JE vaccination EtR document July 16, 2019 

Page 1 of 46

JAPANESE ENCEPHALITIS VACCINE EVIDENCE TO RECOMMENDATIONS

POLICY QUESTION

The primary policy question was “Should inactivated Vero cell culture-derived Japanese 

encephalitis (JE) vaccine (JE-VC) be recommended for use in persons aged ≥2 months at risk of 

travel-related exposure to 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) (Table 1). 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 Advisory Committee on Immunization Practices (ACIP) approved recommendations for use 

of JE-VC in adults [Fischer 2010]. In September 2010, FDA approved a JE-VC booster dose for 

adults and, in February 2011, adult booster dose recommendations were approved [CDC 2011]. 

In May 2013, FDA approval for use of JE-VC was extended to include children aged 2 months 

through 16 years. A Grading of Recommendations, Assessment, Development, and Evaluation 

(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 approval for a booster 

dose was extended to include the pediatric age group. 

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 

[Markoff 2000; Hombach 2005]. JE-VC was licensed based on its ability to induce neutralizing 

https://www.cdc.gov/vaccines/acip/recs/grade/JE-evidence-rec.pdf
JE vaccination EtR document July 16, 2019

Page 2 of 46

antibodies and a non-inferiority 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 [Ahmed 2013]. Additional factors also were assessed in 

considering JE vaccine recommendations, as outlined in the Evidence to Recommendations 

(EtR) framework [Lee 2018]. The results of the work group’s deliberations and the proposed JE 

vaccine recommendations are presented below. 

DOMAINS

DOMAIN 1. THE PROBLEM 

Criterion: Public Health Priority

Criterion question: Is the problem of public health importance?

JE virus is the leading vaccine-preventable cause of encephalitis in Asia, with an estimated 

67,900 cases annually [Campbell 2011]. In the highest risk areas in Asia prior to vaccination 

programs, incidence rates as high as 20 cases per 100,000 children per year were reported. Risk 

areas for JE virus transmission include most of Asia and parts of the Western Pacific. JE clearly 

is of public health importance for residents in these regions. 

While JE incidence is high in some JE-endemic regions, JE cases are infrequently reported 

in the United States. A JE vaccine was first licensed in the United States at the end of 1992. In 

the 25-year period from 1993–2017, 12 JE cases were reported among U.S. tourists or 

expatriates. All cases occurred in 2003 or later and none were immunized. There was a median 

of 0 cases reported 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 during that time period, the 

overall estimated JE risk for a U.S. traveler is <1 case per million trips to Asia. Therefore, JE 

cannot be considered a substantial public health problem for U.S. travelers overall.

JE virus is not found in the United States. When humans are infected with JE virus, they 

have a low level viremia and so are considered “dead end” hosts. Therefore, the risk is extremely 

low for subsequent local transmission of JE virus in the United States from an infected traveler, 

and importation of JE virus by an infected traveler is not a public health concern. 

While the risk for JE in most travelers is low, it varies based on travel duration, season, 

location, activities, and accommodations. Vaccination will be of benefit to some travelers. For 

some persons, such as those taking up long term residence in rural areas of Asia, risk might 

approach a similar level to populations of endemic areas. There are examples of substantial JE 
JE vaccination EtR document July 16, 2019

Page 3 of 46

disease risk among certain groups. For example, more than 300 cases of JE were reported among 

soldiers deployed to Asia from the United States, the United Kingdom, Australia, and Russia in 

the period before JE vaccine was widely available and utilized among military personnel. 

Most JE virus infections in humans are asymptomatic; <1% of infected people develop 

encephalitis. However, when disease occurs, outcome is often severe, with a 20–30% mortality 

rate, and 30–50% of survivors having significant neurologic, cognitive, or behavioral sequelae. 

There is no antiviral therapy and treatment consists of supportive care. Given its substantial 

morbidity and mortality, JE can be considered a serious problem for individual travelers. 

Substantial resources might be needed to care for a person with a serious long-term disability. 

Finally, JE vaccine is paid for out-of-pocket by most U.S. civilian travelers. It is typically 

not covered by private insurers and is not covered under the Vaccines for Children program. 

Therefore, the costs and benefits of immunization are primarily at the individual rather than 

societal level.

Conclusion

The work group agreed 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 is typically paid for out-ofpocket, unlike vaccines in the national immunization program. However, since certain travelers

might have a sufficiently high risk to warrant vaccination, the consensus was that the public 

health importance “varies” related to the individual person’s itinerary and activities. 

DOMAIN 2. BENEFITS AND HARMS

Methodology for GRADE

GRADE was used to assess the benefits and harms of JE-VC. To identify published literature 

that contained relevant evidence, we conducted a search of Medline, Embase, CINAHL, and 

Cochrane Library databases for papers in any language published from May 2013 through 

February 28 2018. The date limits were selected to provide an update to the literature search 

conducted for the previous GRADE for use of JE-VC in children, which covered the period 

January 2006 through April 2013. We used the following search strategy and keywords: 

“Japanese encephalitis” and “vaccine” and “IXIARO or JESPECT or IC51 or JEEV or Vero or 

purified inactivated”. The title and abstract of the studies were reviewed to identify relevant 

articles; if no abstract was provided, the paper itself was reviewed.

Articles that presented data on JE-VC were included if they met the following criteria: 1) 

Involved human subjects; 2) Reported primary data; 3) Included data relevant to the outcome 

measures being assessed (i.e., vaccine efficacy, seroprotection at 1 and 6 months after 

vaccination, serious adverse events, or adverse events of special interest); and 4) Included data 
JE vaccination EtR document July 16, 2019

Page 4 of 46

for an FDA-approved dose (i.e., 0.25mL for children aged 2 months through 2 years and 0.5mL 

for children and adults aged ≥3 years). Publications that met the above criteria but represented a 

single case report were excluded. 

We identified 479 records using the search strategy. Among these studies, 466 were 

excluded as they did not include any JE-VC data or did not present primary data. Four studies 

that included JE-VC human data also were excluded: 1) Two studies that presented safety or 

immunogenicity data at ≥7 months post-vaccination (i.e., outside the timeframe of interest); 2) 

One study that only presented data on cross-protective capacity of JE-VC against various JE 

virus genotypes among a cohort of travelers described in a separate publication; and 3) One 

study that included study groups that received JE-VC and rabies vaccine with or without 

meningococcal vaccine but did not include a study group that received JE-VC alone. Following 

the 470 exclusions, nine studies remained; these were combined with the 12 studies identified in 

the evidence retrieval process for the previous GRADE assessment [ACIP 2013]. In total, data 

from 21 published studies were included in this GRADE evaluation. 

Unpublished data also were considered for JE-VC and another similar inactivated Vero cell 

culture-derived JE vaccine (JEEV) manufactured by Biological E (Hyderabad, India). JEEV is 

manufactured with technology licensed from Valneva. JEEV and IXIARO use the same virus 

strain, adjuvant, and virus purification; however, no process comparability studies have been 

completed and it cannot be assumed that the two final vaccine products are the same. JEEV is 

approved in India for use in children aged 1 through 2 years (two 0.25mL doses administered 28 

days apart) and adults aged 18 through 49 (two 0.5mL doses administered 28 days apart) 

[Central Drugs Standard Control Organization 2013]

Evidence type was assessed through a review of study design, risk of bias, inconsistency, 

indirectness, imprecision, and other considerations (i.e., publication bias, strength of association, 

dose response, or opposing plausible residual confounding).

Criterion 1: Magnitude of desirable anticipated effects

Criterion question: How substantial are the desirable anticipated effects?

Seroprotection at 1 month 

The evidence used to evaluate seroprotection at 1 month after vaccination with JE-VC was from 

12 studies, including four randomized controlled trials (RCTs) (Table 2). Of the 1,673 JE-VC 

recipients in the 12 studies combined, 1,582 (95%) achieved seroprotection levels at 1 month 

after the 2-dose primary series. The only study with a seroprotection rate <95% was conducted 

among a cohort of older adults aged ≥64 years in which 128 (65%) of 197 participants achieved 

seroprotection levels at 42 days after the 2-dose series. These data on immunogenicity in older 

adults 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 compared to 
JE vaccination EtR document July 16, 2019

Page 5 of 46

younger adults, there are no data on safety, immunogenicity, or optimal timing of a possible third 

primary series dose or early booster dose for older adults. 

In the four RCTs, seroprotection rates for 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 (Figure 1). 

In addition to the studies of JE-VC, we reviewed evidence for seroprotection in one RCT 

performed using a similar JE vaccine (JEEV) among children aged 1 and 2 years in India 

[Biological E 2013] (Table 3). The findings were similar to those seen with JE-VC.

Seroprotection at 5 to 6 months

The 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 (Table 4). Of the 941 JE-VC recipients in the six 

studies combined, 864 (92%) achieved seroprotection levels at 5 to 6 months after the 2-dose 

primary series. Seroprotection rates in the individual studies ranged from 83% to 100%. The 

findings from the two RCTs in adults showed that a significantly higher proportion of JE-VC 

recipients achieved seroprotection levels at this time point compared with subjects who received 

mouse brain-derived JE vaccine (Figure 2). 

