Background
Japanese Encephalitis (JE) is a mosquito-borne disease
of particular concern in Asia. IVI has received support
from Korea International Cooperation Agency (KOICA), and
the Bill and Melinda Gates Children's Vaccine Program
at PATH for a multi-country, multi-disciplinary program
addressing JE and JE vaccines.
Despite the availability of JE vaccines, JE remains a
major health problem. Approximately three billion people
(50 percent of the world's population) live in JE-endemic
regions. From these regions, national surveillance systems
reported 25,000-50,000 JE cases annually. However, because
of poor quality surveillance, such numbers likely under-estimate
the true burden of disease. In many Asian countries, the
disease burden due to JE remains unknown.
The clinical signs and symptoms of JE are typically severe,
with a 10 - 30 percent fatality rate. Long-term post-JE
illness-associated disability may be the most important
component of JE disease burden. Studies of JE-associated
disability, based on short-term follow-up of patients,
have demonstrated neurologic sequelae in 25 - 75 percent
of survivors following acute episodes of JE. In developing
countries, children 15 years old or younger are typically
at greatest risk of getting the disease, with incidence
peaking at three to nine or ten years of age.
Several JE vaccines are now available and used in Asian
countries (Table 1).
Table 1: Summary of JE vaccines currently available
or under development.
|
JE
VaccineJE Vaccine
|
Derivation
|
Estimated
Efficacy
(percent)
|
Countries
where Used
|
|
Inactivated
|
Mouse
brain tissue
|
80-91
|
Japan,
Korea, Thailand, Vietnam
|
|
Inactivated
|
Primary
hamster kidney cell
|
76-95
|
China
|
|
Live,
attenuated
(SA14-14-2 strain)
|
Baby
hamster kidney cell
|
96-100
|
China
|
|
Inactivated
|
Vero
cell line
|
Not Available
|
China
|
|
Genetically
derived
|
Yellow
fever/JE virus
(Y17D/SA14-14-2) chimeric
|
Being
Evaluated
|
Not
used
|
|
JE vaccine is provided as part of the routine childhood
immunization programs in China, Japan, Korea, and Thailand.
However, for other JE-endemic countries, the vaccine is
used on a limited basis, because of uncertainty of the
disease incidence, relatively high vaccine costs, and
a lack of knowledge of the severe morbidity and economic
impact associated with JE illness and post-JE disability.
Additional concerns have also arisen regarding adverse
events following immunization with the inactivated, mouse-brain
derived vaccines, although such adverse events have not
been systematically documented.
Goals
The long-term goal of the JE program is to accelerate
the development and introduction of existing and new JE
vaccines to assist in preventing this devastating disease
in JE-endemic countries. The immediate goal is to facilitate
and evaluate the incorporation of existing JE vaccines
into public health programs of JE-endemic countries. The
program focuses on Indonesia, Vietnam and China.
Projects
Prospective surveillance of Japanese encephalitis
Because of the uncertain disease burden in Indonesia,
The IVI has undertaken two JE surveillance studies in
the country. The first took place in Bali from July 2001
to December 2003. Unlike most of Indonesia, the population
of Bali is mainly Hindu and the raising of pigs - which
serve as reservoirs for the JE virus and thus as an amplifying
host - is common. Unlike more limited studies conducted
on the island in the past, the IVI study found a relatively
high JE incidence rate in children under 10 years old
age (adjusted rate of 8.2/100,000). The results of the
study, published in the journal, BMC Medicine in
2006 (Kari K, Lui W, Gautama K, et al. A hospital-based
surveillance for Japanese encephalitis in Bali, Indonesia.
BMC Medicine 2006; 4:8) have prompted calls from the Balinese
government for a JE vaccination program for children on
the island. The study was also cited in Pediatrica
Indonesiana in 2006 (Komang Kari, Wei Liu, IMade Kompiang
Gautautama, I Ketut Subrata, and Zhi-Yi Xu. Clincal profiles
and some associated factors of Japanese encephalitis in
Bali. Pediatrica Indonesiana. 2006; 46:13).
Following the Bali study, the program conducted hospital-based
surveillance in two predominately Muslim areas of Java
- Jakarta and Semarang - to determine if JE is limited
to mainly non-Muslim areas of the country, such as Bali,
or if it is more widespread. The study, which is currently
underway, has found a number of cases of acute viral
encephalitis or meningitis, but none have, to date,
been confirmed as JE.
