Mucosal INFλ mRNA-based immunomodulation with ETH47 confers antiviral protection from influenza A and SARS-CoV-2 in vitro and in vivo

<bold>Introduction:</bold> Virus infections are the main trigger of asthma exacerbations. ETH47 is a novel mRNA drug candidate encoding interferon (INF) λ, a critical and virus-independent mediator of anti-viral mucosal immunity. <bold>Objective:</bold> To investigate antiviral efficiency of ETH47 against influenza A (IAV) and SARS-CoV2 <bold>Methods:</bold> In-vitro antiviral efficiency of ETH47 or control mRNA was tested in A549-ACE2 or human bronchial epithelial cells (NHBE) at air-liquid interface (ALI). In-vivo antiviral efficiency of ETH47 was tested following lethal virus challenge of Mx1 congenic or K18-hACE mice. In addition, antiviral efficacy of ETH47 was tested in a non-lethal IAV ferret challenge model. <bold>Results:</bold> Administration of ETH47 resulted in a dose-dependent production of INFλ and interferon target gene induction in vitro and in vivo. In vitro, pre-treatment with ETH47 reduced virus load for IAV and SARS-CoV-2 by up to 100-fold in both cell systems. In vivo, pre-treatment with ETH47 resulted in a significant reduction of pulmonary virus load and virus-induced body weight loss, and increased survival following lethal SARS-CoV-2 challenge of K18-hACE mice. Furthermore, ETH47 prevented virus-induced body weight loss and significantly increased survival following lethal IAV challenge of Mx1 congenic mice to 80%. In ferrets, ETH47 prevented development of fever and significantly reduced a composite endpoint of signs of infections. <bold>Conclusions:</bold> ETH47 demonstrated antiviral efficiency against IAV and SARS-CoV-2 in vitro and in vivo. This data supports the development of ETH47 as a novel preventer of asthma exacerbations or as a first-line antiviral for pandemic preparedness.