Drug platforms

A method for enhancing viral sensitivity to host IFN could be used to generate highly immunogenic, live virus-based vaccines against infection. The approach involves using saturation mutagenesis and next-generation sequencing to compare genomes of the IFN-treated and untreated virus and identify mutations that enhance viral IFN sensitivity, then engineering the mutations into the wild-type virus to generate a hyper-IFN-sensitive (HIS) virus for use as a vaccine. In proof-of-concept experiments, a HIS influenza A virus containing eight IFN-sensitizing mutations increased expression of IFNβ (IFNB1) in primary human alveolar macrophages 50-fold over the wild-type virus. Mice immunized with the HIS virus had higher titers of influenza A virus hemagglutinin (HA)-neutralizing antibodies in sera and bronchoalveolar lavage samples and higher numbers of T cells in the lungs and spleen than mice immunized with inactivated wild-type influenza A, inactivated HIS virus or a FluMist-based virus. Also in mice, immunization with the HIS virus did not cause weight loss or other markers of active influenza infection up to the highest tested dose of 1x10⁷ 50% tissue culture infective dose (TCID₅₀), whereas immunization with 1x10³-1x10⁶ TCID₅₀ doses of the wild-type virus caused weight loss in all animals. Next steps include applying the method to a vaccine against influenza B virus (see “Interferon Non-interference.” BioCentury Innovations (Feb. 28, 2018))...