Additional information

The work group noted that the majority of data are in adults; however, data from the three 

pediatric studies supported by adult data were considered sufficient for pediatric licensure. While 

herd immunity is important for some vaccines, it is not a consideration for immunization against 

JE, as JE virus circulates in an enzootic cycle in the environment and is not transmitted from 

person-to person. 

Conclusion

On the basis of these seroprotection data at 1 and 5– 6 months after the primary series of JE-VC, 

the work group concluded the desirable anticipated effects were “large”. 

Criterion 2: Magnitude of undesirable anticipated effects

Criterion question: How substantial are the undesirable anticipated effects?

Serious adverse events

The evidence used to evaluate serious adverse events following JE-VC was from 16 studies, 

including 12 clinical trials and four post-marketing assessments that included data from three 

countries. Among the 12 clinical trials, eight were RCTs and four were observational studies

(Table 5). Any serious adverse events within 1 month after either JE-VC dose were reported in 
JE vaccination EtR document July 16, 2019

Page 6 of 46

29 (1%) of the 4,855 subjects in these 12 clinical trials. Serious adverse events within 6 to 7 

months after the first dose were reported in 72 (1%) of 5,269 subjects included in four clinical 

trials (Table 6). Although the relatively small numbers of subjects in these clinical trials limit the 

ability to detect rare serious adverse events, post-marketing surveillance data following 

distribution of >1 million doses provide indirect but reassuring support for the vaccine’s safety. 

Three large post-marketing surveillance evaluations reported 1.1 to 1.8 serious adverse events 

per 100,000 doses distributed (Table 7). These reported rates are similar to or lower than rates of 

serious adverse events per 100,000 doses distributed from post-marketing adverse event 

surveillance for other vaccines, including quadrivalent human papillomavirus vaccine (1.9 per 

100,000 doses), 23-valent pneumococcal polysaccharide vaccine (2.0), yellow fever vaccine 

(3.8), and live attenuated herpes zoster vaccine (4.4)[Arana 2018, Miller 2016, Lindsey 2016, 

Miller 2018]. In one small postlicensure study among children, a retrospective chart review for 

medical visits following administration of JE-VC to 145 children in a travel clinic detected no 

serious adverse events.

When data from the eight RCTs were combined and weighted using a random effects 

model, there was no significant difference in proportions of subjects with serious adverse events 

within 1 month of JE-VC or the comparison vaccines (Figure 3). The risk ratio for serious 

adverse events within 6 to 7 months after the first dose of JE-VC or control vaccine from two 

studies was 0.7, but the result was non-significant (Figure 4). No patterns in the timing or types 

of serious adverse events were identified in the clinical trials or surveillance data.

Adverse events of special interest

The evidence used to evaluate adverse events of special interest (i.e., fever, rash, 

hypersensitivity/urticaria, neurologic, and medically attended adverse events) following JE-VC 

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% (Table 

8). The differences in proportions were likely related to several factors, including the different 

age groups studied, variable locations of study sites (i.e., Europe, United States, Australia, India, 

and the Philippines), differences in study methodology, and the different study population sizes 

with less precision in some smaller studies. In the two studies with the highest fever rates for JEVC recipients, there were no significant differences in fever rates for recipients of the control 

vaccines. Rash within 7 days after either JE-VC dose was reported in 81 (2%) of 3,892 subjects, 

with proportions in individual studies all ≤4% (Table 9). Hypersensitivity or urticaria within 1 

month of either dose was reported in 15 (<1%) of 3,868 JE-VC recipients in six studies, with 

proportions ≤5% in all studies (Table 10). Neurologic adverse events (excluding headache) 

within 1 month of either JE-VC dose were reported in 26 (1%) of 3,668 recipients, and 
JE vaccination EtR document July 16, 2019

Page 7 of 46

proportions were ≤1% in each of the studies (Table 11). Medically attended adverse events 

within 1 month after either dose were reported in 571 (14%) of 3,947 subjects. The proportion of 

subjects with medically attended adverse events 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 (Table 

12). 

In passive post-marketing surveillance, the reported incidence of hypersensitivity was 3.0 

to 4.4 per 100,000 doses distributed (Table 13) and neurologic adverse events (excluding 

headache) was 0.2 to 1.1 per 100,000 doses distributed (Table 14). In a post-marketing adverse 

event surveillance study conducted among military personnel and involving retrospective review 

of medical records, the rate of hypersensitivity reactions was 24.8 per 100,000 doses 

administered and the rate of neurologic events was 22.0 per 100,000 doses administered. These 

much higher rates reflected the different methodology used in the study. An active surveillance 

approach was used and events were identified using ICD-9 codes but complete descriptions of 

events often were lacking, preventing clarification of the nature of some events. In addition, the 

assessment was conducted among military personnel who were often given multiple other 

vaccines concomitantly, including some reactogenic vaccines (e.g., anthrax and smallpox 

vaccines). 

When data from the 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 (Figures 5–9). 

Outcomes for a similar JE vaccine in children

In addition to the studies of JE-VC, we reviewed evidence for serious adverse events and adverse 

events of special interest (fever, rash) in one RCT performed using a similar JE vaccine (JEEV) 

among children aged 1 and 2 years in India [Biological E 2013] (Table 3). The findings were for 

this vaccine were similar to those seen with JE-VC.

Additional information

The results described here include all reported adverse events, whether assessed as related or 

unrelated. Causality often cannot be determined, especially in surveillance data when reported 

events occur among persons who often have received multiple vaccines concurrently. 

Conclusion

On the basis of these adverse event and safety data from clinical trials and surveillance, the work 

group concluded the undesirable anticipated effects were small. 
JE vaccination EtR document July 16, 2019

Page 8 of 46

Criterion 3: Balance of desirable versus undesirable effects

Criterion question: Do the desirable effects outweigh the undesirable effects?

JE-VC is the only JE vaccine licensed and available in the United States. With no alternative 

vaccine, this assessment was focused on comparing the balance of risks and benefits of JE-VC. 

Seroprotection rates were high at both 1 month and 5 to 6 months after the 2-dose primary series 

of JE-VC. JE-VC seroprotection rates were non-inferior to rates for other JE vaccines previously 

available in the United States or used internationally.

Serious adverse events following JE-VC were uncommon within 1 month and 6 to 7 

months of vaccination. In RCTs, there were no significant differences in the proportions of 

subjects with serious adverse events occurring within 1 month or 6 to 7 months in the JE-VC or 

comparison groups. Comparator groups in the largest studies received the commonly used 7-

valent pneumococcal conjugate vaccine (Prevnar) or hepatitis A vaccine (Havrix 720), or 

phosphate buffered saline with 0.1% aluminum hydroxide. For adverse events of special interest 

including fever, rash, hypersensitivity/urticaria, neurologic, and medically attended adverse 

events, there also were no significant differences in the proportions with any of these events 

among JE-VC and comparator vaccine recipients. Post-marketing surveillance data from >1.3 

million doses distributed provided additional reassuring data, with reported rates of serious 

adverse events similar to rates reported in post-marketing surveillance assessments for other 

vaccines used in the United States. No patterns in the timing or types of serious adverse events 

were identified in the clinical trials or surveillance data. Overall, no important safety concerns

were identified. 

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 vaccine effects and the traveler’s 

probable risk based on itinerary and activities, and JE vaccine should be targeted to travelers who 

are at higher risk for disease. 

Criterion 4: Certainty of evidence for outcomes

Criterion question: What is the overall certainty of this evidence for the critical outcomes?

The GRADE approach was followed for assessing the type of evidence [Ahmed 2013]. For the 

benefits considered critical outcomes (i.e., seroprotection at 1 month and 5 to 6 months following 
JE vaccination EtR document July 16, 2019

Page 9 of 46

JE-VC), evidence type is 1 for the RCTs and 3 for observational studies (Table 15). For harms 

considered critical outcomes (i.e., serious adverse events and adverse events of special interest) 

evidence type is 2 for RCTs (downgraded because of inadequate blinding) and 3 for 

observational studies. 

Additional information

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. 

Conclusion

The overall quality of evidence is type 1 (i.e., high) for vaccine effectiveness using 

seroprotection as the endpoint and type 2 (i.e., moderate) for safety (Table 16).

DOMAIN 3. VALUES

Criterion 1: Target population perception of value

Criterion question: Does the target population feel that the desirable effects are large relative 

to undesirable effects?

A population survey was conducted using the Porter Novelli Public Services Styles survey 

mechanism to gather data on perspectives and perceptions of JE disease and the vaccine. Porter 

Novelli maintains a panel of approximately 55,000 persons representative of the noninstitutionalized U.S. population. Members are randomly recruited by mail using probabilitybased sampling by address. Respondents receive cash-equivalent reward points for their 

participation. Porter Novelli regularly conducts surveys covering a variety of topics. For the 

SpringStyles survey conducted from March 21 through April 11, 2018, 10,904 adults were

invited to participate. 

