Knowledge-based mitigation of the environmental risk of Orthoflavivirus live-attenuated vaccines by targeting viral encoded determinants for the mosquito attenuated phenotype.

Many mosquito-borne orthoflaviviruses are important public health problems. Vaccination is critical for disease control because there is no licensed antiviral therapy for any orthoflavivirus. Live-attenuated vaccines (LAVs) that elicit protective immunity with one single immunization are the most effective tool for disease control, as shown by the success of implementing yellow fever (YF) 17D and Japanese encephalitis (JE) SA14-14-2 vaccines in routine immunization programs within endemic regions. Importantly, neither the YFV 17D strain nor the JEV SA14-14-2 LAV strain are mosquito-competent, meaning that neither vaccine strain can effectively infect and disseminate in mosquito tissues following engorgement of viremic blood. The mosquito-attenuated phenotype also ensures the safety of the licensed LAVs IMOJEV, Dengvaxia and QDENGA. In the 21st century, regulators expect the attenuated phenotype of candidate orthoflavivirus LAVs to also include a demonstration of reduced replication and dissemination in arthropod vectors under laboratory conditions in order to support environmental risk assessments of the impacts of these LAVs in nature. Achieving a safe level of attenuation of orthoflaviviruses in mosquitoes requires multigenic mutations to prevent reversion to the wild-type phenotype. This review discusses knowledge of orthoflaviviral encoded determinants for infection and dissemination in mosquito tissues which have potential utility for the rational design of candidate LAVs. Several attenuating mutations discovered to date are located within genomic regions that are conserved among orthoflaviviruses and can potentially support the establishment of a broadly effective attenuating strategy.