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The recent emergence of Zika virus underscores the need for new strategies for a rapid development of safe flavivirus vaccines. Using another flavivirus (Langat virus [LGTV]) that belongs to the group of tick-borne flaviviruses as a model, we describe a dual strategy for virus attenuation which synergistically accesses the specificity of microRNA (miRNA) genome targeting and the effectiveness of internal ribosome entry site (IRES) insertion. To increase the stability and immunogenicity of bicistronic LGTVs, we developed a novel approach in which the capsid (C) protein gene was relocated into the 3' noncoding region (NCR) and expressed under translational control from an IRES. Engineered bicistronic LGTVs carrying multiple target sequences for brain-specific miRNAs were stable in Vero cells and induced adaptive immunity in mice. Importantly, miRNA-targeted bicistronic LGTVs were not pathogenic for either newborn mice after intracranial inoculation or adult immunocompromised mice (SCID or type I interferon receptor knockout) after intraperitoneal injection. Moreover, bicistronic LGTVs were restricted for replication in tick-derived cells, suggesting an interruption of viral transmission in nature by arthropod vectors. This approach is suitable for reliable attenuation of many flaviviruses and may enable development of live attenuated flavivirus vaccines. IMPORTANCE The recent emergence of Zika virus underscores the need for new strategies for a rapid development of safe flavivirus vaccines. Allied separately attenuating approaches based on (i) microRNA genome targeting and (ii) internal ribosome entry site insertion are not sufficient for relievable attenuation of neurotropic flavivirus pathogenesis. Here, we describe a novel dual strategy that combines the specificity of miRNA-based and the effectiveness of IRES-based attenuating approaches, allowing us to overcome these critical limitations. This developed approach provides a robust platform for reliable attenuation of many flaviviruses and may enable development of live flavivirus vaccines.

Synergistic Internal Ribosome Entry Site/MicroRNA-Based Approach for Flavivirus Attenuation and Live Vaccine Development