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Japanese encephalitis (ICD 10: A83.0) is an important specific viral encephalitis caused by the Japanese encephalitis virus, a virus of the Flavivirus group. Millions of people, especially those in endemic areas of developing countries in Asia, are at high risk from this infection. Therefore proper management to deal with this virus is essential. There is no specific treatment for Japanese encephalitis virus. Supportive and symptomatic treatments are usually used, which emphasize the importance of prevention in this specific neurological disorder. Vector control or vaccination can be used to prevent the disease. Because the existing Japanese encephalitis vaccine poses some undesirable problems, a new vaccine is needed. The process of developing a new vaccine is briefly discussed.
Acute inflammation of the brain is the hallmark of encephalitis. Encephalitis has several causes, including biological, chemical and physical insults. Infection is an interesting cause of encephalitis. Several infections can lead to encephalitis, among which viral infections are important.5,6 Viral encephalitis can be fatal, and usually presents problems for the physician.5,6 Many viruses causing encephalitis are documented in the medical literature, among which Japanese encephalitis (ICD 10: A83.0) is important. Japanese encephalitis is a specific neurological disturbance that is caused by Japanese encephalitis virus, which is a member of in the Flavivirus group.7
Japanese encephalitis is classified as an important mosquito-borne infection.8–12 Mosquito vectors are Culex spp, especially C. gelidus and C. tritaeniorhynchus.13–15 These vectors usually live in fields and water reservoirs in rural and suburban areas.8–12 The disease can be frequently seen in developing countries in Asia, where suitable breeding sites of the mosquito vectors are abundant. Because of the nature of this vector-borne disease, it remains a focus of public health around the world, especially in tropical regions (Table 1). Because millions of people, especially those in developing countries, are at high risk from this viral infection, proper management of this disease is essential.
Another interesting feature of the transmission cycle of Japanese encephalitis virus is that pigs can harbor the virus and act as an amplifying host.27–31 Because the virus can then be further transmitted by mosquitoes to humans, it can be classified as a pig-related disease. The disease is common in many pig-farming areas. A case presenting classical viral encephalitis symptoms with a history of living in a pig-farming area or having traveled to or through such an area should raise strong suspicions of infection with Japanese encephalitis.31 During disease surveillance, patients should be asked about their history of contact with pigs (pig farming, slaughtering, butchering and transport, and living in a pig-farming area). However, because other hosts, including other mammals and birds, notably water fowl, can amplify the disease, these should also be taken into account during disease surveillance and control. It should be noted that only 1 in 1000 patients who contract the virus from a mosquito bite develop a full-blown illness. However, the mortality from full-blown disease is very high (up to 10% to 20%), and two-thirds of the survivors suffer permanent neurological defects.
The incubation period after infection from a mosquito bite is usually 2 to 4 days. The common, but not specific, presentation is fever, either high or low. Some cases can also present flu-like symptoms. Most recover from the illness without treatment, but sometimes encephalitis develops. Neurological manifestations are usually the starting point for clinical diagnosis. Indeed, in tropical endemic areas, any patient presenting with fever and the neurological signs and symptoms should receive a complete assessment for possible viral encephalitis. Briefly, the common symptoms include alteration of consciousness and seizure. An alteration in EEG is also detectable. Encephalitis is the presumptive diagnosis for such cases. However, because the neurological manifestations of Japanese encephalitis are highly similar to those of other kinds of viral encephalitis, simple clinical observation does not easily differentiate between Japanese encephalitis and the other kinds of encephalitis. A laboratory investigation is invariably necessary.
As already mentioned, diagnosing Japanese encephalitis is not easy. The clinical diagnosis requires further verification by standard medical laboratory investigation. Immunodiagnosis, the basic diagnostic laboratory test, remains the gold standard. However, confirmed diagnosis is usually late in the course of the disease because the patient will usually have full-blown neurological signs and symptoms before the physician in charge becomes aware of the possibility of a diagnosis of Japanese encephalitis.1–4 A few commercial kits for detecting Japanese encephalitis are available. In addition, as a vector-borne disease of poor, developing countries, pharmaceutical companies in the developed world have little interest in the disease.
As member of the Flavivirus group, there is no specific treatment.1–4 All cases need supportive and symptomatic treatment in hospital, which emphasizes the importance of prevention. Intravenous fluid (usually 5% dextrose half strength saline solution) administration at maintenance dose is recommended. Seizures can be treated with an anticonvulsive drug such as phenytoin and phenobarbital.
