDGMENTS EVIDENCE ADDITIONAL 

INFORMATION

PROBLEM

Is the problem 

of public 

health 

importance?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

JE is of public health importance in Asia and parts of 

the Western Pacific.

• Leading vaccine-preventable cause of encephalitis 

in Asia, with an estimated 67,900 cases annually.

• In the highest risk areas prior to vaccination 

programs, incidence rates as high as 20 cases per 

100,000 children per year were reported.

JE cannot be considered a substantial public health 

problem for U.S. travelers overall.

• A JE vaccine was first licensed for use in the United 

States in 1992. 

• In the 25-year period from 1993–2017, 12 JE cases 

were reported among U.S tourists or expatriates, 

with a median of 0 reported cases per year (range: 

0–2 cases). 

• Based on the 12 reported cases from 1993–2017 

and approximately 4–5 million U.S. citizen trips 

annually to Asia, the overall estimated risk is <1 

case per million trips to Asia. 

Importation of JE virus by an infected traveler is not a 

public health concern 

• There is no risk of subsequent local transmission 

from an infected traveler.

JE is an important individual concern for some 

travelers, especially those with higher risk itineraries.

• Risk for JE varies based on travel duration, season, 

geographic location, activities, and 

accommodations. 

• For some persons, such as those taking up long 

term residence in rural areas of Asia, risk might
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approach a similar level to populations of endemic 

areas.

When disease occurs, only supportive treatment is 

available and the outcome is often severe.

• <1% of infected people develop encephalitis, but 

among encephalitis cases there is a 20–30% 

mortality rate, and 30–50% of survivors have 

significant sequelae. 

• JE can be a serious problem for individual 

travelers, and substantial resources might be 

needed to care for a person with a serious longterm disability.

The costs and benefits of immunization are primarily 

at the individual rather than societal level

• JE vaccine is paid for out-of-pocket by most 

civilian travelers, is typically not covered by 

insurance, and is not covered under the Vaccines 

for Children program.

Overall conclusion: JE is a public health problem in 

JE endemic countries. For the U.S. population, it is an 

individual traveler rather than societal concern, so the 

question of public health importance is not directly 

applicable. In addition, JE vaccine typically is paid for 

by the traveler themselves. However, since certain 

travelers might have sufficiently high risk to warrant 

vaccination, the consensus was that public health 

importance “varies” related to the individual person’s 

itinerary and activities. 
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BENEFITS & HARMS 

How 

substantial 

are the 

desirable 

anticipated 

effects?

Trivial Small Moderate Large Don’t 

know

Varies

X

A Grading of Recommendations, Assessment, 

Development, and Evaluation (GRADE) was 

completed.

Evidence used to evaluate seroprotection at 1 month 

after vaccination with JE-VC was from 12 studies, 

including four randomized controlled trials (RCTs). 

• Of 1,673 JE-VC recipients in the 12 studies 

combined, 1,582 (95%) were seroprotected at 1 

month after the 2-dose primary series. 

• Seroprotection rates in 11 of the 12 studies were 

≥95% (see Additional Information). 

• In the four RCTs, seroprotection rates in JE-VC 

recipients were similar to or higher than 

seroprotection rates for recipients of the 

comparator vaccines. 

• When data from the four RCTs were combined and 

weighted using a random effects model, there was 

no significant difference in seroprotection rates 

between recipients of JE-VC and the other JE 

vaccines. 

Evidence used to evaluate seroprotection at 5 to 6 

months after vaccination with JE-VC was from six 

studies of JE-VC, including two RCTs. 

• Of the 941 JE-VC recipients in the six studies 

combined, 864 (92%) were seroprotected at 5 to 6 

months after the 2-dose primary series. 

• Seroprotection rates in the individual studies 

ranged from 83% to 100%.

• The data from the two RCTs in adults showed that 

a significantly higher proportion of JE-VC 

recipients were seroprotected compared with 

subjects who received mouse brain-derived JE 

vaccine.

