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

在全球范围内，季节性流感每年造成29万至65万人死亡。在英格兰，尽管有完善的疫苗接种和监测计划，但流感每年导致7000-22000人死亡。流感疫苗在某些年份效果更好。在包括儿童在内的所有年龄段，流感疫苗在2015-2020年间预防了15%-52%的流感病例。在英格兰，与流感相关住院相关的二级护理费用为99.5-1.28亿GB/年，床日为28.5万-40万天/年，平均住院时间为7-9天。需要重症监护的流感患者面临c20%的高死亡率。在上个世纪，流感导致了三次大流行，导致数千万人死亡。流感造成的英国生产力损失是巨大的：每年因病假而损失2890万GB，因过早死亡而造成的人力资本成本每年2.7亿GB。疫苗接种是对抗流感的主要武器，但面临着重大挑战：**效果不佳：**流感病毒迅速且不断变异。通过预测即将到来的流感季节的主要毒株，提前一年准备疫苗。2019/20年，美国报告的流感疫苗总有效率为45%，而2017/18年度，英国报告的总有效率仅为25%。后者是由于疫苗与优势毒株(流感A-H3N 2)的一种抗原配对不佳所致。免疫衰老或免疫受损群体可能不会对流感疫苗产生完全的抗体反应；因此，可能会经历更低的疗效。**覆盖率较低：**即使在疫苗接种率相对较高的英国，流感疫苗接种率上一次达到世卫组织的目标是在2005/06年度，65岁以上人群的疫苗接种率为75%，此后徘徊在70.5-74.1%左右。**威胁：**目前在人类中仅检测到3种血凝素(HA)和2种神经氨酸酶(NA)病毒蛋白变体。在鸟类、猪和其他宿主中，已经检测到18-HA和11-NA蛋白质变体，为可能引发大流行爆发的抗原转移提供了巨大的储备库。基于英国剑桥癌症研究所，Eleven Treeutics正在开发改变游戏规则的RNAi疗法，以提供高效和广谱的siRNA分子来对抗多种不同的流感病毒株。在这个项目中，我们将通过在大型动物(猪)模型上进行空气传播流感病毒的实验来验证我们基于鼻腔RNA的鸡尾酒的有效性。我们的预防方法将适合以鼻腔喷雾的形式自我给药，在标准冰箱温度下稳定。我们的创新方法与流感疫苗接种计划高度互补，直接应对覆盖范围和有效性挑战，有可能显著减少季节性流感的社会和经济影响，并改善对大流行的准备。

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.