Host-targeted self-attenuated influenza virus as a potential therapeutic influenza vaccine

Abstract

Abstract Influenza is still one of leading causes of morbidity and mortality around the world, despite of annual influenza immunization in many countries. New strategies are urgently needed for developing effective vaccines and therapeutics against influenza viruses. In this study, we have constructed new recombinant influenza viruses, named host-targeted self-attenuated influenza viruses (SAIVs), which can express functional mammalian species-specific artificial microRNAs (amiRNAs). The expression of these amiRNAs can inhibit expression of some host factors critical for influenza replication, and therefore the resultant recombinant influenza viruses are replication restricted and attenuated in the host cells. One of these SAIVs, which can express an amiRNA that inhibits expression of the host cellular Cdc2-like kinase 1 (CLK1), was produced in embryonic chicken eggs and evaluated in a mouse model of influenza infection. It elicited robust antibody responses against influenza virus and demonstrated significantly protective efficacy against lethal infection with wild type influenza virus H1N1 PR8 after single dose of intranasal vaccination. Additionally, post-exposure treatment with this CLK1-targeted SAIV showed therapeutic effect against PR8 lethal-dose infection. Our research finding provided a proof of concept that the new host targeted self-attenuated influenza virus can be further developed to a therapeutic vaccine for prophylactic and therapeutic use against influenza. Supported by a research grant from National Institute of Allergy and Infectious Diseases (AI133207).