Support: US Army

Period of Performance: April 12th, 2017-April 11th, 2022

Budget: $4,047,800.00

Summary: We will design and evaluate therapeutic interfering particles (TIPs) for the adaptive control of influenza A virus (IAV), one of the deadliest viral pathogens faced by humanity. Despite the existence of a widely-available, annually updated vaccine and the widespread deployment of antiviral drugs, IAV continues to cause tens of thousands of deaths and tens of billions of dollars in economic costs every year in the U.S. alone. Next-generation “universal” influenza vaccines capable of protecting against a broad spectrum of influenza strains and subtypes are being aggressively pursued, however it is likely that the virus will evolve resistance to these vaccines just as they have to previous generations of vaccines and therapeutics. Our program will develop and integrate a series of technical and conceptual breakthroughs across multiple disciplines to make fundamental discoveries about how viral population ecology at the cellular, organismal, and between-host levels influences viral evolution, transmission, and pathogenicity. We will generate an unprecedentedly high-resolution genetic and phenotypic profile of viral infection in vitro and in vivo that will allow us to precisely define and predict how TIPs restructure viral populations. Incorporating this restructuring into our in silico multi-scale models of viral population behavior will allow us to engineer TIPs that work with, rather than against, natural selection to simultaneously reduce pathogenicity and disease spread.