Two JE questions were included in the survey:

1. 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? 

 Possible responses: Very likely/Somewhat likely/Not sure/Somewhat unlikely/Very 

unlikely
JE vaccination EtR document July 16, 2019

Page 10 of 46

2. Which factors were most important in deciding whether you would get the vaccine? (One 

or more factors can be selected) 

 Possible responses: 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

In total, 6,427 (59%) of invited participants completed the survey. Median age was 51 

years (range: 18–94 years) and 2,907 (45%) were male. Races included White, Non-Hispanic 

(n=4,796; 74%), Hispanic (n=675; 11%), Black, Non-Hispanic (n=547; 9%) and other (n=436; 

7%). There were 328 (5%) with no formal education, 1,456 (23%) with up to high school 

education, and 4,643 (72%) with at least some college or higher education. Household income 

was <$20,000 for 5,967 (9%), $25,000 to <$60,000 for 1,890 (29%), and ≥$60,000 for 3,940 

(61%). Data were weighted using eight factors including gender, age, household income, 

race/ethnicity, household size, education, census region, and metro status to match U.S. Current 

Population Survey proportions. 

Responses to the JE questions were provided by 6,384 (99%) of 6,427 participants. Among 

respondents, the likelihood of getting JE vaccine was “very likely” for 1,032 (16%), “somewhat 

likely” for 1,033 (16%), “not sure” for 1,575 (25%), “somewhat unlikely” for 1,088 (17%) and 

“very unlikely” for 1,656 (26%). Overall, there were more unlikely to get vaccinated (43%) 

compared with those likely to get vaccinated (32%). 

Conclusion

The results suggest there is variability in the population perception of whether the potential 

benefits of vaccination outweigh harms. 

Criterion 2: Uncertainty around target population perception of value

Criterion question: Is there important uncertainty about or variability in how much people 

value the main outcomes?

Among the 2,065 respondents “very likely” or “somewhat likely” to get the vaccine, the three 

most important factors for their decision were chance of getting the disease (n=1,439; 70%), the 

chance of dying or being disabled (n=1,209; 59%) and that the vaccine is safe (n=847; 41%). 

Compared with those “very likely” to get the vaccine, those “somewhat likely” to get the vaccine 

more frequently noted vaccine cost (35% versus 10%) and the chance of serious side effects 

(26% versus 16%). Among the 2,744 “very unlikely” or “somewhat unlikely” to get the vaccine, 

the three most important factors were cost of the vaccine (n=1,771; 65%), chance of getting the 

disease (1,281; 47%), and chance of serious side effects (n=756; 28%). Of note, among those 

“very likely” to get the vaccine, 76% selected the chance of getting the disease as an important 
JE vaccination EtR document July 16, 2019

Page 11 of 46

factor in their decision, and among those “very unlikely” to get the vaccine, 41% also selected 

the chance of getting the disease as a factor.

Conclusion

The survey results suggest there are differences in the population regarding perceptions of 

disease risk and the value of vaccination. While some in the population clearly value the 

availability of a vaccine to prevent a rare disease with potentially serious outcomes and no 

specific treatment, others were less likely to place value on it when the vaccine is expensive and, 

while generally 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 

individual perception and tolerance of risk impacting decision-making on vaccination choices. 

DOMAIN 4. ACCEPTABILITY

Criterion: Acceptability to key stakeholders

Criterion question: Is the option acceptable to key stakeholders?

Travel medicine practitioners were considered an important stakeholder group in regards to the 

use of JE vaccine. The work group investigated mechanisms to survey U.S. travel medicine 

practitioners regarding JE vaccine recommendations but none could be identified within the 

timeframe available. Four members of the JE ACIP 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. healthcare providers have included opinions on the 

existing ACIP JE vaccine recommendations [Caldwell 2018, Connor 2017, Burchard 2009, 

Teitelbaum 2009, Shlim 2002]. The opinions on JE vaccination expressed in these publications 

and in meetings range 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. 

The manufacturer of Ixiaro (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 suggested revisions to the JE vaccine 

recommendations and urged broadening of the recommendations to include traveler groups the 

work group considered ill-defined for being at higher risk. The work group reviewed the letters 

and two of the travel medicine practitioners with dissenting opinions on the recommendations 

made presentations to the work group. However, it is unknown how representative their opinions 

are among 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. 
JE vaccination EtR document July 16, 2019

Page 12 of 46

For the public, the proposed recommendations for JE vaccination 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 recommended. Factors that increase risk for JE among travelers are described in the JE 

vaccine recommendations. 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 such as duration of travel. Some travelers who have an insurer that 

covers travel vaccines might prefer a recommendation for vaccination for all travelers. 

Conclusion

While there is some variability among stakeholders opinions on the recommendations, there is 

stakeholder agreement that: 1) There is overall low risk for most travelers; 2) There is a need to 

inform travelers about risks and prevention measures for JE; and 3) Vaccine should be targeted 

to travelers at higher risk. All members of the work group agreed the vaccine recommendations 

were acceptable, and considered that they will probably be acceptable to most stakeholders as 

they are based on individual clinical decision-making with consideration of 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.

DOMAIN 5. RESOURCE USE

Criterion: Resource allocation

Criterion question: Is the option a reasonable and efficient allocation of resources?

JE vaccination is cost-effective or cost-saving for local populations in JE endemic countries [Yin 

2012, Touch 2010, Siraprapasiri 1997]. However, JE vaccination is not expected to be cost 

effective among travelers as there is 1) a substantially lower risk of disease of <1 reported case 

per million U.S. travelers compared with 1–10 cases of JE per 100,000 population per year in 

endemic countries, and 2) use of much lower cost vaccines in most vaccination programs in Asia 

(e.g., a live attenuated JE vaccine manufactured in China and used widely throughout Asia costs 

<1 USD per dose compared with a 2-dose primary series of JE-VC for US travelers which costs 

approximately 600 USD). 

There were several general resource considerations the work group noted 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 
JE vaccination EtR document July 16, 2019

Page 13 of 46

travelers themselves and are not covered under the Vaccines for Children program or by most 

insurance plans. Travelers make individual decisions on vaccination. Mortality and disability 

rates following disease are high, and about one third of participants in the survey described in 

Domain 3 indicated vaccination was probably a reasonable investment. Nonetheless, there are 

opportunity costs in travelers purchasing this vaccine compared with an alternative preventive 

measure. The cost of the vaccine also raises a health equity issue, and could lead to health 

disparities since some higher risk travelers might not be able to afford the vaccine; however, the 

vaccine recommendations cannot address this issue. 

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: 1) Provide perspective on the numbers of travelers needed to be vaccinated and 

associated costs to avert a case; 2) Compare the relative costs of vaccination for travelers with 

different itineraries and disease risk; and 3) Better understand the cost implications of possibly 

expanding the current 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 according to ACIP guidelines [Meltzer 2018]. 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 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.

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 relies upon reported JE cases, to address any uncertainty about the sensitivity 

of surveillance, a sensitivity analysis was conducted increasing the baseline incidence 100 times, 

although it is very unlikely 100 JE cases are occurring among U.S. travelers annually when 

fewer than 1 case is reported. With the incidence 100 times higher, 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. If JE vaccination

recommendations were expanded from Risk group 1 to Risk group 1 and 2, it would cost society 
JE vaccination EtR document July 16, 2019

Page 14 of 46

an additional $1.6 billion to prevent one additional case of JE. Similarly, expanding JE 

vaccination recommendations from Risk groups 1 and 2 to all travelers would cost society an 

additional $14.6 billion to prevent an additional JE case.

Between 1993 and 2017, among 12 JE cases reported in US travelers, 8 (67%) occurred 

among the 20% travelers in the category in which vaccination would have been recommended. 

Among the remainder of travelers for whom itinerary information was known (n=3), all had at 

least some rural exposure which would have warranted discussion of risks, prevention measures, 

and consideration of vaccination [Hills 2017]. 

Conclusion

The work group decided the question of whether the intervention was a reasonable and efficient 

allocation of collective 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 for travelers cannot be considered an efficient use of societal 

resources as it is an expensive vaccine for a low risk disease in this population. Nonetheless, the 

comparative analysis supports the proposed tiered JE vaccine 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.

DOMAIN 6. FEASIBILITY

Criterion: Implementation feasibility

Criterion question: Is the option feasible to implement?

JE vaccination is provided by generalist and specialist healthcare providers. Administration is 

feasible as part of a pre-travel consultation. Barriers to implementation of risk-based vaccine 

recommendations 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 that guides practitioners on factors that 

increase JE risk (Box). Other resources such as the CDC Yellow Book: Health Information for 

International Travel also are readily available [CDC 2017]. 

