Abstract
Genotype V (GV) Japanese encephalitis virus (JEV) has emerged in Korea and China since 2009. Recent findings suggest that current Japanese encephalitis (JE) vaccines may reduce the ability to induce neutralizing antibodies against GV JEV compared to other genotypes. This study sought to produce a novel live attenuated JE vaccine with a high efficacy against GV JEV. Genotype I (GI)-GV intertypic recombinant strain rJEV-EXZ0934-M41 (EXZ0934), in which the E region of the GI Mie/41/2002 strain was replaced with that of GV strain XZ0934, was introduced with the same 10 attenuation substitutions in the E region found in the live attenuated JE vaccine strain SA 14-14-2 to produce a novel mutant virus rJEV-EXZ/SA14142m-M41 (EXZ/SA14142m). In addition, another mutant rJEV-EM41/SA14142m-M41 (EM41/SA14142m), which has the same substitutions in the Mie/41/2002, was also produced. The neuroinvasiveness and neurovirulence of the two mutant viruses were significantly reduced in mice. The mutant viruses induced neutralizing antibodies against GV JEV in mice. The growth of EXZ/SA14142m was lower than that of EM41/SA14142m. In mouse challenge tests, a single inoculation with a high dose of the mutants blocked lethal GV JEV infections; however, the protective efficacy of EXZ/SA14142m was weaker than that of EM41/SA14142m in low-dose inoculations. The lower protection potency of EXZ/SA14142m may be ascribed to the reduced growth ability caused by the attenuation mutations.
Highlights
Japanese encephalitis (JE) is a severe neurological disorder caused by infection with a mosquito-borne arbovirus
We previously examined the neutralization efficacy of inactivated GIII Beijing-1derived JE vaccine against the Genotype V (GV) Muar strain in a mouse model; the neutralizing ability of the vaccine against Muar was reduced compared with Genotype I (GI) and GIII strains [19]
There were 40 residues (8%) that differed between the GIII Beijing-1 and GV Muar strains, but fewer than 12 residues (2.4%) and 8 (1.6%) residues were different between the Beijing-1 strain and the GI strains and between the Beijing-1 strain and the GIII strains, respectively [19]. These findings suggest that GV Japanese encephalitis virus (JEV) may be distinct from GI and GIII
Summary
Japanese encephalitis (JE) is a severe neurological disorder caused by infection with a mosquito-borne arbovirus. Japanese encephalitis virus (JEV) is a critical public health problem in Asian countries. JEV is classified into five genotypes (GI, GII, GIII, GIV, and GV) based on genome sequence [5,6]. GIII strains were widely distributed and were most frequently identified in JE endemic areas until the 1990s. The major genotype has begun to change from the GIII to GI strain since the early 1990s in most JE endemic areas [7,8,9]. The reason for the broad shift from GIII to GI remains unclear, current findings suggest that GI strains circulating in recent years replicate more efficiently in birds and mosquitoes [8,10]
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