- Disease burden and challenges
- JE disease—symptoms, signs, and effects
- Diagnosis and treatment
- Control programs
- JE vaccines
Japanese encephalitis (JE) is a leading cause of disability in Asia. The severity of sequelae, together with the volume of cases, make JE the most important type of viral encephalitis in the world.
Approximately 3 billion people in Asia—including 700 million children—are at risk for JE. JE most commonly affects children between the ages of 1 and 15 years and can also affect adults, especially in areas where the virus is newly introduced. Up to 50,000 cases are reported annually, with an estimated 10,000 to 15,000 deaths. Because of inaccuracies and gaps in reporting, the true number of cases may be much higher.
Although a vaccine has existed since the early 1940s, vaccination has not reached many of the poorest countries in Asia because of problems such as a lack of awareness of the disease, a limited and unstable vaccine supply, the cost of the vaccine, and lack of guidance and programmatic support for immunization. During the 60 years that a vaccine has been available, JE has affected 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 the West Nile, Murray Valley, and St. Louis encephalitis viruses. The virus is transmitted by mosquitoes. In the natural transmission cycle (Figure 1), animals such as pigs and wading birds (including herons and egrets) are the main “amplifying hosts,” or animals in which the virus multiplies to high levels. Humans and horses are “dead-end hosts” (e.g., a mosquito cannot spread the virus from one human to another).
Figure 1. JE transmission cycle
Source: Halstead SB, Jacobson J. Japanese encephalitis vaccines. In: Plotkin S, Orenstein W, Offit P., eds. Vaccines. 5th ed. Philadelphia: Saunders/Elsevier, 2008:322.
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, the Philippines, Russia, Sri Lanka, Thailand, East Timor, Vietnam, North Korea, and South Korea.
Figure 2. Regions reported to have transmission of JE virus
Source: Adapted from Plotkin S, Orenstein O. Vaccines. 4th ed. Philadelphia: WB Saunders, Inc.; 2004:919–958.
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, patients may have seizures or become comatose.
Patients with a fatal infection usually deteriorate rapidly. An average of 30 percent of JE patients die from the disease.
During the convalescence phase, which lasts several weeks, individuals with mild illness may recover completely. Those with severe illness may improve somewhat, but they are frequently left with disabilities.
Among survivors, approximately half to three-quarters will have long-term disabilities. These include intellectual, behavioral, or neurological disabilities such as paralysis or inability to talk. Shadow Lives, a short film produced by PATH, explores the impact of JE on affected children and their families.
Diagnosis of JE is extremely challenging, particularly in low-resource settings. Because the clinical presentation of JE cannot accurately be differentiated from that of other types of encephalitis, laboratory tests need to be done to confirm the diagnosis. Without testing, cases of JE often go undetected, leading to underestimation of the extent of JE disease.
The standard for diagnosing JE is enzyme-linked immunosorbent assay (ELISA) testing of cerebrospinal fluid and blood. Commercial kits to test for JE are only now becoming available. Testing has previously been available only through key sites or individual groups that prepared diagnostic tests and shared them with other sites.
No treatments are available to cure a patient with JE. Antibiotics do not work against viruses, and existing antivirals are not effective against JE. Because there is no effective therapy, care focuses on preventing complications such as 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 is sometimes not available, it can be hard to differentiate the two diseases. Meningitis is frequently caused by bacteria and can be treated effectively with antibiotics. Most encephalitis, by contrast, 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 liquid that surrounds 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.
Human vaccination is the only method that has proved effective for controlling JE disease. Other methods, such as mosquito control and pig control, have had little success.
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. Efforts to control mosquitoes have been tried include spraying, draining mosquito habitats, and 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 difficult and must be repeated frequently (every 10 to 12 days), making it impractical to implement and therefore ineffective.
Bednets also are generally ineffective 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 to control other mosquito-borne diseases such as malaria.
Because 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 5 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 reduce human cases of JE. An average sow produces 18 to 28 piglets a year. Because of the volume and high turnover rates, pig immunization is costly, difficult, and highly time consuming.
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 only after JE vaccine was introduced did the incidence of disease fall dramatically (Figure 3). Experience from Japan also shows the dramatic effect of vaccination (Figure 4).
Figure 3. Evolution of JE control in Thailand
Source: Ministry of Health, Thailand, 1998.
Figure 4. Annual number of JE cases in Japan, 1948 to 1998
Source: Igarashi A. Control of Japanese encephalitis in Japan: immunization of humans and animals, and vector control. Current Topics in Microbiology and Immunology. 2002;267:139–152.
Many experts believe that vaccination of humans is the only realistic tool to control JE. For example:
- International symposia on JE controlheld in 1995, 1998, and 2002 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.
Mouse brain–derived vaccine
Until recently, the most widely available and used 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. This vaccine has several shortcomings, however:
- It is expensive.
- It has a complicated dosing schedule.
- Since the early 1990s, there have been concerns about side effects.
- The supply of the vaccine has never been enough to meet global needs, and now the major manufacturers have stopped production of this vaccine 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, and a single dose might provide life-long protection. Also, more than 200 million doses have been given without any recorded severe side effects. The next step in making this vaccine more widely available will be prequalification by the World Health Organization. Developed and produced in Asia, this vaccine may provide the solution for expanding JE vaccination to all children at risk.
Other new JE vaccines
Several other JE vaccines are in development, but it may be a long time before they are widely available for children. These vaccines include a live, attenuated “chimeric” vaccine that uses a yellow fever vaccine virus strain as its backbone (ChimeriVax-JE, manufactured by Sanofi Pasteur). This vaccine is currently undergoing clinical trials in adults and children to test its safety and immunogenicity.
Clinical trials of an inactivated JE vaccine (Intercell/Novartis/Biological E Ltd.). are also under way in adults and children. This vaccine and other new JE vaccines do not require mouse brains for production.