Seroprotection rates 

were much lower in 

the only study 

conducted 

specifically among 

elderly subjects, 

with 128 (65%) of 

197 adults aged ≥64 

years seroprotected

at 42 days after the 

primary series. 

These data were 

considered by the 

work group and 

presented to ACIP in 

October 2015 and 

were submitted to 

FDA. While there 

are lower 

seroprotection rates 

in older adults, 

there are no data on 

the safety, 

immunogenicity, or 

optimal timing of a 

possible third 

primary series dose 

or early booster 

dose for older 

adults.

The majority of data 

are in adults; 

however, data from 

the three pediatric 

studies, supported

by adult data, were 
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Overall conclusion: The work group concluded the 

desirable anticipated effects were large. 

considered

sufficient for 

pediatric licensure. 

Herd immunity is 

not a consideration 

as JE virus circulates 

in an enzootic cycle 

in the environment 

and is not 

transmitted from 

person-to-person.

CRITERIA JUDGMENTS RESEARCH EVIDENCE ADDITIONAL 

INFORMATION

How 

substantial 

are the 

undesirable 

anticipated 

effects?

Trivial Small Moderate Large Don’t 

know

Varies

X

A GRADE assessment was completed. The following 

data include all reported serious adverse events

(SAEs), whether assessed as related or unrelated.

Evidence used to evaluate SAE was from 16 studies, 

including eight RCTs, four observational studies, and 

four post-marketing assessments.

• SAEs within 1 month after either JE-VC dose were 

reported in 29 (1%) of 4,855 subjects in 12 clinical 

trials. 

• SAEs within 6 to 7 months after the first JE-VC dose 

were reported in 72 (1%) of 5,269 subjects in five 

clinical trials.

• When data from RCTs were combined and weighted 

using a random effects model, there was no 

significant difference in proportions of subjects with 

SAEs within 1 month of JE-VC or the comparison 

vaccines (eight RCTs), or within 6 to 7 months of JEVC and the comparison vaccines (two RCTs). 

• Three large post-marketing surveillance evaluations 

reported 1.1–1.8 serious adverse events per 100,000 

doses distributed, and a retrospective chart review 

for medical visits following administration of JE-VC 

In considering rates 

of adverse events, it 

is important to 

understand that 

causality usually 

cannot be 

determined, 

especially in 

surveillance data 

when reported 

events occur among 

persons who have 

often received 

multiple vaccines.

The relatively small 

numbers of subjects 

in the clinical trials 

limited the ability to 

detect rare SAEs, 

but the findings 

from postmarketing 
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to 145 children detected no SAEs. These rates are 

similar to or lower than rates from post-marketing 

adverse event surveillance for other vaccines, 

including quadrivalent human papillomavirus 

vaccine, 23-valent pneumococcal polysaccharide 

vaccine, yellow fever vaccine, and live attenuated 

herpes zoster vaccine. 

• No patterns in the timing or types of serious adverse 

events were identified. 

Evidence used to evaluate adverse events of special 

interest was from 12 studies, including eight clinical 

trials and four post-marketing assessments.

• Fever within 7 days after either JE-VC dose was 

reported in 296 (8%) of 3,892 subjects in seven 

studies. Proportions of subjects with fever in 

individual studies ranged from 0% to 21% with 

differences likely related to the different age groups 

studied, variable study locations, differences in study 

methodology, and possibly less precision in some 

smaller studies. 

• Rash within 7 days after either JE-VC dose was 

reported in 81 (2%) of 3,892 subjects.

• Hypersensitivity or urticaria within 1 month was 

reported in 10 (<1%) of 3,868 JE-VC recipients in six 

studies.

• Neurologic adverse events (excluding headache) 

within 1 month were reported in 26 (1%) of the 

3,668 recipients. 

• Medically attended adverse events within 1 month 

were reported in 571 (14%) of 3,947 subjects. 

