The Japanese encephalitis virus (JEV) serocomplex-group consists of mosquito-borne flaviviruses, which include West Nile virus (WNV) and JEV, and both may cause severe encephalitis in humans. WNV has spread rapidly across the United States since its introduction in 1999 and its geographical distribution within the western hemisphere is expected to further expand, whereas, JEV is the most common cause of viral encephalitis in Southeast Asia, China and India. Currently, there is no FDA approved specific treatment for both, though there are attempts to develop vaccines against both viruses.
The flaviviruses West Nile virus (WNV) and Japanese encephalitis virus (JEV) are responsible for a large proportion of viral encephalitis in humans. WNV infects a wide range of avian and mammalian species including humans. WNV has also been shown to be transmitted through blood transfusion, organ transplantation, and breast-feeding. The West Nile encephalitis (WNV) virus covers a large geographical area that includes the south of Europe, Africa, central Asia, and more recently North America. The virus often produces symptoms of meningoencephalitis in Israel, Egypt, India and Pakistan. In Egypt, it is responsible for 3% of all meningitis and aseptic encephalitis. JEV is the single-most important cause of viral encephalitis in Asia, with case fatality rates averaging 30%. JEV is a major problem in South-East Asia, India, and China, where the virus is endemic. In recent years, JEV has spread to other geographic areas such as Australia, and Pakistan, and has thus become an important emerging virus infection in these areas.
Japanese encephalitis (JE) is an inflammatory disease in the central nervous system including the cerebrum, the cerebellum, and the spinal cord. Vaccination against JEV using a mouse brain-derived, inactivated vaccine has been shown to be very effective and has led to a decreased disease burden. However, there are concerns about the immunogenicity and the safety of this vaccine. A live-attenuated and a cell culture-based JEV vaccine that are produced on primary hamster kidney (PHK) cells have been licensed for us in China and have been shown to be safe and effective. However, since PHK is not an approved cell line for production of human vaccine, many countries will not use this JEV vaccine.
JEV infections are regarded as one of the most serious viral causes of encephalitis, with a mortality of up to 30-50% and high percentage of neurological sequelae in survivors[8]. Thus, mass immunization programs against Japanese encephalitis are generally recommended for populations residing in the endemic areas by regional and internal public-health authorities, including WHO. In developed, non-endemic countries, JE is regarded as a rare and exotic disease. But in recent decades, cases reports of infections in tourists and other travelers from non-endemic regions have been reported almost every year. However, vaccine coverage in the population of international travelers at risk is very low, which is not only due to a lack of awareness of the disease on the part of travelers and their travel health advisers, but also because of fear of the potential adverse reactions associated with the currently licensed mouse-brain-derived JEV vaccine JE-VAXR[33].
JE-VAXR is a formalin-inactivated vaccine that is produced form mouse brain and licensed for use in children in Japan and for travelers and military personnel in the United States and some European countries. Requirement for multiple-dose regimen and problems with reactogenicity have complicated its use. An affordable vaccine that elicits durable immunity without the need for frequent boosters is needed for control of JE in developing countries. Mouse-brain derived JEV vaccines have been widely used in various countries in Asia and in some developed countries for decades. In adults immunized in Australia, Europe and North America, serious adverse reactions have been reported, consisting of urticaria or angiooedema and, in some cases, dyspnoea. The occurrence of these adverse reactions various and ranges from less than 1 to 104 per 10000 injections, with anaphylaxis as one of the major causes for concern.
The E protein of flaviviruses is the most immunogenic and suitable for the purpose of vaccine development. The protein E consists of three structural domains (DI, DII and DIII), of which DIII contains predominantly sub-complex, and type-specific epitopes. Several vaccines based on DIII have been shown to be immunogenic and effective under certain conditions.
DIII proteins are highly conserved between several WNV and JEV strains. Approximately WNV DIII shares overall amino acid identity and similarity values with JEV DIII of 81 and 94%, respectively. DIII functions as a receptor binding domain, forming a continuous polypeptide segment that can fold independently. Certainly mutations within DIII have shown to affect virulence and tropism of flaviviruses. rDIII is quite a stable protein and hence can become an attractive antigen. The lack of glycosylation of the protein during bacterial expression in prokaryotic cells most likely would not affect its antigenicity since native DIII is not glycosylated as well. Recombinant DIII of JEV and dengue virus has been shown to be immunogenic and protective in mice challenged with the respective virulent viruses, underlining the suitability of DIII base vaccine formulations against flaviviruses. However, in earlier attempts, it was clear that a relatively high concentration of rDIII was needed for induction of neutralizing antibody responses, indicating that rDIII is poorly immunogenic.
A recent molecular analysis of strain of JEV from Asia classified the strain into four distinct genotypic groups[37]. Because the JEV vaccines that are currently available are only based on one strain of JE, this high level of sequence diversity has led to questions and concern about the cross-protective effect of JEV vaccines against circulating strain JEV[12, 13].
DNA vaccines have several advantages over traditional vaccines such as live attenuated virus and recombinant protein-based vaccines in the context of immune therapy[24-26]. DNA vaccines appear to be very well tolerated in humans. Preclinical safety studies indicate that there was little evidence of plasmid integration and DNA vaccines can also be used for repeat administration as the efficacy of plasmid vectors are not influenced by pre-existing neutralizing antibodies. Furthermore, DNA vaccines appear to be very stable and simple to produce. However, initial studies reported that DNA vaccines exhibited low potency in large animals and humans.
Complicating matters for vaccine development, the RNA genome of flaviviruses have high rates of mutation and therefore the JEV circulating in human populations in Asia and Australia are genetically diverse[35,36], although it is generally conceded that all strains in circulation belong to a single serotype defined by neutralization[37].
There still remains a need for a safe and effective JEV vaccine to protect mammals against multiple JEV and WNV serotypes. There also remains a need for an effective adjuvant that can effectively enhance the immune response of a DNA vaccine.
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