The goal of this project is to advance the development of a novel biologic antiviral (SiVEC-IAV™) against human influenza. Influenza is a worldwide public health problem that infects approximately 20% of the U.S. population annually and is associated with an annual economic burden of over $11 billion USD. Although currently available influenza vaccines and antivirals are practical approaches to prevent and treat influenza, the efficacy of all available products is suboptimal and they are contraindicated for many patients. To meet the need for new approaches to prevent and manage influenza, SiVEC Biotechnologies developed a novel biological antiviral. Our core-enabling technology is a versatile nucleic acid delivery platform that is characterized as non-immunogenic, non-pathogenic bacteria. For use as an influenza antiviral (SiVEC-IAV) the bacteria are programmed to constitutively express short hairpin RNA (shRNA) molecules, and target their delivery directly to mucosal epithelial cells, where the RNA interference (RNAi) pathway degrades viral transcripts that are necessary for influenza infection. Phase I studies demonstrated the safety, efficacy, and commercial potential of SiVEC-IAV. Phase II studies will advance SiVEC-IAV through IND-directed and preclinical studies, including optimization of the SiVEC-IAV delivery vehicle (Aim 1); definition of the SiVEC-IAV formulation and preliminary product specifications (Aim 2); and evaluation of SiVEC-IAV in a ferret model of human influenza (Aim 3). The long-term goal is to obtain FDA approval of SiVEC-IAV and make its widespread use possible. We expect that SiVEC-IAV, in combination with annual vaccination and other preventative and treatment measures, will be part of a multimodal approach to reduce the incidence of influenza as well as the cost burden. This unique approach to safely delivering nucleic acids to the appropriate cells and tissues to facilitate a therapeutic effect overcomes multiple barriers associated with the translation of RNAi-based therapeutics into clinical practice. In addition, the SiVEC delivery platform can be tailored to deliver other nucleic acids and gene editing systems to clinically relevant tissues to extend its utility outside the realm of RNAi-based therapeutics.