Proportions in individual studies ranged from 0 

through 19%; the two studies with the highest 

percentage of subjects with medically attended 

adverse events were conducted among children in 

the Philippines and elderly adults in Europe. 

surveillance 

following 

distribution of >1 

million doses 

provide indirect but 

reassuring 

supportive data on 

the vaccine’s safety.
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• When data from RCTs were combined and weighted 

using a random effects model, there were no 

significant differences in the proportions with any of 

these adverse events of special interest between 

recipients of JE-VC and comparison vaccines.

• In passive post-marketing surveillance the reported 

incidence of hypersensitivity was 3.0–4.4 per 

100,000 doses distributed and of neurologic adverse 

events (excluding headache) was 0.2–1.1 per 

100,000 doses distributed. In a post-marketing 

adverse event surveillance study conducted among 

military personnel and involving retrospective 

review of medical records, rates for hypersensitivity 

and neurologic reactions were 24.8 and 22.0 per 

100,000 doses administered, respectively. The 

higher reported rates in this surveillance reflected

the different active surveillance approach. 

Overall conclusion: The work group concluded the 

undesirable anticipated effects were small.

Do the 

desirable 

effects 

outweigh the 

undesirable 

effects?

Favors 

intervention

Favors 

comparison

Favors 

both

Favors 

neither

Unclear

X

JE-VC is the only JE vaccine licensed and available in the 

United States. With no alternative vaccine, this 

assessment focused on comparing the balance of risks 

and benefits of JE-VC. 

Evidence that the desirable effects outweigh the 

undesirable effects includes: 

• High seroprotection rates at both 1 month and 5 to 6 

months after the 2-dose primary series of JE-VC.

• Serious adverse events and adverse events of special 

interest are rare in clinical trials and safety profile is 

similar to other vaccines with good safety profiles, or 

to adjuvant (aluminum hydroxide) alone. 

• Reassuring data from post-marketing surveillance 

following distribution of >1 million doses in the 

United States, with reported rates of serious adverse 
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events similar to rates reported for other routinely 

used vaccines.

• No patterns in the timing or types of serious adverse 

events identified in the clinical trials or surveillance 

data. 

Overall conclusion: In general, with high seroprotection 

rates following vaccination and with no important safety 

concerns identified, the work group considered the 

desirable effects of a vaccine to prevent a rare but 

potentially serious, untreatable disease outweighed the 

undesirable effects of vaccination. However, as with any 

vaccine, rare serious adverse events can occur and so for 

some travelers with lower risk itineraries, even a low 

probability of vaccine-related serious adverse events 

might be higher than the risk for disease. Therefore, for 

each traveler, a healthcare provider should consider and 

discuss the balance of desirable and undesirable effects 

and the traveler’s risk based on itinerary and activities, 

and JE vaccine should be targeted to travelers who are at 

increased risk for disease.

What is the 

overall 

certainty of 

this evidence 

for the critical 

outcomes?

Effectiveness of the intervention

No

included

studies

4 

Very low

3 

Low

2

Moderate

1

High

X

Safety of the intervention

No

included

studies

4

Very low

3

Low

2

Moderate

1

High

X

The GRADE approach was followed for assessing type of 

evidence. 

• Overall evidence type 1 for vaccine effectiveness 

using seroprotection as the endpoint.

• Overall evidence type 2 for safety, with evidence type 

downgraded because of risk of bias due to 

inadequate blinding of study participants and 

personnel. 

Overall conclusion: Evidence is type 1 (i.e., high) for 

vaccine effectiveness using seroprotection as the 

endpoint and type 2 (i.e., moderate) for safety.

For serious adverse 

events at 1 month, 

there was some 

concern about 

inconsistency and 

imprecision in the 

RCTs. However, 

complementary 

information from 

surveillance 

assessments and 

observational 

studies provided 

additional data 

supportive of the 

vaccine’s safety.
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VALUES

Does the 

target 

population 

feel that the 

desirable 

effects are 

large relative 

to undesirable 

effects?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

A population survey was conducted using the Porter 

Novelli Public Services Styles (SpringStyles) survey 

mechanism 

• Panel of participants representative of the noninstitutionalized U.S. population and randomly 

recruited by mail. 

