In vivo animal demonstration of a novel RNAi-based prophylaxis to fight influenza

Globally, seasonal influenza is responsible for 290,000-650,000 deaths/year. In England, despite a well-developed vaccination and surveillance programme, flu kills 7,000-22,000 people/year. The flu vaccine works better in some years than others. Across all age groups including children, flu vaccines prevented 15-52% of flu cases between 2015-2020\. Secondary care costs associated with influenza-related hospitalisations in England account for £99.5-£128million/year, and 285,000-400,000 bed days/year, with average 7-9 days hospitalisation. Influenza patients requiring intensive care face a high mortality rate of c20%. Over the last century, influenza has caused three pandemics, killing tens of millions of people. Resultant UK productivity losses arising from influenza are significant: costing £28.9million/year in sick days and £270million/year in human capital costs arising from premature mortality. Vaccination is the main weapon against influenza but faces significant challenges: **Poor efficacy:** Flu viruses rapidly and constantly mutate. Vaccines are prepared a year in advance by predicting predominant strains in the upcoming flu season. Overall efficacy of 45% reported for flu vaccine in the US in 2019/20, while efficacy as low as 25% was reported in England in 2017/18\. Latter resulted from poor match by vaccine to one of predominant strain's (Flu A-H3N2) antigen. Immune senescent or immunocompromised groups may not develop a full antibody response to the flu vaccine; thus, are likely to experience even lower efficacy. **Poor coverage:** Even in the UK, with relatively high vaccination rates, flu vaccination rates last met WHO target: 75% vaccination rate amongst people aged 65+years in 2005/06, since then hovering around 70.5-74.1%. **Threat:** Currently only 3 haemagglutinin (HA) and 2 neuraminidase (NA) viral protein variants have been detected in humans. In birds, pigs, and other hosts, 18-HA and 11-NA protein variants have been detected, providing an enormous reservoir for antigenic shifts that could trigger pandemic outbreaks. Based in the Cancer Research UK Cambridge Institute, Eleven Therapeutics is developing game-changing RNAi therapeutics to deliver highly effective and broad-spectrum siRNA molecules against multiple disparate flu strains. In this project, we will validate the efficacy of our intranasal RNA-based cocktail by conducting airborne flu virus transmission experiments in a large-animal (pig) model. Our prophylaxis will be suitable for self-administration in the form of a nasal spray, stable at standard fridge temperatures. Our innovative approach is highly complementary to flu vaccination programmes and directly addresses both coverage and efficacy challenges, with potential to significantly reduce social and economic impacts of seasonal influenza and improve pandemic preparedness.