Partial cross-protection between Japanese encephalitis virus genotype I and III in mice.

Jianchao Wei,Lihong Liu,Donghua Shao,Frederik Widén,Xin Wang,Kun Shi,Ke Liu,Yafeng Qiu,Linlin Pang,Zhiyong Ma,Beibei Li,Shuang Guo,Junjie Zhang,Maia A Rabaa

doi:10.1371/journal.pntd.0007601

Abstract

Genotype III (GIII) Japanese encephalitis virus (JEV) predominance has gradually been replaced by genotype I (GI) over the last 20 years in many Asian countries. This genotype shift raises concerns about the protective efficacy of Japanese encephalitis (JE) vaccines, as all of the currently licensed JE vaccines are derived from GIII strains. In this study, we conducted vaccination-challenge protection assays to evaluate the cross-protective efficacy of GI- or GIII-derived vaccines against the challenge of a heterologous genotype using a mouse challenge model. Titration of the neutralizing antibodies elicited by SA14-14-2 live-attenuated JE vaccine (SA14-14-2 vaccine), a GIII-derived vaccine, indicated that the titer of neutralizing antibodies specific to heterologous genotype GI stain was significantly lower than that specific to homologous genotype GIII strain in both pigs and mice immunized with the SA14-14-2 vaccine. Vaccination of mice with SA14-14-2 vaccine or a GIII-inactivated vaccine at high and medium doses completely protected vaccinated mice against challenge with the homologous genotype GIII strains, but failed to provide the vaccinated mice complete protection against the challenge of heterologous genotype GI strains. The protection rates against GI strain challenge were 60%–80%, showing that these vaccines were partially protective against GI strain challenge. Additionally, vaccination of mice with a GI-inactivated vaccine conferred 100% protection against the challenge of homologous genotype GI strains, but 50%–90% protection against the challenge of heterologous genotype GIII strains, showing a reduced protective efficacy of a GI-derived vaccine against GIII strain challenge. Overall, these observations demonstrated a partial cross-protection between GI and GIII strains and suggested a potential need for new JE vaccine strategies, including options like a bivalent vaccine, to control both genotype infection.

Highlights

Japanese encephalitis virus (JEV) is the causative agent of Japanese encephalitis (JE) which is prevalent in ~25 Asia-Pacific countries, with the estimated number of human cases ranging from 50,000 to 175,000 each year [1]
We evaluated the protective efficacy of JE vaccines against the heterologous genotype strain using a mouse challenge model and found a partial cross-protection between genotype I (GI)- or genotype III (GIII)-derived vaccines against the challenge of the heterologous genotype
After inoculation with JEV, BHK-21 were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 2% fetal bovine serum (FBS) at 37 ̊C. 50% lethal dose (LD50) of each JEV strain was tested on three-week-old C57BL/6 strain mice by intraperitoneal inoculation of serially diluted JEV (S1 Table)

Summary

Introduction

Japanese encephalitis virus (JEV) is the causative agent of Japanese encephalitis (JE) which is prevalent in ~25 Asia-Pacific countries, with the estimated number of human cases ranging from 50,000 to 175,000 each year [1]. Approximately 75% of human cases happen in children and adolescents, making JE the leading cause of viral childhood encephalitis in Asia [2]. Pigs and horses are susceptible to JEV infection. JEV genotype III (GIII) was the historically dominant genotype throughout most of Asia but has been gradually replaced by genotype I (GI) over the last 20 years in many Asian countries. GI has replaced GIII as the dominant genotype, co-circulation of GI and GIII viruses is present in many Asian countries [8,9,10]

Methods

Results

Discussion

Conclusion