Conclusion

The work group considered risk-based recommendations were probably feasible to implement. 
JE vaccination EtR document July 16, 2019

Page 15 of 46

CONCLUSIONS AND ADDITIONAL CONSIDERATIONS

Conclusions

Overall, the work group determined the desirable consequences probably outweigh undesirable 

consequences in most settings when risk-based recommendations are appropriately implemented. 

We recommend the intervention for individuals based on clinical decision-making. The proposed 

recommendations are presented below. 

Additional considerations

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, weighing the risks and benefits, the work 

group members considered vaccine recommendations should be targeted to the subset of 

travelers with greater risk of infection.
JE vaccination EtR document July 16, 2019

Page 16 of 46

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 vector-borne 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, longer-term (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.
JE vaccination EtR document July 16, 2019

Page 17 of 46

Box. 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.
JE vaccination EtR document July 16, 2019

Page 18 of 46

REFERENCES

1. ACIP. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) 

for Use of Inactivated Vero Cell Culture-derived Japanese Encephalitis Vaccine in Children. 

2013. Available at: https://www.cdc.gov/vaccines/acip/recs/GRADE/je-child.html. Accessed 

April 11, 2018

2. Ahmed F. U.S. Advisory Committee on Immunization Practices handbook for developing 

evidence-based recommendations. Version 1.2. Atlanta, GA: Centers for Disease Control and 

Prevention (CDC); 2013. Available from 

https://www.cdc.gov/vaccines/acip/recs/grade/downloads/handbook.pdf

3. Arana JE, Harrington T, Cano M, et al. Post-licensure safety monitoring of quadrivalent 

human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 

2009-2015.Vaccine 2018;36:1781–8.

4. Biological E. Unpublished data presented to the ACIP JE Vaccine Work Group by Katrin 

Dubischar-Kastner (Intercell AG, now Valneva Austria GmbH). April 2013.

5. Burchard GD, Caumes E, Connor BA, et al. Expert opinion on vaccination of travelers 

against Japanese encephalitis. J Travel Med 2009;16:204–16.

6. Butler S, Sutter D, Maranich A. Tolerability of Japanese encephalitis vaccine in pediatric 

patients. J Pediatric Infect Dis Soc 2017;6:149–152.

7. Caldwell JP, Chen LH, Hamer DH. Evolving epidemiology of Japanese encephalitis: 

implications for vaccination. Curr Infect Dis Rep 2018;20:30.

8. Campbell GL, Hills SL, Fischer M, e al. Estimated global incidence of Japanese encephalitis: 

a systematic review. Bull World Health Organ 2011;89:766–74

9. CDC. Recommendations for use of a booster dose of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine: Advisory Committee on Immunization Practices, 2011. 

MMWR 2011;60:661–3.

10. CDC. CDC Yellow Book 2018: Health Information for International Travel. New York: 

Oxford University Press; 2017.

11. Central Drugs Standard Control Organization. Product approval information for JEEV 

(Japanese encephalitis purified inactivated vaccine adsorbed). Biological E Limited, 

Hyderabad, India. 2013. 

12. Connor B, Bunn W. The changing epidemiology of Japanese encephalitis and new data: The 

implications for new recommendations for Japanese encephalitis vaccine. Trop Dis Travel 

Med Vaccines 2017;3:14.

13. Cramer JP, Dubischar K, Eder S, et al. Immunogenicity and safety of the inactivated 

Japanese encephalitis vaccine IXIARO® in elderly subjects: Open-label, uncontrolled, multicenter, phase 4 study. Vaccine 2016(a);34:4579–85.

14. Cramer JP, Jelinek T, Paulke-Korinek M, et al. One-year immunogenicity kinetics and safety 
JE vaccination EtR document July 16, 2019

Page 19 of 46

of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese 

encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated 

primary series. J Travel Med 2016(b);23(3). 

15. Dubischar-Kastner K, Eder S, Buerger V, et al. Long-term immunity and immune response 

to a booster dose following vaccination with the inactivated Japanese encephalitis vaccine 

IXIARO, IC51. Vaccine 2010(a);28:5197–202.

16. Dubischar-Kastner K, Kaltenboeck A, Klingler A, et al. Safety analysis of a Vero-cell culture 

derived Japanese encephalitis vaccine, IXIARO® (IC51), in 6 months of follow-up. Vaccine 

2010(b);28:6463–9.

17. Dubischar KL, Kadlecek V, Sablan JB, et al. Immunogenicity of the inactivated Japanese 

encephalitis virus vaccine IXIARO in children from a Japanese encephalitis virus-endemic 

region. Pediatr Infect Dis J 2017(a);36:898–904.

18. Dubischar KL, Kadlecek V, Sablan B et al. Safety of the inactivated Japanese encephalitis 

virus vaccine IXIARO in children: An open-label, randomized, active-controlled, phase 3 

study. Pediatr Infect Dis J 2017(b);36:889–897.

19. Erra EO, Hervius Askling H, Rombo L, et al. A single dose of Vero cell–derived Japanese 

encephalitis (JE) vaccine (IXIARO) effectively boosts immunity in travelers primed with 

mouse brain–derived JE vaccines. Clin Infect Dis 2012;55:825–34.

20. Food and Drug Administration. CFR – Code of Federal Regulations 21CFR312.32. Available 

at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32. 

Accessed October 12, 2018.

21. Fischer M, Lindsey N, Staples JE, Hills S. Japanese encephalitis vaccines: Recommendations 

of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(RR-1):1-

27.

22. Hills S. Epidemiology and risk of Japanese encephalitis in U.S. travelers. Presentation to the 

Advisory Committee on Immunization Practices (ACIP), October 26, 2017, Atlanta, GA. 

Available at 

https://stacks.cdc.gov/gsearch?pid=cdc%3A56588&parentId=cdc%3A56588&ss_publishyea

r=2017&subject_topic=Encephalitis%2C%20Japanese/epidemiology. Accessed July 16, 

2019. 

23. Hombach J, Solomon T, Kurane I, et al. Report on a WHO consultation on immunological 

endpoints for evaluation of new Japanese encephalitis vaccines, WHO, Geneva, 2–3 

September, 2004. Vaccine 2005;23:5205–11.

24. Jelinek T, Burchard GD, Dieckmann S et al. Short-term immunogenicity and safety of an 

accelerated pre-exposure prophylaxis regimen with Japanese encephalitis vaccine in 

combination with a rabies vaccine: A phase III, multicenter, observer-blind study. J Travel 

Med 2015(a);22:225–31.
JE vaccination EtR document July 16, 2019

Page 20 of 46

25. Jelinek T, Cramer JP, Dieckmann S, et al. Evaluation of rabies immunogenicity and 

tolerability following a purified chick embryo cell rabies vaccine administered concomitantly 

with a Japanese encephalitis vaccine. Travel Med Infect Dis 2015(b);13:241–50.

26. Jelinek T, Cromer MA, Cramer JP, et al. Safety and immunogenicity of an inactivated Vero 

cell-derived Japanese encephalitis vaccine (IXIARO®, JESPECT®) in a pediatric population 

in JE non-endemic countries: An uncontrolled, open-label phase 3 study. Travel Med Infect 

Dis 2018;22:18–24. 

27. Kaltenböck A, Dubischar-Kastner K, Eder G, et al. Safety and immunogenicity of 

concomitant vaccination with the cell-culture based Japanese encephalitis vaccine IC51 and 

the hepatitis vaccine HAVRIX1440 in healthy subjects—A single-blind, randomized, 

controlled phase 3 study. Vaccine 2009;27:4483–9.

28. Kaltenböck A, Dubischar-Kastner K, Schuller E, et al. Immunogenicity and safety of 

IXIARO (IC51) in a phase II study in healthy Indian children between 1 and 3 years of age. 

Vaccine 2010;28:834–9.

29. Lee G, Carr W. Updated framework for development of evidence-based recommendations by 

the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 

2018;67:103–8.

30. Lindsey NP, Rabe IB, Miller ER et al. Adverse event reports following yellow fever 

vaccination, 2007–13. Travel Med 2016;23:1–6.

31. Lyons A, Kanesa-thasan N, Kuschner RA, et al. A Phase 2 study of a purified, inactivated 

virus vaccine to prevent Japanese encephalitis. Vaccine 2007;25:3445–53.

32. Markoff L. Points to consider in the development of a surrogate for efficacy of novel 

Japanese encephalitis virus vaccines. Vaccine 2000;18 Suppl 2:26–32.

33. Meltzer M. Comparative analysis of strategies for JE vaccination for U.S. travelers to Asia. 

Presentation to the Advisory Committee on Immunization Practices (ACIP), June 21, 2018, 

Atlanta, GA. Available at https://www.cdc.gov/vaccines/acip/meetings/downloads/slides2018-06/JE-03-Hills-Fischer-508.pdf. Accessed September 20, 2018. 

34. Miller ER, Moro PL, Cano M, et al. Post-licensure safety surveillance of 23-valent 

pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System 

(VAERS), 1990-2013. Vaccine 2016;34:2841–6. 

