Journal of the Pediatric Infectious Diseases Society

ORIGINAL ARTICLE

Tolerability of Japanese Encephalitis Vaccine in Pediatric

Patients
Shauna Butler, Deena Sutter, and Ashley Maranich
Department of Pediatrics, San Antonio Military Medical Center, Joint Base San Antonio, Fort Sam Houston, Texas

Background.  Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus endemic to parts of Asia. Manufacture of JE-VAX,
the mouse brain-derived vaccine against JEV, was discontinued in February 2011. IXIARO, an inactivated cell culture-derived vac-
cine, was approved in 2009 for use in adult patients. Although IXIARO was not licensed for pediatric patients until 2013, our clinic
routinely used this vaccine in at-risk children starting in 2011. The purpose of this study was to review our experience as to the
tolerability of the new IXIARO vaccine in children.
Methods.  We performed a retrospective chart review of all patients less than 18 years of age who received at least 1 dose of
IXIARO in our Family Travel Clinic from November 2011 through August 2014. Subjects' electronic medical records were reviewed
for any documented medical visits within 3 months after vaccination. Each visit was assessed for possible adverse events with rela-
tionship to vaccine administration as determined by the reviewer.
Results.  Ninety-two patients less than 18 years of age received a total of 145 doses of IXIARO between November 2011 and
August 2014. Seven adverse events were documented. Only 1 was deemed to be possibly related. No serious adverse events were
found on chart review.
Conclusions.  Our study reinforces the recent decision to expand IXIARO vaccination to the pediatric population. The expe-
rience in our clinic since vaccine introduction shows it to be overall tolerable when used in routine clinical practice. Practitioners
should feel comfortable recommending vaccination against JEV for any pediatric traveler to an area of risk.
Keywords.  adverse events; IXIARO; Japanese encephalitis vaccine; safety; tolerability.

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus
endemic to parts of Asia and the Pacific Islands [1]. Infection
with JEV is usually asymptomatic, but disease presentations can
range from a mild febrile syndrome with headache to severe
encephalitis and death [2]. Less than 1% of JE virus infections
lead to Japanese encephalitis; however, up to 20%–30% of
affected patients die, whereas 30%–50% of surviving patients
have associated neurologic or psychiatric morbidity [1, 3]. In
endemic areas, JEV is primarily a disease of childhood. With
the widespread implementation of routine JEV vaccination,
rates of pediatric disease in endemic regions have declined.
Despite this, the World Health Organization estimates that over
67 000 cases and 13 600–20 400 deaths occur each year [4].
Inactivated mouse brain-derived JEV vaccines were first
developed in the 1930s, with subsequent purified versions used
in Japan since the 1950s. JE-VAX, a mouse brain-derived vac-
cine, was licensed in the United States in 1992. Adverse effects
Received 25 December 2015; accepted 1 May 2016; published online June 4, 2016.
Correspondence: S. Butler, MD, 3551 Roger Brooke Dr, JBSA, Ft. Sam Houston, TX 78234
(shauna.m.butler.mil@mail.mil).
Journal of the Pediatric Infectious Diseases Society   2017;6(2):149–52
Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious
Diseases Society 2016. This work is written by (a) US Government employee(s) and is in the
public domain in the US.
DOI: 10.1093/jpids/piw029
of this vaccine included severe allergic reactions and neuro-
logic side effects, with severe local reaction reported in 20% of
recipients and 10% with systemic adverse effects [2]. Since the
development of JE-VAX, both live-attenuated and inactivated
cell culture vaccines have been developed against JEV [5]. In
2009, an inactivated Vero cell-derived vaccine, IXIARO, was
approved in the United States for patients 17 years of age and
older [6].
Because IXIARO was not approved in pediatric patients,
the Advisory Committee on Immunization Practices (ACIP)
recommended continued use of JE-VAX for children trav-
eling to risk areas [7]. After existing JE-VAX doses were
exhausted or expired, healthcare providers caring for chil-
dren with travel to high-risk areas were left with the option
of off-label use of IXIARO or enrolling children into ongoing
clinical trials [8]. One pediatric clinical trial in the United
States, Europe, and Australia was initiated in 2011 and has
now been completed, although the results of the study have
not yet been published. Preliminary data from 60 of the 100
planned subjects showed that 66.7% of subjects reported
adverse events, although 60% of those events were mild.
Serious or medically attended adverse events were reported
in only 5% of subjects. The most frequent adverse events
reported within 7 days of vaccination were injection site pain
or tenderness and muscle pain [9].

