Development of a novel highly effective influenza vaccine

新型高效流感疫苗的研制

• 批准号: 8868029
• 负责人: Pamuk Bilsel
• 金额: $ 30万
• 依托单位: FLUGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868029
• 关键词: Address; Adult; Antibodies; Antibody Response; Attenuated Live Virus Vaccine; B-Lymphocytes; Belief; Body Weight decreased; Categories; Cell Culture System; Cells; Cessation of life; Child; Complement; Data; Development; Disadvantaged; Effectiveness; Elderly; Epitopes; Evaluation; Flu virus; Generations; Genes; Goals; Health; Histology; Hospitalization; Human; Immune response; Immunity; Immunocompromised Host; Individual; Infection; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Life; Longevity; Lung; Mediating; Meta-Analysis; Methods; Mucosal Immune Responses; Mus; National Institute of Allergy and Infectious Disease; Pathology; Population; Production; Property; Public Health; Risk; Role; Safety; Seasons; Solid; T cell response; T memory cell; T-Lymphocyte; Testing; TimeLine; Uncertainty; Vaccinated; Vaccination; Vaccines; Vertebral column; Viral; Viral Antigens; Viral Genome; Viral Proteins; Virion; Virus; Virus Shedding; Vulnerable Populations; Wheezing; aged; base; cell type; cytokine; egg; eosinophil; flu; in vivo; influenza virus vaccine; influenzavirus; meetings; mortality; neutrophil; novel; novel vaccines; pandemic influenza; pathogen; phase 2 study; pre-clinical; rapid technique; research clinical testing; response; seasonal influenza; vaccine safety; vaccine-induced immunity

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.

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，引起广泛感染，导致全球至少300 - 500万例严重疾病和25万-50万例死亡。幼儿和老年人或免疫功能低下的人通常有更大的风险患上严重疾病或死于流感。新出现的病毒株可导致流感大流行，甚至在年轻健康的成年人中也有更高的死亡率。为了应对这一对公共卫生的威胁，建议美国所有6个月以上的人每年进行一次全民疫苗接种。目前的疫苗包括灭活的三价裂解疫苗或亚单位疫苗和活减毒疫苗，这两种疫苗都有缺点，即它们必须使用费力的方法在鸡蛋中生长，并且每年根据预测在下一个流感季节流行的流感毒株重新配制。然而，这些疫苗的主要缺点是令人惊讶地缺乏有效性，这在美国最近对流感疫苗（活疫苗和灭活疫苗）的Meta分析中得到了强调。即使在最近的2012-13赛季，疫苗与流行毒株匹配良好，但在人群中仅实现了59%的有效性，在老年人中仅实现了9%的有效性，这对长期以来认为疫苗病毒株与流行毒株之间的紧密匹配导致高有效性的信念产生了怀疑。迫切需要开发高效和交叉保护性的流感疫苗以及新的快速制造方法。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（M2 SR）。病毒基因组中的这种缺失允许疫苗病毒在宿主中的单次复制和病毒蛋白的产生，其诱导强交叉保护性免疫而不产生子代病毒体（脱落），这是当前疫苗策略未达到的目标。M2 SR是一种平台骨架病毒，可以进行修饰以编码来自任何流感毒株的病毒抗原，并在新型细胞培养系统中生产，避免使用鸡蛋。我们假设M2 SR将提供安全、高效、广谱、持久的流感保护。我们的初步数据支持这一假设，并表明该疫苗激发了强烈的全身和粘膜免疫应答，并提供了有效的交叉反应保护，以对抗流感的致命攻击。我们将在3个具体目标中检验这一假设：目标1。确定M2 SR疫苗提供的保护效力。我们将进一步研究针对同源和异源病毒攻击的保护效力和寿命。目标2.确定M2 SR是否具有任何病理学效应。在接种疫苗和攻毒后评估肺组织学和炎症反应。目标3.探讨异源保护的机制。我们将研究病毒特异性T和B细胞应答在交叉保护中的作用。这些研究将对M2 SR疫苗的有效性和安全性进行全面的临床前评价。