35. Miller ER, Lewis P, Shimabukuro TT, et al. Post-licensure safety surveillance of zoster 

vaccine live (Zostavax®) in the United States, Vaccine Adverse Event Reporting System 

(VAERS), 2006-2015. Hum Vaccin Immunother 2018; 14:1963–9. 

36. Rabe IB, Miller ER, Fischer M, Hills SL. Adverse events following vaccination with an 

inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 

2009-2012. Vaccine 2015;33:708–12. 

37. Schuller E, Jilma B, Voicu V, et al. Long-term immunogenicity of the new Vero cell-derived, 
JE vaccination EtR document July 16, 2019

Page 21 of 46

inactivated Japanese encephalitis virus vaccine IC51 Six and 12 month results of a 

multicenter follow-up phase 3 study. Vaccine 2008;26:4382–6.

38. Schuller E, Klade CS, Wolfl G, et al. Comparison of a single, high-dose vaccination regimen 

to the standard regimen for the investigational Japanese encephalitis vaccine, IC51: A

randomized, observer-blind, controlled Phase 3 study. Vaccine 2009;27:2188–93.

39. Schuller E, Klingler A, Dubischar-Kastner K, et al. Safety profile of the Vero cell-derived 

Japanese encephalitis virus (JEV) vaccine IXIARO. Vaccine 2011;29:8669–76.

40. Shlim D, Solomon T. Japanese encephalitis vaccine for travelers: Exploring the limits of risk. 

Clin Infect Dis 2002;35:183–8.

41. Siraprapasiri T, Sawaddiwudhipong W, Rojanasuphot S. Cost benefit analysis of Japanese 

encephalitis vaccination program in Thailand. Southeast Asian J Trop Med Public Health 

1997;28:143–8.

42. Tauber E, Kollaritsch H, Korinek M, et al. Safety and immunogenicity of a Vero-cellderived, inactivated Japanese encephalitis vaccine: A non-inferiority, phase III, randomised 

controlled trial. Lancet 2007;370:1847–53.

43. Tauber E, Kollaritsch H, von Sonnenburg F, et al. Randomized, double-blind, placebocontrolled phase 3 trial of the safety and tolerability of IC51, an inactivated Japanese 

encephalitis vaccine. J Infect Dis 2008;198:493–9.

44. Taucher 2017. VLA-401: JE-VC post-marketing adverse event surveillance among U.S. 

military personnel. Presentation to the Advisory Committee on Immunization Practices 

(ACIP), October 26, 2017, Atlanta, GA. Available at: 

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-10/je-03-taucher.pdf

45. Teitelbaum P. Expert opinion on vaccination of travelers against Japanese encephalitis. J 

Travel Med 2009;16:441. 

46. Touch S, Suraratdecha C, Samnang C, et al. A cost-effectiveness analysis of Japanese 

encephalitis vaccine in Cambodia. Vaccine 2010;28:4593–9.

47. Walker WL, Hills SL, Miller ER, et al. Adverse events following vaccination with an 

inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 

2012–2016. Vaccine 2018;36:4369–74.

48. Woolpert T, Staples JE, Faix DJ, et al. Immunogenicity of one dose of Vero cell culturederived Japanese encephalitis (JE) vaccine in adults previously vaccinated with mouse brainderived JE vaccine. Vaccine 2012;30:3090–6.

49. Yin Z, Beeler Asay GR, Zhang L, et al. An economic evaluation of the use of Japanese 

encephalitis vaccine in the expanded program of immunization of Guizhou province, China. 

Vaccine 2012;30:5569–77.
JE vaccination EtR document July 16, 2019

Page 22 of 46

Table 1. Summary of outcome measure ranking and inclusion for use of inactivated Vero cell culture-derived 

JE vaccine (JE-VC) 

Outcome Importance

Data 

available

Include in 

evidence 

profile

Benefits

Vaccine efficacy to prevent JE disease Critical No No

Seroprotection at 1 month after primary series1 Critical Yes Yes

Seroprotection at 6 months after primary series1 Critical Yes Yes

Harms

Serious adverse events2 Critical Yes Yes

Adverse events of special interest3 Critical Yes Yes

Injection site reactions Important -- No

Interference with response to other vaccines Important -- No

JE=Japanese encephalitis

1

Seroprotection defined as a neutralizing antibody titer ≥10 by 50% plaque reduction neutralization test against the 

SA14-14-2 JE virus [Markoff 2000; Hombach 2005].

2

Serious adverse event defined as any of the following outcomes: 1) death, 2) life-threatening adverse event, 3) 

inpatient hospitalization, 4) persistent or significant incapacity or substantial disruption of the ability to conduct 

normal life functions, or 5) congenital anomaly/birth defect [FDA. 21 CFR 312.32].

3

Systemic adverse events evaluated include fever, rash, hypersensitivity/urticaria, neurologic, and medically-attended 

adverse events.
JE vaccination EtR document July 16, 2019

Page 23 of 46

Table 2. Seroprotection at 1 month after a 2-dose primary series of inactivated Vero cell culture-derived JE vaccine (JE-VC) 

administered according to the FDA-approved dose and schedule

PRNT50 titer ≥10

Study Sites Type Age group

JE-VC

Other 

JE vaccine1

No. (%) No. (%)

Kaltenbock 2010 India RCT Children (1–2 yrs) 22/23 (96)2 10/11 (91)

Tauber 2007 U.S./Europe RCT Adults (≥18 yrs) 352/361 (98) 347/364 (95)

Lyons 2007 U.S. RCT Adults (18–49 yrs) 21/22 (95) 14/19 (74)

Biological E 2013 India RCT Adults (18–49 yrs) 53/54 (98) 107/108 (99)

Dubischar 2017(a) Philippines Obs3 Children (2 mos–17 yrs) 384/385 (99)4 -- --

Jelinek 2018 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 62/62 (100) -- --

Schuller 2009 Europe Obs3 Adults (≥18 yrs) 110/113 (97) -- --

Kaltenbock 2009 Europe Obs3 Adults (≥18 yrs) 126/127 (99) -- --

Woolpert 2012 U.S. Obs Adults (≥18 yrs) 88/92 (96) -- --

Erra 20125 Europe Obs Adults (≥18 yrs) 30/31 (97) 13/15 (87)

Jelinek 2015(a) Europe Obs3 Adults (18–65 yrs) 206/206 (100)6 -- --

Cramer 2016(a)7 Europe Obs Adults (64–83 yrs) 128/197 (65) -- --

JE=Japanese encephalitis; PRNT50=50% plaque reduction neutralization test; RCT=Randomized controlled trial; Obs=Observational 

study

1

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross (Korea) [Kaltenbock 2010; Erra 2012], 

inactivated mouse brain-derived JE vaccine (JE-VAX) manufactured by Biken (Japan) [Tauber 2007; Lyons 2007], or inactivated Vero 

cell culture-derived JE vaccine adsorbed (JEEV) manufactured by Biological E (India) [Biological E 2013].

2

Of an additional 21 children aged 1–2 years who received two 0.5mL doses of JE-VC, 20 (95%) were seroprotected at 1 month after 

the second dose.

3

RCT with no comparative immunogenicity data.

4

Of an additional 98 children aged 3–11 years who received two 0.25mL doses of JE-VC, 94 (96%) were seroprotected at 1 month 

after the second dose.

5

Seroprotection measured at 4–8 weeks after final vaccine dose. 

6

Complete data unavailable and estimated from graph. 

7

Seroprotection measured at 42 days after dose 2 of JE-VC.
JE vaccination EtR document July 16, 2019

Page 24 of 46

Figure 1. Pooled risk ratio for seroprotection at 1 month after a 2-dose primary series of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion seroprotected in JE-VC 

group / Proportion seroprotected in other Japanese encephalitis (JE) vaccine group. Risk ratio >1.0 favors JE-VC versus other JE vaccine. 
JE vaccination EtR document July 16, 2019

Page 25 of 46

Table 3. Seroprotection, serious adverse events, and systemic adverse events following receipt of JEEV1,2

JEEV JenceVac3

Outcome No. (%) No. (%)

Seroprotection (PRNT50 titer ≥10) at 1 month after a 2-dose primary series 258/280 (92) 140/142 (99)

Serious adverse events within 1 month of any dose 1/304 (<1) 1/152 (1)

Solicited systemic adverse events within 7 days after any dose

Fever 34/304 (11) 24/152 (16)

Rash 4/304 (1) 2/152 (1)

1

JEEV is manufactured by Biological E (Hyderabad, India) with technology licensed from Intercell (now Valneva Austria GmbH). 

JEEV and JE-VC (IXIARO) use the same virus strain, adjuvant, and virus purification; however, no process comparability studies have 

been completed and it cannot be assumed that the two final vaccine products are the same [Central Drugs Standard Control Organization 

2013].

