- Disease burden and challenges
- JE disease—symptoms, signs, and effects
- Diagnosis and treatment
- Control programs
- JE vaccines
Disease burden and challenges
Japanese encephalitis (JE) is the leading cause of viral neurological disease and disability in Asia. The severity of sequelae, together with the volume of cases, make JE the most important cause of viral encephalitis in the world.
Approximately 3 billion people in Asia—including 700 million children—live in areas at risk for JE. JE most commonly infects children between the ages of 1 and 15 years and can also infect adults, especially in areas where the virus is newly introduced. Up to 50,000 cases are reported annually and cause an estimated 10,000 to 15,000 deaths. This figure is believed to represent only a small proportion of the cases that actually occur, due to inaccuracies and gaps in reporting of cases.
A vaccine has existed since the early 1940s, but problems including lack of awareness of the disease, a limited and unstable vaccine supply, the expense of vaccine, and lack of guidance and programmatic support for immunization means vaccination has not reached many of the poorest countries in Asia. During the 60 years that a vaccine has been available, JE has infected an estimated 10.5 million children, resulting in more than 3 million deaths and more than 4 million children living with long-term disabilities.
About the virus
JE is caused by an arbovirus in the Flaviviridae family that is similar to West Nile, Murray Valley, and St. Louis encephalitis viruses. It is transmitted by mosquitoes. The natural transmission cycle of JE virus is illustrated below (Figure 1). Animals like pigs and wading birds (such as herons or egrets) are the main “amplifying hosts,” or animals, in which the virus multiplies to high levels. Humans and horses are “dead-end hosts” (i.e., a mosquito cannot spread the virus from one human to another).
Figure 1. JE transmission cycle
Distribution
JE is widespread across Asia and parts of the western Pacific region. It has spread over the past 25 years, most recently onto mainland Australia in 1998 (Figure 2). Countries affected by JE include Bangladesh, Bhutan, Cambodia, China, India, Indonesia, Japan, Laos, Malaysia, Myanmar, Nepal, Papua New Guinea, Philippines, Russia, Sri Lanka, Thailand, East Timor, Vietnam, North Korea, South Korea, and islands in the Torres Strait of Australia.
Figure 2. Regions reported to have transmission of JE virus
Source: Adapted from Plotkin S, Orenstein O. Vaccines, 4th edition, WB Saunders, Inc., Philadelphia, PA, 2004;919-958.
JE disease—symptoms, signs, and effects
Clinical symptoms and signs
The JE virus causes encephalitis, or infection and swelling of the brain. JE illness usually begins just like the flu with high fever, chills, tiredness, severe headache, nausea, and vomiting. A person may show abnormal behavior or become confused and agitated or a child may be unusually sleepy. As the illness progresses, seizures may occur and often patients become comatose.
Fatal cases usually deteriorate rapidly. Fatality rates vary, but on average 30 percent of JE patients die from the disease.
During the convalescence phase, which lasts several weeks, individuals with mild cases may recover completely. Those with severe cases may improve somewhat, but they are frequently left with disabilities.
Long-term effects
Among survivors, approximately half to three quarters will have long-term disabilities, including intellectual, behavioral, or neurological disabilities, like paralysis or inability to talk. The greater number of people who survive JE, the greater number of patients left with disabilities. Shadow Lives, a film produced by PATH, explores the impact of JE on affected children and their families.
Diagnosis and treatment
Diagnostic methods
Diagnosis of JE is extremely challenging, particularly in low-resource settings. Because the clinical presentation of JE cannot accurately be differentiated from other causes of encephalitis, laboratory tests need to be done to confirm the diagnosis. Without testing of patients, cases of JE are often not detected and the extent of JE disease is often not realized.
The standard for diagnosing JE in practice is enzyme-linked immunosorbent assay (ELISA) testing of cerebrospinal fluid and blood. It is only now that commercial kits to test for JE are becoming available. Prior to that, testing was only available through key sites or individual groups that prepared diagnostic tests and shared them with other sites.
Treatment
Once a person gets sick with JE, there is no treatment that can be used to cure the patient.
Antibiotics do not work against viruses, and no antivirals are effective. Because there is no specific therapy for JE, attention is given to prevention of complications. Care of patients is focused on steps like preventing seizures and decreasing brain swelling, which can reduce the number of deaths and the risk of subsequent disabilities.
Confusion with meningitis
Because the symptoms of encephalitis (infection and swelling of the brain) are similar to those of meningitis (inflammation of the meninges, the membranes that cover the brain and spinal cord), and because laboratory diagnosis sometimes is not available in the developing world, it can be hard to differentiate the two diseases. Meningitis frequently is caused by bacteria and therefore it is treatable with antibiotics. Most encephalitis is viral and not treatable with antibiotics. For this reason, a lumbar puncture is recommended to collect and test cerebrospinal fluid for diagnosis. Cerebrospinal fluid is the fluid that is around the spinal cord, and it is collected by inserting a needle into the back. This is a safe, common, and routine procedure practiced around the world. It is an important test to help differentiate bacterial infections, which are treatable with antibiotics, from those more likely to be viral.