• Survey response rate was 6,427 (59%) of 10,904 

adults; among respondents, 6,384 (99%) completed 

the JE question. 

Participants were asked two questions:

• You are going on a trip to another country. You have 

a one in a million chance of getting a disease. About 

one-third of people who get the disease will die and 

one-third of people will have a permanent disability 

like problems with walking or thinking clearly. There 

is a vaccine that prevents the disease. It is safe 

although on rare occasions can cause serious side 

effects. It costs $600 and is not covered by insurance. 

How likely are you to get the vaccine? (Very 

likely/Somewhat likely/Not sure/Somewhat 

unlikely/Very unlikely)

• Which factors were most important in deciding 

whether you would get the vaccine? (One or more 

factors can be selected of Chance of getting the 

disease/Chance of dying or being disabled/The 

vaccine is safe/Chance of serious side effects/Cost of 

the vaccine/I do not get any vaccinations/Other 

reasons not listed)

Demographics of respondents

• Male: 45%

• Median age 51 years (range: 18-94 years)

• White, non-Hispanic: 74%

• At least some college or higher education: 72% 

• Household income ≥60K: 61%

Results
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• Likelihood of getting JE vaccine was “very likely” 

(16%), “somewhat likely” (16%), “not sure” (25%), 

“somewhat unlikely” (17%) and very unlikely (26%). 

Overall conclusion: The results suggest there is 

variability in the population perception of whether the 

potential benefits of vaccination outweigh harms.

CRITERIA JUDGMENTS RESEARCH EVIDENCE ADDITIONAL 

INFORMATION

Is there 

important 

uncertainty 

about or 

variability in 

how much 

people value 

the main 

outcomes?

Important 

uncertainty 

or 

variability

Possibly 

important 

uncertainty 

or 

variability

Probably 

no 

important 

uncertainty 

or 

variability

No 

important 

uncertainty 

or variability

No known 

undesirable 

outcomes

X

Among the groups “likely” to choose vaccination 

influential factors were chance of getting disease, and 

dying or being disabled

• Comparing “very likely’ and “somewhat likely” 

groups, latter group had additional concern about 

cost and chance of serious side effects 

Among the groups “unlikely” to choose vaccination

• Cost most important factor

• Chance of getting the disease also major factor

Overall conclusion: The survey results suggest that the 

population has different perceptions of disease risk and 

value of vaccination. While some of the population 

clearly value the availability of a vaccine to prevent a 

rare disease with potentially serious outcomes and no 

treatment, others were less likely to place value on it 

when the vaccine is expensive and, while safe, has the 

possibility of rare serious side effects. Disease risk was 

considered a reason to both receive and not receive the 

vaccine. There is clearly substantial variability in 

perception and tolerance of risk with an important 

impact on decision-making on vaccination choices.
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ACCEPTABILITY

Is the 

intervention 

acceptable to 

key 

stakeholders?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

Travel medicine practitioners were considered an 

important stakeholder. The work group could not 

identify a feasible mechanism to survey U.S. travel 

medicine practitioners within the timeframe available. 

Four members of work group who are travel medicine 

practitioners and members of the International Society 

of Travel Medicine played an active role in discussions 

about the recommendations. 

Several publications authored by U.S. health care 

providers have included opinions on the existing ACIP JE 

vaccine recommendations, ranging from suggesting 

limited use based on an individual assessment for each 

traveler to broader consideration for any traveler to a 

rural or peri-urban area irrespective of duration of travel 

or itinerary. 

Valneva sponsored an “Expert Advisory Group on JE 

Prevention” that has had several meetings and written 

three letters to ACIP in January 2015, April 2017, and 

October 2017. The group has urged broadening of the 

recommendations to include traveler groups the work 

group considers ill-defined for being at higher risk. The 

work group reviewed the letters and had two travel 

medicine practitioners with dissenting opinions on the 

recommendations present to the work group. It is 

unknown how representative this group might be of 

other travel medicine practitioners. The manufacturer 

has similarly suggested broadening of the 

recommendations, but due to a conflict of interest, 

acceptability to the manufacturer was given low priority.

