Project Summary Seasonal infections from human influenza virus (INFV) represents a major public health burden. The flu vaccine only averts ~15% of medical visits and ~12% of hospitalizations due to INFV, whereas current antivirals are only modestly effective if given soon after symptoms emerge, which is achievable in only half of infected patients due to practical limitations in how quickly INFV infections can be diagnosed. Human monoclonal antibodies (mAb) delivered topically to mucosal surfaces offer exceptional promise as antivirals, combining safety, effectiveness and unparalleled specificity. Adding further to the promise of mAb, we have recently discovered a novel Ab function in mucus ? trapping individual pathogens? and have pioneered a technology enhancing the use of mAb in mucosal secretions based on carefully-tuned affinity between IgG-Fc and mucins, which has been exclusively licensed to Mucommune. Trapping pathogens in mucus prevents them from infecting target cells and spreading locally, facilitates rapid elimination from the airways, and enables effective protection in vivo. We believe the technology is uniquely suited to treat INFV infections, due to the unique pathophysiology of INFV. Studies have shown INFV to bud exclusively from the apical surface of epithelial cells. INFV also shares many pathological and clinical manifestations with Respiratory Syncytial Virus (RSV), which also sheds exclusively from the apical surface of infected cells and must traverse airway mucus (AM) before spreading to neighboring cells. This implies delivery of muco-trapping mAb into the airways can provide an immediate therapeutic benefit by trapping shed progeny virus in AM and facilitating their rapid clearance, unlike oral antivirals that have substantial delay in distribution to the lung. We have stably nebulized ?muco-trapping? mAb to treat RSV infections in neonatal lambs, reducing the viral load by nearly 4-log by Day 6 post-infection after starting treatment as late as Day 3 post-infection. This motivated us to harness our platform to develop a ?muco-trapping? mAb against INFV. In Aim 1, we will produce and characterize muco-trapping mAb against INFV, including their ability to bind and neutralize INFV. In Aim 2, working with IBT Biosciences (a CRO that specializes in animal models of infectious disease), we will assess whether muco-trapping mAb against INFV dosed intranasally can improve survival, clinical scores, and reduce lung viral titers relative to treatment with oseltamivir, the current gold standard of care, even after delayed treatment post-infection. Successful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on mAb optimization, development of a nebulizable formulation, and efficacy/transmission studies in larger animal models. By enabling enhanced mAb functionality in mucus secretions, we expect Mucommune will help pave the way for improved, molecularly targeted therapies and prophylaxis against a broad spectrum of pathogens and microbes across all major mucosal surfaces.