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 In 2013, IXIARO was approved by the US Food and Drug
Administration for use in children aged 2  months to 17  years.
Early clinical experience of routine use of IXIARO in children has
not yet been described. For those living outside of endemic areas,
travel to such areas in Asia confers risk for contracting JEV [10].
There are currently 19 military installations located in countries
where disease with JEV has been identified including Cambodia,
China, Japan, the Philippines, South Korea, and Vietnam among
others [11]. United States military personnel are often accompa-
nied by family members on overseas tours. Although most will
reside in urban areas, the ACIP recommends immunization of
long-term travelers and expatriates due to the likelihood of rural
travel or sporadic epidemics of JEV. Given the need to provide the
pediatric dependents of these active duty service members appro-
priate protection against JEV, our clinic regularly used IXIARO
off-label for patients under 17 years of age after JE-VAX became
unavailable. Thus, our experience provides an opportunity to
evaluate the tolerability of this vaccine in routine use in a travel
clinic setting. This study was designed to identify characteristics
of patients, compliance with the 2-dose series, and adverse events
for which parents sought medical care.
METHODS
A retrospective review of medical records from the San Antonio
Military Medical Center (SAMMC) Family Travel Clinic was
performed. Subjects aged 2 months to 16 years were included
if they received at least 1 dose of IXIARO between November
1, 2011 and August 31, 2014. This clinic is staffed by pediatric
infectious disease specialists and is the only military facility in
San Antonio that routinely provides travel medicine consul-
tation for pediatric patients and their accompanying family
members. Subjects were identified by reviewing the existing
paper and electronic clinic vaccination records generated at the
time the vaccine was ordered by a provider and given by nurs-
ing staff. The study was approved by the Brooke Army Medical
Center Institutional Review Board.
Identified subjects' electronic medical records were reviewed
for any medical visit within 3 months after vaccination. Military
treatment facilities use the Armed Forces Health Longitudinal
Technology Application (AHLTA) as a universal electronic med-
ical record, which permits review of outpatient records from mil-
itary clinics both in the United States and overseas. In addition,
the US Air Force documents all vaccinations in the Aeromedical
Services Information Management System (ASIMS). Each med-
ical encounter within 3  months of vaccination documented in
AHLTA, to include those outside of our treatment facility, was
recorded utilizing an electronic data collection form. The ASIMS
entries were reviewed for each patient who received their initial
dose of the vaccine in the SAMMC Family Travel Clinic to ensure
capture of patients who received their second dose of the vaccine
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at an Air Force facility overseas that may not have been docu-
mented in AHLTA.
Adverse events were defined according to the International
Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use Good Clinical
Practice guidelines [12]. An adverse event was defined as any
untoward medical occurrence in a patient or clinical inves-
tigation subject administered a pharmaceutical product and
which does not necessarily have a causal relationship with this
treatment. A serious adverse event was defined as any untow-
ard medical occurrence that at any dose results in death, is
life-threatening, requires inpatient hospitalization or pro-
longation of existing hospitalization, results in persistent or
significant disability/incapacity, or is a congenital anomaly/
birth defect. A  single researcher assessed each medical event
with classification as either a possible adverse event or serious
adverse event, with the relationship to vaccine administration
subsequently determined as probably related, possibly related,
unlikely related, or not related.
RESULTS
In the study period, 92 children received 145 doses of IXIARO.
Patient age ranged from 2 months to 16 years (mean = 6 years,
median = 6 years). Thirty-nine subjects (42%) received 1 dose
and 53 subjects (58%) received 2 doses. The majority of subjects
were traveling to Japan (n = 49) or South Korea (n = 34), most
commonly as part of long duration assignments of the military
service member (Supplementary Table  1). Nine subjects were
visiting friends and relatives.
Seven total adverse events (5% of doses) were documented
in the 3  months after vaccination, with 6 adverse events in
the 2- to 23-month age group and 1 adverse event in the
6- to 12-year age group. Three of these adverse events were
directly observed by a clinic provider and 4 were by patient
report only. Only 1 event, a fever that occurred 3 days after
the second dose of the vaccine, was deemed to be possibly
related to vaccine administration (Table 1). This patient also
received an inactivated influenza vaccine on the same day as
the IXIARO dose.
None of the other documented adverse events were seri-
ous nor were they deemed to be related to IXIARO dosing.
These included a fever that developed 36 days after admin-
istration of dose number 2, a fever in the setting of an acute
otitis media infection 27 days after vaccination, a cough that
developed 15 days after vaccination, a fever in the setting of
an upper respiratory infection 79  days after vaccination, a
cough that developed 37  days after administration of dose
number 2, and a cough in the setting of an upper respira-
tory infection 60  days after dosing. None of these children
required hospitalization.
 Table 1.  Summary of IXIARO Administration and Adverse Events During Study Period

Adverse Event
Total no. of Doses = 145 (%Total
Age in Years Doses in Age Group) Any Visit Within 90 Days Observed By Report Only Related Adverse Events
0–1 25 (17) 14 2 4 1
2–5 36 (25) 14 0 0 0
6–12 72 (50) 24 1 0 0
13–16 12 (8) 5 0 0 0
Total 145 57 7 1