Prospective JE surveillance is also taking place in
HaTay province, Vietnam, as part of a vaccination demonstration
project (see below).
By documenting the magnitude of JE disease burden in
certain areas that do not routinely report JE disease,
the results of these studies may have a significant
impact on policy decision-making regarding JE immunization
in Indonesia and elsewhere in Asia.
Studies of the long-term effectiveness and impact
of JE immunization strategies
The IVI is working with the Vietnamese government to
evaluate different JE vaccination strategies, in order
to inform decision-making regarding its current JE immunization
program and possible expansion. The Vietnam EPI program
provides JE vaccination to children through yearly campaigns
in high-incidence districts, mainly in the northern
part of the country. The JE program is conducting a
case-control study to determine the long-term effectiveness
of the JE vaccine delivered through the EPI program,
which provides three pediatric doses of the locally-produced
mouse-brain vaccine to 2-5 year olds in the target districts.
The program has also conducted a "model" JE
demonstration project in Ha Tay province, during which
more than 62,000 children were vaccinated in 2004/05.
The "model" program involved a larger age
cohort (1-10 year olds) and a different vaccine regimen
(pediatric doses for children under three and adult
doses for 3-10 year olds). The JE program is currently
analyzing the impact of this "model" vaccination
program on disease incidence in the province, relative
to that of the EPI JE program, as well as its cost and
cost-effectiveness.
Assessment of post-JE illness-associated disability
Comparative observations in a control group are essential
to evaluate the proportion of cases with psychomotor
retardation, fine motor deficits, and behavioral disorders.
The JE program conducted a study of long-term JE disability
using a controlled cohort design method in Shanghai,
China, where the diagnostic specificity of routine immunodiagnostic
tests for JE is high. JE cases previously diagnosed
from 1973 through 1994 were assembled from the Children's
Hospital and the Pediatric Hospital of Shanghai. All
subjects were examined by neurologists with a battery
of standardized neurobiological tests. The results of
this study were published in the Chinese Journal
of Clinical Neurology in 2001 (Hong Zheng, Ding
Ding, Wang Bei and Xu Zhi-Yi. A retrospective study
of sequelae after Japanese encephalitis. Chinese Journal
of Clinical Neurology. 2001; 9(2):172), and in the
Journal of Neurological Diseases and Hygiene in
2002 (Ding Ding, Hong Zheng, Wang Bei, Zhou Feng, Huang
Mou-sheng, Cao jun, Guo qi-hao, Liu Wei, Sheng Bin,
Tao Fanbiao and Xu Zhi-Yi: Long term disability after
acute illness of Japanese encephalitis. Journal of Neurological
Diseases and Hygiene. 2002; 2(5):259).
Cost-effectiveness analysis of JE immunization programs
There are few pharmaco-economic studies of JE vaccine,
and thus governments of JE-endemic countries have given
little consideration to the economics of immunization
when making public health decisions about control of
JE. The JE Program is conducting cost-effectiveness
analyses to guide the introduction of JE vaccine into
the routine immunization programs of JE-endemic countries.
For cost-effectiveness analyses, the Program uses routinely
available data as well as data on JE disease burden,
disability, treatment costs, and vaccine protection
collected in other components of the Program. The analyses
focus on current national JE immunization programs in
China, Thailand, and Vietnam. These analyses take into
account the costs of JE immunization, treatment savings
for care of JE patients and post-JE sequelae, work time
lost, and person-years lost following death. The results
of a study in China were published in the
Bulletin of the World Health Organization in
2003 (Ding D, Kilgore PE, Clemens JD, Lui W, Xu ZY.
Cost-effectiveness of routine immunization to control
Japanese encephalitis in Shanghai, China. Bull World
Health Organ. 2003/May; 81(5): 334-42).
Assessment of JE immunization policy
The IVI's JE program has conducted analyses of JE immunization
policy in China and Vietnam, in the aim of informing
future policy decisions and policy modifications. The
studies, consisting of document reviews and interviews
with key informants, examine the impact, costs and financing
of JE immunization programs, as well as local JE vaccine
production issues. Results of the policy analysis in
China were published in Vaccine in 2006 (*Liu
W, Clemens JD, Yang JY, Xu ZY, Immunization against
Japanese encephalitis in China: a policy analysis; Vaccine
2006; 24: 5178-5182).
The program will also be conducting an economic analysis
of different JE immunization program options for Vietnam,
to assist the country as it expands its JE control program.
Last updated: July 2006
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