2

Randomized, controlled, open-label study in India in which children aged 1–2 years received two 0.25mL doses of JEEV (N=304) or 

three doses of JenceVac (N=152). The seroprotection rate in JEEV recipients was non-inferior to that in JenceVac recipients 

[Biological E 2013].

3

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross (Korea).
JE vaccination EtR document July 16, 2019

Page 26 of 46

Table 4. Seroprotection at 5 to 6 months after a 2-dose primary series of inactivated Vero cell culture-derived JE vaccine 

(JE-VC) administered according to the FDA-approved dose and schedule1

PRNT50 titer ≥10

Study Sites Type Age group

JE-VC

Other

JE vaccine2

No. (%) No. (%)

Lyons 2007 U.S. RCT Adults (18–49 yrs) 17/17 (100) 7/13 (54)

Schuller 2008 Europe RCT Adults (≥18 yrs) 172/181 (95) 61/82 (74)

Dubischar 2017(a) Philippines Obs3 Children (2 mos–17 yrs) 358/389 (92)4 -- --

Jelinek 2018 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 31/34 (91) -- --

Dubischar-Kastner 2010(a) Europe Obs Adults (≥18 yrs) 96/116 (83) -- --

Cramer 2016(b) Europe Obs3 Adults (18–65 yrs) 190/204 (93) -- --

JE=Japanese encephalitis; PRNT50=50% plaque reduction neutralization test; RCT=Randomized controlled trial; Obs=Observational 

study

1

For studies in children, follow-up was at 6 months after completing the 2-dose primary series. For studies in adults, follow-up was at 

5 months after completing the 2-dose primary series or 6 months after the first dose.

2

Inactivated mouse brain-derived JE vaccine (JE-VAX) manufactured by Biken (Japan).

3

RCT with no comparative immunogenicity data.

4

Of an additional 96 children aged 3–11 years who received two 0.25mL doses of JE-VC, 74 (77%) were seroprotected at 6 months 

after the second dose.
JE vaccination EtR document July 16, 2019

Page 27 of 46

Figure 2. Pooled risk ratio for seroprotection at 5 to 6 months after a 2-dose primary series of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion seroprotected in JE-VC 

group / Proportion seroprotected in other Japanese encephalitis (JE) vaccine group. Risk ratio >1.0 favors JE-VC versus other JE vaccine.
JE vaccination EtR document July 16, 2019

Page 28 of 46

Table 5. Serious adverse events reported within 1 month after either dose of JE-VC

Study Sites Type Age group

JE-VC

Comparison 

vaccines1

No. (%) No. (%)

Kaltenbock 2010 India RCT Children (1–2 yrs) 0/48 (0) 0/12 (0)

Dubischar 2017(b)2 Philippines RCT Children (2 mos–17 yrs) 6/1411 (<1) 5/458 (1)

Tauber 20073 U.S./Europe RCT Adults (≥18 yrs) 1/428 (<1) 0/435 (0)

Tauber 20084 U.S./Europe/Australia RCT Adults (≥18 yrs) 10/1993 (1) 6/657 (1)

Lyons 2007 U.S. RCT Adults (18–49 yrs) 0/24 (0) 0/21 (0)

Biological E 2013 India RCT Adults (18–49 yrs) 0/54 (0) 0/108 (0)

Kaltenbock 20095 Europe RCT Adults (≥18 yrs) 1/127 (1) 0/65 (0)

Jelinek 2015(a)6 Europe RCT Adults (18-65 yrs) 5/56 (9) 1/220 (<1)

Jelinek 2018 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 0/100 (0) -- --

Schuller 2009 Europe Obs7 Adults (≥18 yrs) 0/125 (0) -- --

Woolpert 2012 U.S. Obs Adults (≥18 yrs) 0/123 (0) -- --

Cramer 2016(a)8 Europe Obs Adults (64-83 yrs) 5/200 (3) -- -- 1

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross (Korea) [Kaltenbock 2010], 7-valent pneumococcal 

conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer Inc.) or hepatitis A vaccine (Havrix 720) manufactured by GSK [Dubischar 

2017b], hepatitis A vaccine (Havrix 1440) manufactured by GSK [Kaltenbock 2009], inactivated mouse brain-derived JE vaccine (JE-VAX) 

manufactured by Biken (Japan) [Tauber 2007; Lyons 2007], phosphate buffered saline with 0.1% aluminum hydroxide [Tauber 2008], inactivated 

Vero cell culture-derived JE vaccine (JEEV) manufactured by Biological E (India) [Biological E 2013], or purified chick embryo cell culture rabies 

vaccine (Rabipur)[Jelinek 2015(a); data presented in Jelinek 2015(b)].

2

Six serious adverse events following JE-VC included two febrile seizures (2 days after dose 2 and 20 days after dose 1), cellulitis (9 days after 

dose 2), gastroenteritis and hematoma (12 days after dose 1), pneumonia (23 days after dose 2), and dengue (24 days after dose 1). Five serious 

adverse events following comparison vaccines included three febrile seizures (9 days and 4 weeks after Havrix and 4 weeks after Prevnar), dyspnea 

(14 days after Havrix), and gastroenteritis (20 days after Havrix).

3

Only serious adverse event following JE-VC was a myocardial infarction at 3 weeks after dose 2.

4

Ten serious adverse events following JE-VC included one each of rectal hemorrhage, chest pain, limb abscess, appendicitis, facial injury, facial 

fracture, ulna fracture, adnexal pain, ovarian cyst, and dermatomyositis. Six serious adverse events after placebo included appendicitis (n=2), acute 

coronary syndrome, proctalgia, urinary calculus, and circulatory collapse.

5

Only serious adverse event following JE-VC was a seizure in a patient with a history of epilepsy.

6

Only one event, considered related to vaccination, described and was eyelid edema and generalized pruritus a few hours after first JE-VC dose.

7

RCT with no comparative safety data. 

8

Adverse events collected until day 42 after dose 2 of JE-VC; the five serious adverse events were not described.
JE vaccination EtR document July 16, 2019

Page 29 of 46

Table 6. Serious adverse events reported within 6 to 7 months after the first dose of JE-VC1

Study Sites Type Age group

JE-VC

Comparison 

vaccines2

No. (%) No. (%)

Dubischar 2017(b)3 Philippines RCT Children (2 mos–17 yrs) 23/1411 (2) 11/458 (2)

Dubischar-Kastner 2010(b)4 U.S./Europe/Australia RCT Adults (≥18 yrs) 38/3558 (1) 16/1092 (1)

Jelinek 20185 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 3/100 (3) -- --

Cramer 2016(a)6 Europe Obs Adults (≥64yrs) 8/200 (4) -- --

1

For studies in children, follow-up was at 7 months after the first dose of vaccine. For studies in adults, follow-up was at 6 months after 

the first dose.

2

7-valent pneumococcal conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer Inc.), hepatitis A vaccine (Havrix 720) 

manufactured by GSK [Dubischar 2017b], or inactivated mouse brain-derived JE vaccine (JE-VAX) manufactured by Biken (Japan) 

or phosphate buffered saline with 0.1% aluminum hydroxide [Dubischar-Kastner 2010 (b)].

3

Serious adverse events reported in 23 JE-VC recipients included pneumonia (n=6), febrile seizures (n=5), dengue (n=2), gastroenteritis 

(n=2), and one each with hematoma, cellulitis, hepatitis A, strabismus, car accident, Kawasaki disease, typhoid, upper respiratory 

infection, urinary tract infection, stillbirth, meningitis, and disseminated intravascular coagulation. One subject had two preferred terms 

reported (gastroenteritis and hematoma) and two subjects had three preferred terms reported (one with meningitis, pneumonia and 

disseminated intravascular coagulation, and one with dengue, pharyngitis, and upper respiratory infection). The stillbirth occurred in a 

subject who became pregnant >4 months after vaccination. One death occurred in a 12 year old male with meningitis, pneumonia, and 

disseminated intravascular coagulation with onset 4 months after he received dose 2 of JE-VC. Serious adverse events in 11 comparison 

vaccine recipients included febrile seizures (n=4), pneumonia (n=3), dengue (n=1), gastroenteritis (n=1), familial periodic paralysis 

(n=1), hyponatremia (n=1), dyspnea (n=1); one subject had two preferred terms reported.

4

The 38 serious adverse events occurring within 6 months following receipt of JE-VC were not delineated. One death occurred in a 70 

year old female with adenocarcinoma of the lung diagnosed 1 month after she received dose 2 of JE-VC.

5

Three serious adverse events in JE-VC recipients included one subject each with diabetes mellitus (3 months after dose 2), dizziness 

(4 months after dose 2), and intentional self-injury; only 92 subjects completed the study but timing of discontinuation is unknown. 

6

The eight serious adverse events were not described
JE vaccination EtR document July 16, 2019

Page 30 of 46

Table 7. Serious adverse events reported through post-marketing surveillance following receipt of JE-VC1

Serious adverse events reported

Study Countries

Reporting 

Period

Doses 

distributed No.

