Pathogenesis of Japanese Encephalitis Virus Infection in a Golden Hamster Model and Evaluation of Flavivirus Cross-Protective Immunity

Abstract

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus endemic to Southeast Asia and surrounding Pacific Islands, and it has most recently emerged in northern Australia. JEV is closely related to West Nile virus (WNV) and St. Louis encephalitis virus (SLEV), both endemic to the United States. In the event that JEV is introduced into the Americas, it will be important to determine whether immunity to WNV or SLEV might afford protection from infection and development of viremia in susceptible hosts. We investigated a hamster model of JEV infection and showed that a large fraction of animals infected with either a genotype I or III isolate of virus developed viremia and encephalitic lesions without clinical signs of disease. Using this model, we showed that prior infection with WNV or SLEV, vaccination using a chimeric WNV vaccine, and passive immunization with anti-JEV immune sera prevented viremia in hamsters challenged with JEV.

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

“…Neuronal apoptotic death was observed prior to perivascular cuffing and microglial infiltration, indicative of direct infection, and neuronal death was a prerequisite for secondary inflammatory responses [193]; however, alterations in BBB permeability were not demonstrated to be associated with neuroinvasion of WNV in this model [111]. In contrast, experimental inoculation of Syrian hamsters with SLEV genotypes I and III resulted in the development of viremia and encephalitic lesions without any outward signs of clinical disease [16].…”

“…The vast majority of studies investigating neuropathogenesis in non-murine models have been performed with Syrian golden hamsters (Mesocricetus auratus) [143,147,159,173,176,184,193]. Although the hamster model has been used extensively for the assessment of immunological correlates of protection [16,95], the study of the efficacy of vaccine [172] and therapeutic monoclonal antibodies and antivirals [110], and the modeling of persistent renal infection and renal shedding of WNV [176], this section will focus solely on the development and use of the hamster model for the study of mechanisms of flaviviral neuropathology and neuroinvasion.…”

An Inactivated Cell Culture Japanese Encephalitis Vaccine (JE-ADVAX) Formulated with Delta Inulin Adjuvant Provides Robust Heterologous Protection against West Nile Encephalitis via Cross-Protective Memory B Cells and Neutralizing Antibody

“…Prompted by the outbreak of WNV encephalitis in the United States, the cross-protective value of JE-VAX against WNV was tested in a small human vaccine trial but failed to induce cross-neutralizing WNV antibodies (17). However, it is still possible that newer-generation JEV vaccines under development, such as inactivated cell culture JEV vaccines containing novel adjuvants (18) or live attenuated vaccines (19,20), could confer cross-protection against WNV (reviewed in reference 15).…”

JE-ADVAX Vaccine Protection against Japanese Encephalitis Virus Mediated by Memory B Cells in the Absence of CD8+T Cells and Pre-Exposure Neutralizing Antibody

“…In the same study, we also found that JE-ADVAX elicited levels of neutralizing antibody against serologically related flaviviruses of medical significance (West Nile and Murray Valley encephalitis viruses) that were indicative of cross-protective immunity, because they exceeded the titers against the homologous virus (JEV) generated by immunization with the gold standard JE-VAX (11). The possible feasibility of cross-protective vaccination against multiple flaviviruses belonging to the JE serocomplex using a single antigen had previously been proposed only for live attenuated JE vaccines (12,13) (reviewed in reference 14).…”