Abstract
Japanese encephalitis virus (JEV) is the etiological agent of Japanese encephalitis (JE). The most commonly used vaccine used to prevent JE is the live-attenuated strain SA14-14-2, which was generated by serial passage of the wild-type (WT) JEV strain SA14. Two other vaccine candidates, SA14-5-3 and SA14-2-8 were derived from SA14. Both were shown to be attenuated but lacked sufficient immunogenicity to be considered effective vaccines. To better contrast the SA14-14-2 vaccine with its less-immunogenic counterparts, genetic diversity, ribavirin sensitivity, mouse virulence and mouse immunogenicity of the three vaccines were investigated. Next generation sequencing demonstrated that SA14-14-2 was significantly more diverse than both SA14-5-3 and SA14-2-8, and was slightly less diverse than WT SA14. Notably, WT SA14 had unpredictable levels of diversity across its genome whereas SA14-14-2 is highly diverse, but genetic diversity is not random, rather the virus only tolerates variability at certain residues. Using Ribavirin sensitivity in vitro, it was found that SA14-14-2 has a lower fidelity replication complex compared to SA14-5-3 and SA14-2-8. Mouse virulence studies showed that SA14-2-8 was the most virulent of the three vaccine strains while SA14-14-2 had the most favorable combination of safety (virulence) and immunogenicity for all vaccines tested. SA14-14-2 contains genetic diversity and sensitivity to the antiviral Ribavirin similar to WT parent SA14, and this genetic diversity likely explains the (1) differences in genomic sequences reported for SA14-14-2 and (2) the encoding of major attenuation determinants by the viral E protein.
Highlights
Japanese encephalitis virus (JEV) is the prototype member of the JE serogroup within the genus Flavivirus, which contains other mosquito-borne encephalitic viruses such as West Nile and St.Louis encephalitis
The WT strain SA14 used in our studies was found to have three to eleven nucleotide changes encoding two to six amino acid substitutions compared to previously published SA14 strain
It is clear that the mechanism of attenuation of SA14-14-2 is different to that of a previously investigated flavivirus LAV (YFV 17D), in that 17D is characterized by a highly homogenous genotype whereas that of SA14-14-2 is heterogenous
Summary
Japanese encephalitis virus (JEV) is the prototype member of the JE serogroup within the genus Flavivirus, which contains other mosquito-borne encephalitic viruses such as West Nile and St. Louis encephalitis. JEV is the leading cause of epidemic, viral encephalitis in mainland Asia and the Western Pacific causing an estimated 57,000 to 175,000 cases annually with a 20–30% case fatality rate. Thirty to fifty percent of those who survive the acute infection report serious neurological sequelae[1,2]. There are no licensed antivirals to treat the disease making vaccination the primary control strategy. A number of JEV vaccines have been licensed including live attenuated (LAV), chimeric LAVs and inactivated vaccines. The most commonly used in Asia is the LAV strain SA14-14-2, which is highly efficacious showing 90%
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