DISCUSSION Maximizing compliance with vaccinations and other rec-

ommendations is a significant focus in a travel clinic setting.
Vaccinations have long been the standard of care for preven-
Our clinic provides intensive counseling regarding all travel
tion of disease. Although vaccine safety is often a topic of
risks and the various ways to mitigate those risks, to include
debate, the medical literature clearly supports their routine use.
completion of all recommended vaccines. In addition, walk-in
A  recent review article published in Pediatrics examining the
appointments for subsequent doses are scheduled during the
safety of routine vaccinations in children less than 6  years of
initial visit while allowing families the flexibility of rescheduling
age demonstrated that although evidence was found of serious
this appointment with a single phone call. Despite these efforts
adverse events related to routine vaccinations, these instances
to maximize both education and convenience in a system pro-
were extremely rare [13]. Such large-scale studies are difficult to
viding immunization at no direct financial cost to the patient,
perform for vaccines that are only used in small at-risk groups,
overall compliance with the 2-dose series in our population was
such as the JEV vaccine.
only 58%. As of February 1, 2015, JEV vaccine was required for
Immunization against JEV is recommended for long-term
all active duty Air Force personnel assigned to Japan or Korea, as
travelers to endemic areas to prevent rare but serious disease
well as for those deploying to areas deemed to have an increased
associated with infection. There was a high adverse event profile
risk for Japanese encephalitis. Vaccination was encouraged for
with JE-VAX, and although several newer vaccines for JEV with
all dependents already living in or scheduled to be moving to
better safety profiles had been developed, there was no alter-
Japan or Korea with the active duty member [17]. Despite this
native option for pediatric patients in the United States until
recommendation, compliance with completing the vaccination
IXIARO was approved in 2013. IXIARO has been associated
series has remained poor. As of July 2015, in 9238 Air Force
with a low rate of adverse events in postmarketing data [14].
beneficiaries <17 years of age residing in Korea and Japan, 15%
A  review of the US Vaccine Adverse Event Reporting System
received at least 1 dose and only 9% received 2 doses (R. Hall,
for adults greater than or equal to 17 years of age who received
unpublished data). Further investigation into the specific fac-
IXIARO from May 2009 through April 2012 showed an adverse
tors contributing to this noncompliance is warranted in order
event rate of 15.2 per 100 000 doses administered with a serious
to improve these numbers.
adverse event rate of 1.8 per 100 000 doses administered [15].
Our study was limited by its retrospective nature. We
Although postmarketing data regarding IXIARO in pedi-
focused solely on chart review to determine adverse events, and
atric patients remains limited, the previously mentioned
thus we were unable to identify minor events that caregivers did
clinical trial reported 66.7% of pediatric recipients had 1 or
not believe warranted further evaluation or medical care. The
more adverse events with 5% requiring additional medical
military medical system design, which allows no cost, universal
care. Compared to this single preliminary report, our review
access to care across any treatment facility regardless of geo-
found far less adverse events than expected. As a retrospec-
graphic location, along with a common medical record system
tive study, our review was not designed to detect minor events
makes it likely that we captured most, if not all, visits made by
that did not come to medical attention. However, such events
our subjects in the time window studied.
are unlikely to be of significant concern to prescribing pro-
viders. Overall, this review shows that serious adverse events
CONCLUSIONS
requiring medical care are uncommon and reinforces the tol-
erability of this vaccine in the pediatric age group. Because Our study's confirmation of IXIARO's tolerability in a pediatric
it has been demonstrated that perceived vaccine safety is a population reinforces the recent decision to expand its use into
significant predictor of compliance with JEV vaccine admin- this younger age group. Our data support this recommendation
istration [16], providers, patients, and patient families can be in a real-life clinical practice. Practitioners should feel comfort-
reassured by the results of our review. able universally recommending vaccination against JEV for any

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 pediatric traveler to an area of risk, and they can reassure fami-
lies about the vaccine's tolerability.
Supplementary Data
Supplementary materials are available at Journal of the Pediatric Infectious
Diseases Society online.
Notes
Author contribution.  We certify the following: all individuals who
qualify as authors have been listed; each has participated in the concep-
tion and design of this work, the analysis of the data (when applicable), the
writing and revision of the document, and the approval of the submission
of this version; the document represents valid work; if we used information
derived from another source, we obtained all necessary approval to use the
information and made appropriate acknowledgements in the document,
and each author takes public responsibility for it.
Acknowledgments.  We thank the Information Delivery Division
Defense Health Agency (Air Force Medical Operations Agency) for sup-
plying data on Japanese encephalitis vaccination rates within the Armed
Forces.
Disclaimer.  The view(s) expressed herein are those of the author(s)
and do not reflect the official policy or position of Brooke Army Medical
Center, the US Army Medical Department, the US Army Office of the
Surgeon General, the Department of the Army, the United States Air Force,
Department of Defense or the US Government.
Potential conflicts of interest.  All authors: No reported conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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