Development of a novel highly effective influenza vaccine

描述（由申请人提供）：季节性流感（流感）病毒是NIAID C类优先病原体，可引起广泛感染，导致全球至少300万至500万例严重疾病和25万至50万例死亡。幼儿、老年人或免疫功能低下的个体通常更容易患严重疾病或死于流感。新出现的毒株可导致死亡率高得多的流感大流行，即使在年轻健康的成年人中也是如此。为了应对这一对公共卫生的威胁，美国建议所有6个月以上的人每年普遍接种疫苗。目前的疫苗包括灭活的三价分裂或亚基疫苗和减毒活疫苗，这两种疫苗都有一个缺点，那就是它们必须用艰苦的方法在鸡蛋中生长，并且每年都要根据预计在下一个流感季节流行的流感病毒株重新配制。然而，这些疫苗的主要缺点是令人惊讶的缺乏有效性，最近在美国对流感疫苗（活疫苗和灭活疫苗）的荟萃分析中强调了这一点。即使在最近的2012- 2013年季节，疫苗与流行毒株的匹配程度很高，但在人群中仅达到59%的有效性，在老年人中仅达到微薄的9%的有效性，这使人们对长期以来认为疫苗病毒毒株与流行毒株之间的密切匹配导致高有效性的观点产生了怀疑。目前迫切需要开发高效和交叉保护的流感疫苗和新的快速生产方法。为了满足这一需求，FluGen开发了一种基于M2基因缺失的新型疫苗病毒（M2SR）。病毒基因组中的这种缺失允许疫苗病毒在宿主中进行单次复制并产生病毒蛋白，从而诱导强烈的交叉保护性免疫，而不会产生子代病毒粒子（脱落），这是当前疫苗策略无法实现的目标。M2SR是一种平台骨干病毒，可以对其进行修饰，以编码来自任何流感毒株的病毒抗原，并在一种新的细胞培养系统中产生，避免使用鸡蛋。我们假设M2SR将提供安全、高效、广谱、持久的流感防护。我们的初步数据支持这一假设，并表明该疫苗引起强烈的全身和粘膜免疫反应，并提供有效的交叉反应保护，以抵御流感的致命攻击。我们将在3个具体目标中检验这一假设：目的：确定M2SR疫苗的保护效果。我们将进一步研究对同源和异源病毒攻击的保护效果和寿命。目标2。确定M2SR是否有病理作用。在接种疫苗和刺激后，将评估肺部组织学和炎症反应。目标3。确定异源保护的机制。我们将研究病毒特异性T细胞和B细胞反应在交叉保护中的作用。这些研究将对M2SR疫苗的有效性和安全性进行全面的临床前评估。

DESCRIPTION (provided by applicant): Seasonal influenza (flu) virus, an NIAID category C priority pathogen, causes widespread infection, resulting in at least 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide. Young children and elderly or immunocompromised individuals are typically at greater risk of severe illness or death from influenza. Newly emerging strains can result in influenza pandemics with much higher mortality rates, even in young healthy adults. To address this threat to public health, annual universal vaccination is recommended for all individuals aged over 6 months in the US. Current vaccines include inactivated trivalent split or subunit and live attenuated vaccine, both of which have the drawback that they must be grown using laborious methods in eggs and reformulated every year based on the influenza strains predicted to be prevalent in the next flu season. However, the major disadvantage of these vaccines is a surprising lack of effectiveness, which was highlighted in a recent meta analysis of influenza vaccine (live and inactivated) in the US. Even in the recent 2012-13 season in which the vaccine was well-matched to circulating strains, only 59% efficacy across the population and a meager 9% efficacy in the elderly was achieved, casting doubt on the long-standing belief that a close match between the vaccine virus strains and circulating strains results in high effectiveness. There is an urgent need for the development of highly effective and cross-protective influenza vaccines and new rapid methods of manufacturing. To meet this need FluGen has developed a novel vaccine virus (M2SR) based on the deletion of the M2 gene. This deletion in the viral genome allows for single replication of the vaccine virus in the host and production of viral proteins, which induces strong cross-protective immunity without the generation of progeny virions (shedding), a goal unmet by current vaccine strategies. The M2SR is a platform backbone virus that can be modified to encode the viral antigens from any influenza strain and is produced in a novel cell culture system, avoiding the use of eggs. We hypothesize that M2SR will provide safe, highly effective, broad spectrum, long-lasting protection against influenza. Our preliminary data support this hypothesis and show that the vaccine elicits strong systemic and mucosal immune responses and provides effective cross-reactive protection against lethal challenge with influenza. We will test this hypothesis in 3 Specific Aims: Aim 1. To determine the efficacy of protection afforded by the M2SR vaccine. We will further investigate the efficacy and longevity of protection against homologous and heterologous viral challenge. Aim 2. To determine whether M2SR has any pathological effects. Lung histology and the inflammatory response will be assessed after vaccination and challenge. Aim 3. To determine the mechanism of heterologous protection. We will investigate the role of virus-specific T and B cell responses in cross-protection. These studies will provide a comprehensive pre-clinical evaluation of the efficacy and safety of the M2SR vaccine.