Rate per 100,000 

doses distributed

Schuller 20112 U.S./Europe/Australia Apr 2009–Mar 2010 246,687 43 1.6

Rabe 20152 U.S. May 2009–Apr 2012 275,848 54 1.8

Walker 2018 U.S. May 2012–Apr 2016 802,229 95 1.1

Butler 2017 U.S. Nov 2011–Aug 2014 1456 0 0

1

Adverse events reported through VAERS and other similar passive surveillance systems may or may not be causally related to the 

vaccine.

2 85,583 doses distributed in the United States from May 2009–March 2010 are included in both studies, but there was no overlap in 

the 9 serious adverse events identified in the two studies.

3

One report each of neuritis (9 hours after vaccination), oropharyngeal spasm (day of vaccination), meningismus (1 day after 

vaccination), and iritis (1 day after vaccination). The patient with iritis had also received typhoid vaccine.

4

Includes one report each of an immediate hypersensitivity reaction (day of vaccination), a delayed hypersensitivity reaction (2 days 

after vaccination), appendicitis (5 days after vaccination), myopericarditis (11 days after vaccination), and encephalomyelitis (39 days 

after vaccination). Two serious adverse events occurred after administration of JE-VC alone and three events occurred after 

concomitant administration of JE-VC with other vaccines. 

5

Includes one death that occurred 8 days after JE-VC administration as a result of cardiovascular collapse due to ischemic heart disease. 

The remaining eight events included cardiomyopathy (n=1), myocardial infarct/acute myocarditis (n=1), angina pectoris (n=1), 

systemic febrile reaction (n=1), acute kidney injury/myopathy (n=1), anaphylaxis (n=1), immediate hypersensitivity (15 minutes after 

administration of JE-VC) (n=1), and seizure (n=1). Eight of the serious events occurred following administration of JE-VC 

concomitantly with other vaccines.

6

Doses administered
JE vaccination EtR document July 16, 2019

Page 31 of 46

Figure 3. Pooled risk ratio for serious adverse events within 1 month after either dose of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with serious adverse event 

in JE-VC group / Proportion with serious adverse event in control vaccine group. Risk ratio <1.0 favors JE-VC versus control vaccine.
JE vaccination EtR document July 16, 2019

Page 32 of 46

Figure 4. Pooled risk ratio for serious adverse events within 6 to 7 months after the first dose of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with serious adverse event 

in JE-VC group / Proportion with serious adverse event in control vaccine group. Risk ratio <1.0 favors JE-VC versus control vaccine.
JE vaccination EtR document July 16, 2019

Page 33 of 46

Table 8. Fever reported as a solicited adverse event within 7 days after either dose of JE-VC

Study Sites Type Age group

JE-VC

Comparison 

vaccines1

No. (%) No. (%)

Kaltenbock 20102 India RCT Children (1–2 yrs) 1/48 (2) 1/12 (8)

Dubischar 2017(b)3 Philippines RCT Children (2 mos–17 yrs) 216/1411 (15) 62/458 (14)

Tauber 20084 U.S./Europe/Australia RCT Adults (≥18 yrs) 64/1993 (3) 20/657 (3)

Lyons 20075 U.S. RCT Adults (18–49 yrs) 5/24 (21) 1/21 (5)

Jelinek 20183 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 4/100 (4) -- --

Woolpert 20126 U.S. Obs Adults (≥18 yrs) 6/116 (5) -- --

Cramer 2016(a) Europe Obs Adults (≥64 yrs) 0/200 (0) -- --

1

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross (Korea) [Kaltenbock 2010], 7-valent 

pneumococcal conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer Inc.) or hepatitis A vaccine (Havrix) manufactured by 

GSK [Dubischar 2017(b)], phosphate buffered saline with 0.1% aluminum hydroxide [Tauber 2008], or inactivated mouse brainderived JE vaccine (JE-VAX) manufactured by Biken (Japan) [Lyons 2007].

2

Fever defined as temperature ≥38.0C.

3

Exact numbers not provided so calculated from percentages; fever defined as ≥37.7C.

4

May include unsolicited adverse events of fever that occurred up to 28 days after either dose of JE-VC.

5

Fever defined as ≥37.6C.

6

Fever was collected for 4 days following vaccination and was subjective as reported by the participant.
JE vaccination EtR document July 16, 2019

Page 34 of 46

Table 9. Rash reported as a solicited adverse event within 7 days after either dose of JE-VC

Study Sites Type Age group

JE-VC

Comparison 

vaccines1

No. (%) No. (%)

Kaltenbock 2010 India RCT Children (1–2 yrs) 1/48 (2) 0/12 (0)

Dubischar 2017(b) Philippines RCT Children (2 mos–17 yrs) 48/1411 (3) 15/458 (3)

Tauber 20082 U.S./Europe/Australia RCT Adults (≥18 yrs) 26/1993 (1) 10/657 (2)

Lyons 2007 U.S. RCT Adults (18–49 yrs) 0/24 (0) 1/21 (5)

Jelinek 2018 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 4/100 (4) -- --

Woolpert 20123 U.S. Obs Adults (≥18 yrs) 2/116 (2) -- --

Cramer 2016(a) Europe Obs Adults (≥64 yrs) 0/200 (0) -- --

1

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross [Kaltenbock 2010], 7-valent pneumococcal 

conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer Inc.) or hepatitis A vaccine (Havrix) manufactured by GSK 

[Dubischar 2017b], phosphate buffered saline with 0.1% aluminum hydroxide [Tauber 2008], or inactivated mouse brain-derived JE 

vaccine (JE-VAX) manufactured by Biken (Japan) [Lyons 2007].

2

May include unsolicited adverse events of rash that occurred up to 28 days after either dose of JE-VC.

3

Rash was collected for 4 days following vaccination
JE vaccination EtR document July 16, 2019

Page 35 of 46

Table 10. Hypersensitivity or urticaria1 reported as an unsolicited adverse event within 1 month after either dose of JE-VC

Study Sites Type Age group

JE-VC

Comparison 

vaccines2

No. (%) No. (%)

Kaltenbock 2010 India RCT Children (1–2 yrs) 0/48 (0) 0/12 (0)

Dubischar 2017(b)3 Philippines RCT Children (2 mos–17 yrs) 4/1411 (<1) 0/458 (0)

Tauber 2008 U.S./Europe/Australia RCT Adults (≥18 yrs) 1/1993 (<1) 1/657 (<1)

Jelinek 2018 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 5/100 (5) -- --

Woolpert 2012 U.S. Obs Adults (≥18 yrs) 0/116 (0) -- --

Cramer 2016(a)4 Europe Obs Adults (≥64 yrs) 5/200 (3) -- --

1

Unsolicited adverse events reported within 28 days after vaccination and classified by the study investigator as hypersensitivity or 

urticaria.

2

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross [Kaltenbock 2010], 7-valent pneumococcal 

conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer Inc.) or hepatitis A vaccine (Havrix) manufactured by GSK 

[Dubischar 2017(b)], or phosphate buffered saline with 0.1% aluminum hydroxide [Tauber 2008].

3

Events within 14 days of either dose of JE-VC

4

Adverse events collected until day 42 after dose 2 of JE-VC.
JE vaccination EtR document July 16, 2019

Page 36 of 46

Table 11. Neurologic adverse events1 reported as an unsolicited adverse event within 1 month after either dose of JE-VC

Study Sites Type Age group

JE-VC

Comparison 

vaccines2

No. (%) No. (%)

Kaltenbock 2010 India RCT Children (1–2 yrs) 0/48 (0) 0/12 (0)

Dubischar 2017(b) Philippines RCT Children (2 mos–17 yrs) 0/1411 (0) 0/458 (0)

Tauber 2008 U.S./Europe/Australia RCT Adults (≥18 yrs) 26/1993 (1) 8/657 (1)

Jelinek 2018 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 0/100 (0) -- --

Woolpert 2012 U.S. Obs Adults (≥18 yrs) 0/116 (0) -- --

1

Unsolicited adverse events reported within 28 days after vaccination and classified by the study investigator as nervous system disorder 

other than headaches. No cases of meningitis, encephalitis, acute disseminated encephalomyelitis, or Guillain Barré syndrome were 

reported among JE-VC or comparison vaccine recipients.