Prevention can be by either vector control or vaccination. Mosquito control is difficult because of their sheer numbers. Preventing mosquito bites will be more effective than mosquito control, but this is also sometimes very difficult. Vaccination seems to be the most effective alternative preventive. Japanese encephalitis vaccine is available and used in many countries. In clinical practice, the inactivated mouse brain Japanese encephalitis vaccine (BIKEN/JEVAX vaccine) is widely used. Other vaccines are also used in some parts of the world, including the dead Nakayama strain vaccine used in parts of China and the live SA14-14-2 vaccine used in China and some Asian countries, including Thailand.38,39
A three-dosage vaccination schedule is recommended to achieve full immunity in endemic areas in which the virus is endemic. It has been proved that 80% immunogenicity can be achieved after the second vaccination and the generated immunity can last for 1 year. If the third vaccination is completed, immunogenicity can reach 100% and the generated immunity can last for at least 5 years.42–48 However, the risk of excessive repeated booster vaccinations has been noted in the medical literature.
The presently used vaccine is derived from mouse brain and can induce unwanted adverse neurological effects. This is the main reason for the need to find a new vaccine. A vaccine based on cell culture or recombinant technology has the potentioal to reduce unwanted adverse neurological effects.49,50
The presently used vaccination schedule, a three-dosage regimen over a year-long period, poses the problem of loss of follow-up, especially for the third dosage, resulting in an unsuccessful vaccination program. A single-dosage vaccine would overcome this disadvantage, and is the target of new vaccine development. Recently, a new Japanese encephalitis vaccine has been produced. The Japanese encephalitis vaccine IC-51, known as IXIARO, is the newest inactivated virus (strain SA(14)-14-2), which is manufactured in cultured Vero cells and needs only two doses in a vaccination program,51,52 thus solving the problem of a too-long vaccination program.
In certain situations, some specific vaccines cannot be used, for example, in the pregnant. This presents a challenge for vaccinologists.
Affordability in developing countries can limit the effectiveness of vaccines. Although Japanese encephalitis vaccination is included in the national policy of some countries, high cost can still be a barrier. Japanese encephalitis is a disease of the poor and has received very little attention in wealthy countries except Japan.
Because of the problems discussed above, a new vaccine for Japanese encephalitis is needed.53–55 A new vaccine must be more effective, safer and of higher immunogenicity, and without the problems of the presently used vaccine, ie, adverse neurological effects and a long vaccination schedule.
Finding a new epitope is usually the first step in finding a new vaccine. The focus can be the immunogenic protein already used in vaccine production. Despite the protein’s availability, it is still difficult to find a new epitope. It is a time-consuming process if based on classical techniques. Immunomics,56–59 a new branch of bioinformatics, can be useful for this purpose. Since Japanese encephalitis is a viral infection, the favorable epitope should be a specific T cell epitope which has an important role in immunogenicity via the T cell immune system. Alternative T cell epitopes can be useful in developing a multi-epitope vaccine.
Once the desired epitopes have been found, a new vaccine can be developed. Basically, because the vaccine is usually a peptide, advanced protein technology can be helpful in vaccine production. The new Japanese encephalitis vaccine should be a cell culture-based vaccine or a recombinant protein-based vaccine. The use of current genetic recombination technology can help produce the desired peptide in large amounts in a short time. This process also guarantees the purity of the new peptide, which would eliminate the problem of adverse neurological effects with classical Japanese encephalitis vaccine.
The next step in the process is testing the new vaccine’s properties. Although they can be predicted from the vaccine’s expression of visible action or function through in silico gene expression technology, classical in vitro and in vivo testing are still needed to confirm the vaccine’s efficacy and safety.60–65 Several new new peptides have been discovered within the past few years, based on cell culture, recombinant technology or DNA technology, and their effectiveness is being trialed.60–65
The newest vaccine, IXIARO, was also developed by a cell culture technique. Its safety and efficacy have been confirmed, it is newly licensed in both Europe and the US, and is now poised to be licensed in many Asian countries.51,52 Combined vaccines containing a specific vaccine for other viruses are also the focus of current developmental research on Japanese encephalitis vaccine.66,67 ChimeriVax-JE, a chimeric live attenuated vaccine using yellow fever (YF) 17D vaccine as a vector, is the best example.68,69 ChimeriVax-JE is accepted as a cost-effective prophylactic vaccine for Japanese encephalitis and can provide protective levels of neutralizing antibody after a single dose.70 ChimeriVax-JE can also protect against other viruses belonging to the Japanese encephalitis virus serocomplex.71 ChimeriVax-JE vaccine is licensed in some countries, for example, Thailand, China and India.
If the results from classical trials on a new vaccine are favorable, it will be launched on the market after passing the regulatory and registration processes of each country. Finally, post-marketing surveillance, similar to that for any new drug or vaccine, will still be required to complete the process of finding a new vaccine for Japanese encephalitis.
The author discloses no conflicts of interest.