A Novel Live Non-replicating Universal Vaccine for Influenza

一种新型非复制型流感通用活疫苗

• 批准号: 8846539
• 负责人: Sally R. Sarawar
• 金额: $ 79.95万
• 依托单位: BIOMEDICAL RESEARCH INSTIT/ SOUTHERN, CA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846539
• 关键词: Address; Affect; Antibodies; Antibody Response; Attenuated Live Virus Vaccine; B-Lymphocytes; Bacterial Infections; Belief; Birds; Cell Culture System; Cessation of life; Clinical Research; Collaborations; Complement; Data; Development; Disadvantaged; Dose; Effectiveness; Epitopes; Evaluation; Ferrets; Generations; Genes; Goals; Haemophilus influenzae; Health; Histology; Hospitalization; Human; Immune response; Immunity; Individual; 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 Security; Pathology; Pathway interactions; Population; Predisposition; Production; Role; Safety; Seasons; Secondary to; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Toxicology; Uncertainty; Vaccinated; Vaccination; Vaccines; Vertebral column; Viral; Viral Antigens; Viral Genome; Viral Proteins; Virion; Virus; adaptive immunity; aged; base; egg; flu; influenza virus vaccine; influenzavirus; meetings; mouse model; novel; novel vaccines; pandemic disease; pandemic influenza; pre-clinical; rapid technique; research clinical testing; response; seasonal influenza; secondary infection; vaccine response; vaccine safety

DESCRIPTION (provided by applicant): Previous influenza pandemics have resulted in 50-100 million deaths worldwide, while seasonal influenza viruses cause between 3000 and 50,000 deaths and 200,000 hospitalizations per year in the US alone. The recent emergence of highly pathogenic avian H5N1 and H7N9 strains and the 2009 H1N1 influenza pandemic emphasize the continuing threat to human health and national security posed by pandemic influenza. To address this threat, 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 was achieved, casting doubt on the long- standing belief that a close match between the vaccine 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 an 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 4 Specific Aims: Aim 1. To determine the efficacy and spectrum 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 evaluate the safety profile of the vaccine. Lung histology and the inflammatory response will be assessed after vaccination and challenge. We will also conduct a toxicology study and determine the effect of pre-existing influenza infection on the vaccine. 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. