Control of Japanese Encephalitis
Submitting InstitutionsUniversity of Liverpool,
Liverpool School of Tropical Medicine
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Medical Microbiology
Summary of the impact
Globally the most important cause of encephalitis (inflammation and
swelling of the brain) is the mosquito-borne Japanese encephalitis virus
(JEV), which causes an estimated 70,000 cases annually across Asia.
Although vaccines were developed years ago, their uptake in Asian
countries has been hampered through lack of disease burden data, a
consequence of poor surveillance, complicated diagnostics, and
insufficient knowledge about disease outcomes. Research at the University
of Liverpool has addressed each of these areas in turn, to overcome the
roadblocks in vaccine implementation. The University of Liverpool (UoL),
through its leading role on all the relevant WHO committees groups and
meetings, has ensured that its research findings are translated through to
impact by supporting new vaccination programmes across Asia. By 2013
vaccination had begun in 11 new countries, and the vaccine had reached
more than 200 million people. The public health benefits, estimated from a
health economic modelling study, are 854,000 cases and 214,000 deaths
avoided, with an associated saving across Asia of US$ 1.024 billion.
Encephalitis is inflammation of the brain, most often caused by a virus.
Numerically, the most important cause of epidemic encephalitis in the
world is the mosquito-borne Japanese encephalitis virus (JEV), which UoL
led research has shown to cause an estimated 70,000 cases annually across
Asia. The virus's natural cycle is among wading birds and pigs; humans
become infected when bitten by an infected mosquito. Approximately 4
billion people live in areas at risk of Japanese encephalitis (JE).
Although vaccines were developed years ago, their uptake by governments
has been hampered through lack of disease burden data. There were no
reliable methods of diagnosing and tracking the disease, no standard
diagnostic tests, no surveillance systems, and little knowledge about
disease outcomes. Without these it was hard for countries in Asia to
understand the extent of JE, prioritize it, and focus prevention efforts
on the regions and people most needing protection.
At UoL, Professor Tom Solomon, of the Institute of Infection and Global
Health, along with the multidisciplinary Brain Infections Group has been
addressing these challenges. To strengthen surveillance the team
demonstrated (1995-8), with Wellcome Trust funding, the wide range of
clinical presentations the virus can cause, including a previously unknown
poliomyelitis-like illness , and acute symptomatic seizure
presentations. This was achieved through careful clinical descriptive and
epidemiological studies led by Solomon in Vietnam
The UoL has had a leading role in the development by WHO of Surveillance
Standards, Solomon chaired the WHO Group producing the Clinical Care
Guidelines (2005), and then field-tested the Standards, by applying them
to a cohort of patients with suspected central nervous system infections
in Asia to see how many patients with JE were accurately identified .
To improve diagnostics, the UoL worked with colleagues at the University
of Malaysia, Sarawak from 1995-8 to develop and field-test simple rapid
kits for diagnosing JE in the rural field hospitals where it occurs .
Many of these have subsequently been further refined over subsequent
years. These diagnostic kits allow JE to be distinguished from the related
dengue virus, which can also cause neurological disease , and from
other emerging causes of acute central nervous system infection such as
enterovirus 71 . In 2003, the team showed with a randomised controlled
trial that interferon treatment, which was being used increasingly for JE
and related flaviviruses such as West Nile virus, was ineffective ,
thus focusing attention on the importance of disease control through
Approximately 20% of children with JE die, but those that survive with
severe disability are actually a greater socio-economic burden. However
there were no good data on the extent of the problem, making it difficult
for governments to make rational choices on the cost effectiveness of
vaccine implementation programmes. With funding from PATH/Gates Foundation
and MRC, the UoL developed a simple outcome score (2008-10) with
colleagues in India and Malaysia to assess disability after JE , and
using it showed the extent of the problem in survivors.
References to the research
1. Solomon T, Kneen R, Dung NM, Khanh VC, Thuy TTN, Ha
DQ, Day NPJ, Nisalak A, Vaughn DW, White NJ. Poliomyelitis-like illness
due to Japanese encephalitis virus. Lancet. 1998;351:1094-7. Citations: 3
Impact Factor: 39.060
2. Solomon T, Thao TT, Lewthwaite P, Ooi MH,
Kneen R, Dung NM, White N. A cohort study to assess the new WHO Japanese
encephalitis surveillance standards. Bulletin of the World Health
Organization. 2008;86:178-86. Citations: 30 Impact Factor: 5.250
3. Solomon T, Thao LT, Dung NM, Kneen R, Hung NT, Nisalak
A, Vaughn DW, Farrar J, Hien TT, White NJ, Cardosa MJ. Rapid diagnosis of
Japanese encephalitis by using an immunoglobulin M dot enzyme immunoassay.
