Development of a novel highly effective influenza vaccine

新型高效流感疫苗的研制

基本信息

批准号：
8781471
负责人：
Pamuk Bilsel
金额：
$ 30万
依托单位：
FLUGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8781471
关键词：
Address Adult Antibodies Antibody Formation 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 public health relevance rapid technique research clinical testing response seasonal influenza vaccine safety

项目摘要

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，可引起广泛感染，导致全球至少 3-500 万重症病例和 250,000-500,000 人死亡。幼儿和老年人或免疫功能低下的人通常因流感患严重疾病或死亡的风险更大。新出现的毒株可能导致流感大流行，死亡率更高，即使是年轻健康的成年人也是如此。为了应对这一对公共健康的威胁，建议美国所有 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裂解疫苗或亚单位疫苗以及减毒活疫苗，这两种疫苗都有一个缺点，即必须使用鸡蛋中的费力方法来培养它们，并且每年根据预计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，美国最近对流感疫苗（活疫苗和灭活疫苗）的荟萃分析强调了这一点。即使在最近的 2012-13 季节，疫苗与流行毒株完全匹配，但在人群中的功效仅达到 59%，在老年人中的功效仅为 9%，这使人们对长期以来认为密切相关的观点产生了怀疑。疫苗病毒株与流行毒株匹配可产生高效效果。迫切需要开发高效、具有交叉保护性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，从而诱导强大的交叉保护性免疫，而不产生子代病毒颗粒（脱落），这是当前疫苗策略未实现的目标。 M2SR 是一种平台骨干病毒，可经过修饰以编码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 M2SR 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，并表明该疫苗能引发强烈的全身和粘膜免疫反应，并提供有效的交叉反应保护，防止流感的致命攻击。我们将在 3 个具体目标中检验这一假设：目标 1. 确定 M2SR 疫苗提供的保护功效。我们将进一步研究针对同源和异源病毒攻击的保护的功效和寿命。目标 2. 确定 M2SR 是否具有任何病理作用。接种疫苗和攻击后将评估肺组织学和炎症反应。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。这些研究将为 M2SR 疫苗的有效性和安全性提供全面的临床前评估。