For the public, the proposed recommendations are likely 

to be acceptable as they describe and target vaccination 

of travelers with the highest risk for infection and so

limit the number of travelers for whom an expensive 

vaccine for a very low risk disease might be 
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recommended. Most travelers are likely to value a 

discussion of the risks and benefits of vaccination,

including consideration of the traveler’s tolerance of 

risk, while others might prefer more concrete 

recommendations that clearly define who should receive 

vaccine based on a specific factor. Some travelers who 

have an insurer that covers travel vaccines might prefer 

a recommendation for vaccination for all travelers. 

Overall conclusion: While there is some variability in 

stakeholders thoughts on the recommendations, there is 

stakeholder agreement that 

• Overall, JE risk is low for most travelers

• There is need to inform travelers about risks and 

prevention measures for JE

• Vaccine should be targeted to travelers at higher risk

All members of the work group agreed the vaccine 

recommendations were acceptable, and felt they will 

probably be acceptable to most stakeholders as they are 

based on individual clinical decision-making with 

consideration of risks and benefits of vaccination. 

RESOURCE USE

Is the 

intervention a

reasonable 

and efficient 

allocation of 

resources?

No Probably

no

Uncertain Probably

yes

Yes

X

JE vaccination is cost-effective or cost-saving for local 

populations in JE endemic countries. However, JE 

vaccination is not expected to be cost effective among 

travelers as there is 1) a substantially lower risk of 

disease, and 2) use of much lower cost vaccines in most 

vaccination programs in Asia. 

There were several general resource considerations 

noted by the work group when discussing JE vaccination 

for travelers. From a societal perspective, JE vaccination 

is probably not an efficient use of resources. The vaccine 

is expensive and the disease is rare. However, the 

question of resource use is less relevant for travel 

vaccines which are usually paid for by the travelers 

themselves and are not covered under the Vaccines for 

Children program or by most insurance plans. Travelers 

The vaccine is 

expensive which 

raises equity issues. 

The cost could lead 

to health disparities 

as some travelers 

might not be able to 

afford the vaccine. 

However, the 

vaccine 

recommendations 

cannot address this 

issue.
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make individual decisions on vaccination. Mortality and 

disability rates following disease are high, and about one 

third of participants in the survey described above 

indicated vaccination was probably a reasonable 

investment. Nonetheless, there are opportunity costs for 

travelers in purchasing this vaccine compared with an 

alternative preventive measure. 

The work group did not consider a cost-effectiveness 

analysis of JE-VC essential. However, the work group 

decided to perform a comparative analysis of different 

vaccination strategies to understand the numbers 

needed to vaccinate and cost per case averted for

travelers with different itineraries and disease risk, and 

the cost implications of expanding the existing JE vaccine 

recommendations to a broader group of travelers. 

A comparative analysis of strategies for JE vaccination 

for U.S. travelers to Asia was performed by CDC’s Health 

Economics and Modeling Unit. An analytic horizon of 6 

years was used, but productivity losses were evaluated 

over average life expectancy. The analysis compared JE 

vaccination in three groups. 

• Risk group l included travelers who plan to spend ≥1 

month in JE endemic areas and approximates the 

group for whom JE vaccine is recommended under 

the ACIP guidelines.

• Risk group 2 included travelers who will spend <1 

month in JE endemic areas, with at least 20% of their 

time doing outdoor activities in rural areas. This 

group approximates travelers for whom JE 

vaccination should be considered after evaluating 

their itinerary and weighing the benefits, risks, and 

costs. 

• Risk group 3 included the remainder of shorter-term 

and lower-risk U.S. travelers to Asia for whom JE 

vaccination is not recommended.
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To prevent one JE case, the number of travelers who 

would need to be vaccinated was 0.7 million in Risk 

group 1, 1.6 million in Risk group 2, and 9.8 million in 

Risk group 3. 