Control programs
Human vaccination is the only method that has proven effective in control of JE disease. Other methods, such as mosquito control and pig control, have been used but with little success.
Mosquito control
JE is transmitted by a mosquito, most commonly the species Culex tritaeniorhynchus. These mosquitoes lay their eggs in quiet pools such as rice-paddy fields or drainage ditches. Mosquito control efforts that have been tried include spraying, draining mosquito habitats, or using bednets.
Spraying is both resource-intensive and expensive. To be effective, all mosquito habitats must be covered, including rice-paddy fields, puddles, and drainage areas. This is not only difficult, but must be repeated very frequently (every 10 to 12 days), making it impractical to implement and therefore ineffective.
Bednets also are not effective because the Culex mosquito bites in the early twilight hours before most people go to bed. Though they are not effective against JE, bednets can help control other mosquito-borne diseases like malaria.
Pig control
As the pig is one of the main animals in which the JE virus multiplies, strategies to control JE sometimes have been directed at controlling pigs by segregation, slaughtering, and vaccination. Pigs must be segregated at least five kilometers from humans (the flying radius of the mosquito). This is not practical in most developing-world settings. Slaughtering also has a high economic impact and affects many families’ ability to make a living.
Pig vaccination has not been shown to reliably impact human cases of JE. An average sow produces 18 to 28 piglets a year; due to the volume and high turnover rates, pig immunization is costly, difficult, and highly time consuming.
Human vaccination
Human vaccination has been the only reliable tool to control JE. Thailand, for example, for many years attempted to control mosquitoes and to respond to outbreaks, but it was not until JE vaccine was introduced into the country that the incidence of JE fell dramatically (Figure 3). Experience from Japan also shows the dramatic effect vaccination can have (Figure 4).
Figure 3. Evolution of JE control in Thailand
Figure 4. Annual number of JE cases in Japan, 1948 to 1998
Numerous experts support the conclusion that the vaccination of humans is the only realistic tool to control JE. For example:
- International symposia on JE control held in 1995, 1998, and 2002 have recommended JE immunization in all endemic areas to control the disease.
- In a 2006 update to its position paper on JE, the World Health Organization recommended the use of vaccine for JE control where the vaccine is affordable.
Presently vaccination is being used in varying degrees in countries with JE. India and Nepal recently introduced JE vaccine through large-scale campaigns and routine immunization. However, many countries are without any JE vaccination at all: Bangladesh, Bhutan, Cambodia, East Timor, Indonesia, North Korea, Laos, Myanmar, Papua New Guinea, and Philippines.
JE vaccines
Mouse brain-derived vaccine
Until recently, the most widely used and available JE vaccine has been a mouse brain-derived, inactivated vaccine. It has been produced by several countries, including Japan, South Korea, Thailand, India, and Vietnam and has been used in many more. However, there are reasons the mouse brain-derived vaccine is not the answer to JE vaccine needs in Asia:
- It is expensive.
- It has a complicated dosing schedule.
- Since the early 1990s, there have been concerns about side effects from this vaccine.
- The limited supply of the vaccine has never been enough for global needs, and now the major manufacturers of this vaccine have stopped production in anticipation of improved vaccines becoming available (see below).
Live, attenuated SA 14–14–2 vaccine
There is now another option for JE vaccination, the live, attenuated SA 14–14–2 vaccine. This vaccine was developed in China and has been used there since 1988. Outside China, it has been licensed and used in South Korea, Nepal, Sri Lanka, and Thailand. The vaccine is very effective and inexpensive. More than 200 million doses have been given without any recorded severe side effects. It also appears feasible that a single dose of vaccine will provide life-long protection.
The next step in making this vaccine more widely available will be prequalification of the vaccine by the World Health Organization. It is exciting that this vaccine, developed and produced in Asia, may provide the solution for expanding JE vaccination to protect all the children of Asia.
Other new JE vaccines
Several other JE vaccines are in development, but there will be a longer timeline until they are widely available for children. These vaccines include a live, attenuated “chimeric” vaccine which uses a yellow fever vaccine virus strain as its backbone (ChimeriVax-JE, manufactured by Sanofi Pasteur). It is currently undergoing clinical trials in adults and children to test its safety and immunogenicity.
Clinical trials also are underway in adults and children for an inactivated JE vaccine (Intercell/Novartis/Biological E Ltd.). This vaccine does not require mouse brains for production.
Kill or Cure? Japanese Encephalitis
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