Journal of Clinical Microbiology. 1998;36:2030-4. Citations: 53 Impact
4. Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LTT,
Raengsakulrach B, Day NPJ, Farrar J, Myint KSA, Nisalak A, White
NJ. Neurological manifestations of dengue infection. Lancet.
2000;355:1053-59. Citations: 218 Impact Factor: 39.060
5. Ooi MH, Wong SC, Podin Y, Akin W, Sel SD, Mohan A, Chieng CH,
Perera D, Clear D, Wong D, Blake E, Cardosa J, Solomon T. Human
enterovirus 71 disease in Sarawak, Malaysia: a prospective clinical,
virological, and molecular epidemiological study. Clinical Infectious
Diseases. 2007;44:646-56. Citations: 64 Impact Factor: 9.374
6. Solomon T, Dung NM, Wills B, Kneen R, Gainsborough M,
Diet TV, Thuy TTN, Loan HT, Khanh VC, Vaughn DW, White NJ, Farrar JJ.
Interferon alfa-2a in Japanese encephalitis: a randomised double-blind
placebo-controlled trial. Lancet. 2003;361:821-6. Citations: 80 Impact
7. Lewthwaite P, Begum A, Ooi MH, Faragher B, Lai BF,
Sandaradura I, Mohan A, Mandhan G, Meharwade P, Subhashini S, Abhishek G,
Penkulinti S, Shankar MV, Ravikumar R, Young C, Cardosa MJ, Ravi
V, Wong SC, Kneen R, Solomon T. Disability after
encephalitis: development and validation of a new outcome score. Bulletin
of the World Health Organization. 2010;88:584-92. Citations: 3 Impact
Key Research Grants
2005 - 2011. Medical Research Council Senior Clinical Fellowship
(T Solomon). Inflammation in Japanese encephalitis. £946,704
2005 - 2008. Wellcome Trust Training Fellowship, (Dr Mong How
Ooi), Enterovirus-71 associated hand foot and mouth disease in Sarawak,
2000 - 2005. Wellcome Trust Career Development Fellowship (T.
Solomon; Grant no. 054682). The Host Immune Response and Strain Virulence
Determinants in Japanese Encephalitis. £498,505, University of Liverpool,
UK, and University of Texas Medical Branch, Galveston, USA.
2005 - 2007. Gates Japanese Encephalitis Control Fellowship
(funded through PATH, Seattle). £206,982
Details of the impact
Solomon's research at the UoL has been pivotal in changing the way a life
threatening illness is understood, diagnosed and prevented across Asia.
Through a partnership with a consortium of Governments, Academic Partners,
and Health agencies, facilitated by a series of meetings ranging from WHO
small working groups to large international conferences, critical
information on the prevalence, diagnostics, treatment and prevention of
Japanese Encephalitis has been disseminated to at risk populations
supported by guidelines and awareness campaigns. For example, the UoL Team
developed the online e-learning tools for Clinical Assessment of Children,
and for using the disease outcome score UoL developed (now known as the
Liverpool Outcome Score). By tackling each of the core issues relating to
the lack of vaccine uptake, the impacts of Solomon's research have been
felt throughout the entire REF period; this has benefited individuals in
at risk areas by massively limiting the number of cases, which has in
turn, benefited governments by significantly reducing the economic burden
of caring for individuals disabled by this devastating disease.
The JE surveillance guidelines that the UoL developed on the back of its
clinical-epidemiological research, have been used across Asia since 2008,
and are helping with disease recognition. In 2012, 18 (75%) of the 24
countries with JE virus transmission risk conducted at least some JE
The UoL rapid diagnostic kit for diagnosing JE was the prototype for kits
developed by the UoL, and others, some of which have gone through to
commercialisation, such as that produced by Venture Technologies,
Singapore, and since 2008, Pan Bio, Australia, and Excyton Diagnostics,
India . Such kits are now widely used across Asia, through the JE
laboratory diagnostic network that the UoL helped establish . This is
playing an essential role in helping recognition of JE so that the disease
burden can be ascertained.