The cost to prevent one JE case from a societal 

perspective was approximately $0.6 billion for Risk 

group 1, $1.3 billion for Risk group 2, and $7.9 billion for 

Risk group 3. The variable with the greatest influence on 

the cost-effectiveness of vaccination was disease 

incidence among travelers. As baseline incidence is 

based on reported JE cases, to address any uncertainty 

about the sensitivity of surveillance, a sensitivity analysis 

was conducted increasing baseline incidence 100 times.

In this analysis, the numbers needed to vaccinate to 

prevent a case were 7,000, 16,000 and 98,000, and the 

cost per case averted was $5 million, $12 million, and 

$78 million in each Risk group, respectively. 

The cost to society to prevent one additional case of JE if 

JE vaccination recommendations were expanded would 

be 

• $1.6 billion if expanding from Risk group1 to Risk 

groups 1 and 2.

• $14.6 billion if expanding from Risk groups 1 and 2 

to all travelers. 

Overall conclusion: The work group decided the 

question of whether the intervention was a reasonable 

and efficient allocation of resources was not directly 

applicable to JE vaccination as travel vaccines are usually 

paid for by the travelers themselves who make 

individual decisions on vaccine purchase. In general, JE 

vaccination cannot be considered an efficient use of 

societal resources as it is an expensive vaccine for a low 

risk disease. Nonetheless, the comparative analysis 

supports the proposed tiered JE vaccine 
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recommendations as it indicated a large increased cost 

to society to prevent a case of JE when including Risk 

groups 1 and 2 compared with Risk group 1 alone, 

supporting a more cautious approach or “consideration” 

of vaccination for those in Risk group 2. In addition, 

there was a very large increased cost to society if Risk 

group 3 was included, which does not support a broad 

recommendation of JE vaccination for all travelers. 

Overall, vaccine recommendations targeted to higher 

risk groups are probably a reasonable allocation of 

resources as the financial implications of vaccine 

purchase will be borne by travelers most at risk of a 

severe disease who will therefore receive the most 

benefit.

FEASIBILITY

Is the 

intervention 

feasible to 

implement?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

JE vaccination is provided by generalist and specialist 

health care providers. Administration is feasible as part 

of a pre-travel consultation. Barriers to implementation 

of risk-based vaccine recommendations might include 

lack of understanding of factors that might increase the 

risk for JE, and therefore which travelers might benefit 

most from vaccination. However, specific information is 

provided in a table accompanying the recommendations 

and other resources also are readily available. 

Overall conclusion: Risk-based recommendations are 

probably feasible to implement. 

Balance of 

consequences

Undesirable 

consequences 

clearly outweigh

desirable 

consequences

in most settings

Undesirable 

consequences 

probably outweigh

desirable 

consequences

in most settings

The balance 

between 

desirable and 

undesirable 

consequences 

is closely balanced 

or uncertain

Desirable 

consequences 

probably outweigh 

undesirable 

consequences

in most settings

X

Desirable 

consequences 

clearly outweigh

undesirable 

consequences

in most settings

There is 

insufficient 

evidence to 

determine the 

balance of 

consequences
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Overall, the work group determined the desirable consequences probably outweigh undesirable consequences in most settings when 

risk-based recommendations are appropriately implemented. 

Is there sufficient information to move forward with a recommendation?

Yes x No 

Type of 

recommendation

We do not recommend the 

intervention

We recommend the intervention for 

individuals based on clinical decisionmaking

X

We recommend the intervention
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Recommendation Recommendations for the Prevention of JE Among Travelers

JE is a very low risk disease for most U.S. travelers to JE-endemic countries. However, some travelers will be 

at increased risk of infection based on their planned itinerary. Factors that increase the risk of JE virus 

exposure include: 1) longer duration of travel, 2) travel during the JE virus transmission season, 3) spending 

time in rural areas, 4) participating in extensive outdoor activities, and 5) staying in accommodations 

without air conditioning, screens, or bed nets (Box).

