One of the major safety concerns in the development of WNV vaccines is that antibody-dependent enhancement of infection (ADE) increases the risk of vaccinated individuals becoming infected with related flaviviruses. Here we report the development of a plant-based vaccine candidate that minimizes the risk of Zika (ZIKV) and dengue virus (DENV) ADE infection while providing protective immunity against lethal his WNV-carrying mice. Notably, plant-produced virus-like particles (VLPs) containing WNV coat protein domain III (wDIII) induced both high neutralizing antibody titers and antigen-specific cellular immune responses in mice by lethal challenge of WNV infection. Surprisingly, VLP-induced antibodies did not enhance infection of Fc-γ receptor-expressing K562 cells with ZIKV or ADE with DENV. Therefore, plant-derived wDIII-presenting VLPs may induce protective immunity and induce ADE-susceptible antibodies to minimize concerns that vaccinated individuals may be susceptible to severe infection with her DENV or ZIKV.
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