The Liverpool Outcome Score has been disseminated widely through the WHO
and PATH partners, and the biannual WHO JE Regional meetings in Southeast
Asia. It is publicly available (www.path.org/vaccineresources/details.php?i=677)
and is used in many Asian countries to help quantify the disease burden of
In the 1990s, other than China which had developed its own vaccine,
sustained JE vaccination programmes were restricted to wealthier Asian
countries. The UoL work on establishing the disease burden through
improved surveillance, diagnosis and quantification of disability has
played a major role in helping Governments decide on JE vaccination
programmes. The UoL team had a leading role in the JE control partnership
which included other HEIs, Governments across Asia, WHO, and
non-governmental organisations. Together, with US$ 14m funding from the
Bill and Melinda Gates Foundation, the partnership supported vaccine roll
out . The UoL research was disseminated by way of participation in all
the main WHO working groups, committees, meetings and conferences,
advising, for example on vaccine development, and surrogate markers of
vaccine efficacy .
The impact of this research can be examined through the new vaccination
programmes across Asia, which the UoL has catalysed and supported. In the
summer of 2006, 19 million children were immunised in India, and by the
end of 2013, 88 million Indian children had been vaccinated. By 2013
vaccination had begun in 11 countries outside China (eight of them since
2008), and the vaccine had reached more than 200 million people;
approximately 170 million since Jan 2008.
The public health benefits can be estimated from a health economic
modelling study: in a cohort of 100 000 unvaccinated children followed up
from birth to 30 years of age, the model predicted 488 cases and 122
deaths associated with JE . In the absence of JE immunization it was
estimated that the treatment of acute JE would cost US$ 483,672 and that
7,441 Disability Adjusted Life Years (DALYs) would be lost because of JE.
Relative to the no-vaccination strategy, the use of the vaccine would
result in 427 fewer JE cases, 107 fewer deaths, and 6556 fewer DALYs lost.
For the 170 million people vaccinated since 2008, this equates to 660,000
cases and 165,000 deaths avoided. The estimated total direct costs
associated with the treatment of JE and disability during the 30-year
follow-up of 100 000 neonates who were not vaccinated is US$ 738,315, and
the corresponding costs of using the vaccine are US$ 225,859 . The
savings per 100 000 neonates are thus US$ 512 456, or US$ 791m for the 170
million people vaccinated since 2008.
Sources to corroborate the impact
Each source listed below provides evidence for the corresponding numbered
claim made in section 4 (details of the impact).
- Centers for Disease C, Prevention. Japanese encephalitis surveillance
and immunization-- Asia and the Western Pacific, 2012. MMWR Morbidity
and Mortality Weekly Report. 2013;62:658-62.
- Khalakdina A, Shrestha SK, Malla S, Hills S, Thaisomboonsuk B,
Shrestha B, Gibbons RV, Jacobson J. Field evaluation of commercial
immunoglobulin M antibody capture ELISA diagnostic tests for the
detection of Japanese encephalitis virus infection among encephalitis
patients in Nepal. International Journal of Infectious Diseases 2010;14
- World Health Organization. Japanese encephalitis laboratory network -
overview; accessed June 2013 at http://www.wpro.who.int/immunization/laboratory/je/overview/en/index.html.
- Ma J, Jiang L. Outcome of children with Japanese encephalitis and
predictors of outcome in southwestern China. Transactions of the Royal
Society of Tropical Medicine and Hygiene. 2013;107:660-5.
- Maha MS, Moniaga VA, Hills SL, Widjaya A, Sasmito A, Hariati R,
Kupertino Y, Artastra IK, Arifin MZ, Supraptono B, Syarif I, Jacobson
JA, Sedyaningsih ER. Outcome and extent of disability following Japanese
encephalitis in Indonesian children. International Journal of Infectious
- Hills SL, Van Cuong N, Touch S, Mai HH, Soeung SC, Lien TT, Samnang C,
Sovann L, Van Diu P, Lac LD, Heng S, Huong VM, Grundy JJ, Huch C,
Lewthwaite P, Solomon T, Jacobson JA. Disability from Japanese
encephalitis in Cambodia and Viet Nam. Journal of Tropical Pediatrics.
- Solomon T. Control of Japanese encephalitis--within our grasp? New
England Journal of Medicine. 2006;355:869-71.
- Hombach J, Solomon T, Kurane I, Jacobson J, Wood D. Report on a WHO
consultation on immunological endpoints for evaluation of new Japanese
encephalitis vaccines, WHO, Geneva, 2-3 September, 2004. Vaccine.
- Ding D, Kilgore PE, Clemens JD, Wei L, Zhi-Yi X. Cost-effectiveness of
routine immunization to control Japanese encephalitis in Shanghai,
China. Bulletin of the World Health Organization. 2003;81:334-42.