Healthcare providers should assess each traveler’s risk for mosquito exposure and JE virus infection 

based on their planned itinerary, and discuss ways to reduce their risk. All travelers to JE-endemic countries 

should be advised to take precautions to avoid mosquito bites to reduce the risk for JE and other vectorborne diseases. These precautions include using insect repellent, permethrin-impregnated clothing, and bed 

nets, and staying in accommodations with screened or air-conditioned rooms. 

For some people who might be at increased risk for JE based on travel duration, season, location, 

activities, and accommodations, JE vaccine can further reduce the risk for infection. The decision whether to 

vaccinate should be individualized and consider the: 1) risks related to the specific travel itinerary, 2) 

likelihood of future travel to JE-endemic countries, 3) high morbidity and mortality of JE when it occurs, 4) 

availability of an effective vaccine, 5) possibility, but low probability, of serious adverse events following 

vaccination, and 6) traveler’s personal perception and tolerance of risk.

JE vaccine is recommended for persons moving to a JE-endemic country to take up residence, longerterm (e.g., ≥1 month) travelers to JE-endemic areas, and frequent travelers to JE-endemic areas. JE vaccine 

also should be considered for shorter-term (e.g., <1 month) travelers with an increased risk of JE based on 

planned travel duration, season, location, activities, and accommodations (Box). Vaccination also should be 

considered for travelers to endemic areas who are uncertain of specific duration of travel, destinations, or 

activities. 

JE vaccine is not recommended for travelers with very low risk itineraries, such as shorter-term 

travel limited to urban areas or travel that occurs outside of a well-defined JE virus transmission season.
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Box 1. Factors that increase risk for Japanese encephalitis among travelers

Duration

• Highest incidence of disease has been reported among longer-term travelers. 

• Although no specific duration of travel puts a traveler at risk for JE, longer-term travel 

increases the likelihood that a traveler might be exposed to an infected mosquito.

• Longer-term travel includes cumulative periods in endemic areas; this includes frequent 

travelers, and persons residing in urban areas who are likely to visit higher risk rural 

areas.

Season

• JE virus transmission occurs seasonally in some areas, and year-round in other areas.

• Information on expected JE virus transmission by country is available on the CDC website 

(see Japanese encephalitis chapter in CDC Health Information for International Travel 

[the Yellow Book]). These data should be interpreted cautiously because JE virus 

transmission varies within countries and from year to year.

Location

• Highest risk occurs from mosquito exposure in rural or agricultural areas.

• Mosquitoes that transmit JE virus typically breed in flooded rice fields, marshes, and 

other stagnant collections of water. 

• Some cases have been reported among travelers to coastal areas or resorts located in or 

adjacent to rural or rice growing areas.

• JE can occur in large, focal outbreaks indicating extensive active JE virus transmission in 

those areas.

Activities

• The mosquitoes that transmit JE virus feed most often in the outdoors, particularly from 

sunset through dawn, so examples of activities that increase risk include:

o Outdoor recreation such as camping, hiking, trekking, biking, rafting, fishing, 

hunting, or farming.

o Spending substantial time outdoors, especially during the evening or night.

Accommodations

• Accommodations without air conditioning, screens, or bed nets increase risk of mosquito 

exposure.
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Additional 

considerations

(optional)

Among the shorter-term travelers for whom vaccination would be “considered” rather than “recommended” there 

was no consistent risk factor, destination, or feature to enable further targeting of recommendations. This suggests 

the only way to prevent every case would be to recommend vaccination for all travelers; however, based on risks 

and benefits, the work group members felt vaccine recommendations should be targeted to a subset of travelers 

with greater risk of infection.

This Evidence to Recommendation table is based on the GRADE Evidence to Decision framework developed through the DECIDE project. Further 

information is available athttp://www.decide-collaboration.eu/evidence-decision-etd-framework