2

Inactivated mouse brain-derived JE vaccine (JenceVac) manufactured by Green Cross [Kaltenbock 2010], 7-valent pneumococcal 

conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer, Inc.) or hepatitis A vaccine (Havrix) manufactured by GSK 

[Dubischar 2017b], or phosphate buffered saline with 0.1% aluminum hydroxide [Tauber 2008].
JE vaccination EtR document July 16, 2019

Page 37 of 46

Table 12. Medically attended adverse events within 1 month after either dose of JE-VC

Study Sites Type Age group

JE-VC

Comparison 

vaccines1

No. (%) No. (%)

Dubischar 2017(b)2 Philippines RCT Children (2 mos–17 yrs) 256/1411 (18) 83/458 (18)

Tauber 2008 U.S./Europe/Australia RCT Adults (≥18 yrs) 254/1993 (13) 80/657 (12)

Kaltenbock 2009 Europe RCT Adults (≥18 yrs) 11/127 (9) 11/65 (17)

Jelinek 20183 U.S./Europe/Australia Obs Children (2 mos–17 yrs) 12/100 (12) -- --

Woolpert 2012 U.S. Obs Adults (≥18 yrs) 0/116 (0) -- --

Cramer 2016(a)4 Europe Obs Adults (≥64 yrs) 38/200 (19) -- --

1

7-valent pneumococcal conjugate vaccine (Prevnar) manufactured by Wyeth (now Pfizer Inc.) or hepatitis A vaccine (Havrix 720) 

manufactured by GlaxoSmithKline [Dubischar 2017(b)], phosphate buffered saline with 0.1% aluminum hydroxide [Tauber 2008], or 

hepatitis A vaccine (Havrix 1440) manufactured by GSK [Kaltenbock 2009].

2

Majority of medically attended events in both groups were respiratory, gastrointestinal, or skin infections

3

Medically attended events affecting at least 2 subjects included nasopharyngitis, bronchitis, diarrhea, hematochezia, nausea, upper 

abdominal pain, vomiting, pyrexia, and cough

4

Adverse events collected until day 42 after dose 2 of JE-VC.
JE vaccination EtR document July 16, 2019

Page 38 of 46

Table 13. Hypersensitivity reactions reported through post-marketing surveillance following receipt of JE-VC1

Hypersensitivity reactions

Study Countries

Reporting 

Period

Doses 

distributed No.

Rate per 100,000 

doses distributed

Schuller 20112 U.S./Europe/Australia Apr 2009–Mar 2010 246,687 103 4.1

Rabe 20152 U.S. May 2009–Apr 2012 275,848 124 4.4

Walker 2018 U.S. May 2012–Apr 2016 802,229 245 3.0

Taucher 2017 U.S Jul 2010-May 2011 36,3586 97 24.8

1

Adverse events reported through VAERS and other similar passive surveillance systems may or may not be causally related to the 

vaccine.

2

85,583 doses distributed in the United States from May 2009–March 2010 are included in both studies

3

Includes five reports of rash, and one report each of urticaria, glossodynia, oral hypoaesthesia/swollen tongue, oropharyngeal spasm, 

pruritus. One (oropharyngeal spasm) was classified as a serious adverse event.

4

The 12 events included occurred within 10 days after vaccination. Seven hypersensitivity reactions occurred after administration of 

JE-VC alone and five events occurred after concomitant administration of JE-VC with other vaccines. Two reports were classified as 

serious adverse events.

5

The 24 events included one report of anaphylaxis, seven immediate hypersensitivity events (occurred <2 hours after administration of 

JE-VC), 15 delayed hypersensitivity events, and one hypersensitivity event that occurred within 1 day after administration but lacked 

more specific timing data to classify as immediate or delayed hypersensitivity. Two reports were classified as serious adverse events. 

Fifteen (63%) events, including both serious events, occurred after concomitant administration of JE-VC with other vaccines. 

6

Doses administered

7

Includes four reports of events with ICD-9 codes for delayed hypersensitivity/serum sickness, two reports with codes for anaphylactic 

shock, and three reports with codes for angioedema. For four reports there was concurrent administration of other vaccines. 
JE vaccination EtR document July 16, 2019

Page 39 of 46

Table 14. Neurologic adverse events other than headaches reported through post-marketing surveillance following receipt of 

JE-VC1

Neurologic adverse events

Study Countries

Reporting 

Period

Doses 

distributed No.

Rate per 100,000 

doses distributed

Schuller 20112 U.S./Europe/Australia Apr 2009–Mar 2010 246,687 23 0.8

Rabe 20152 U.S. May 2009–Apr 2012 275,848 34 1.1

Walker 2018 U.S. May 2012–Apr 2016 802,229 25 0.2

Taucher 2017 U.S Jul 2010-May 2011 36,3586 87 22.0

1

Adverse events reported through VAERS and other similar passive surveillance systems may or may not be causally related to the 

vaccine.

2

85,583 doses distributed in the United States from May 2009–March 2010 are included in both studies

3

Includes one report each of neuritis and meningism. 

4

Includes one report of encephalomyelitis at 39 days after vaccination with JE-VC and two reports of seizures on the day of vaccination. 

All subjects had received other vaccines. One of the reports was classified as a serious adverse event.

5

Two reports of seizures, both following concomitant administration of JE-VC with other vaccines. One classified as serious. 

6

Doses administered

7

Includes 6 reports with codes for convulsions and 2 with a code for meningitis. For four reports there was concurrent administration 

of other vaccines.
JE vaccination EtR document July 16, 2019

Page 40 of 46

Figure 5. Pooled risk ratio for fever as a solicited adverse event within 7 days after either dose of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with fever in JE-VC group / 

Proportion with fever in control vaccine group. Risk ratio <1.0 favors JE-VC versus control vaccine.
JE vaccination EtR document July 16, 2019

Page 41 of 46

Figure 6. Pooled risk ratio for rash as a solicited adverse event within 7 days after either dose of inactivated Vero cell culture-derived 

Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with rash in JE-VC group / 

Proportion with rash in control vaccine group. Risk ratio <1.0 favors JE-VC versus control vaccine.
JE vaccination EtR document July 16, 2019

Page 42 of 46

Figure 7. Pooled risk ratio for hypersensitivity or urticaria as an unsolicited adverse event within 1 month after either dose of 

inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with hypersensitivity or 

urticaria in JE-VC group / Proportion with hypersensitivity or urticaria in control vaccine group. Risk ratio <1.0 favors JE-VC versus control 

vaccine.
JE vaccination EtR document July 16, 2019

Page 43 of 46

Figure 8. Pooled risk ratio for neurologic adverse events other than headache within 1 month after either dose of inactivated Vero cell 

culture-derived Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with neurologic adverse 

events in JE-VC group / Proportion with neurologic adverse events in control vaccine group. Risk ratio <1.0 favors JE-VC versus control 

vaccine.
JE vaccination EtR document July 16, 2019

Page 44 of 46

Figure 9. Pooled risk ratio for medically attended adverse events within 1 month after either dose of inactivated Vero cell culturederived Japanese encephalitis vaccine (JE-VC) in randomized controlled trials*

*Pooled risk ratios computed using the random effects model (Mantel-Haenszel method). Risk ratio = Proportion with medically attended 

adverse events in JE-VC group / Proportion with medically attended adverse events in control vaccine group. Risk ratio <1.0 favors JE-VC 

versus control vaccine.
JE vaccination EtR document July 16, 2019

Page 45 of 46

Table 15. Limitations and evidence type for benefits and harms for JE-VC

Outcome

Design 

(# studies) Risk of bias Inconsistency Indirectness Imprecision Other1

Evidence 

type2

Benefits

Seroprotection at 1 month RCT (4) No serious No serious No serious No serious None 1

Obs (8) No serious No serious No serious No serious None 3

Seroprotection at 6 months RCT (2) No serious No serious No serious No serious None 1

Obs (4) No serious No serious No serious No serious None 3

Harms

Serious adverse events RCT (8) Yes3 No serious No serious No serious None 2

Obs (8) No serious No serious No serious No serious None 3

Adverse events of special interest RCT (5) Yes3 No serious No serious No serious None 2

Obs (7) No serious No serious No serious No serious None 3

RCT = Randomized controlled trial with JE-VC; Obs = Observational study, RCT without comparative data for the outcome 

measure, or post-marketing surveillance data.

1

Publication bias, strength of association, dose response, or opposing plausible residual confounding.

2

Evidence type:

1 = RCTs or overwhelming evidence from observational studies

2 = RCTs with important limitations, or exceptionally strong evidence from observational studies

3 = Observational studies, or RCTs with notable limitations

4 = Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations

3

Risk of bias due to inadequate blinding of study participants and personnel.
JE vaccination EtR document July 16, 2019

Page 46 of 46

Table 16. Overall quality of evidence for JE-VC

Outcome

Study 

design 

(# studies) Finding

Evidence

type1,2

Overall quality 

of evidence

Seroprotection at 1 month RCT (4) High (≥95%) at 1 month in all but one study 1 1

Seroprotection at 6 months RCT (2) Maintained (83-100%) at 6 months 1

Serious adverse events RCT (8) Low incidence; similar to comparison vaccines 2 2

Adverse events of special interest RCT (5) Similar to comparison vaccines 2

RCT = Randomized controlled trial.

1

Evidence type:

1 = RCTs or overwhelming evidence from observational studies

2 = RCTs with important limitations, or exceptionally strong evidence from observational studies

3 = Observational studies, or RCTs with notable limitations

4 = Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations

2

Body of evidence for each outcome includes both RCTs and observational studies; the study design that provides higher quality of 

evidence was selected.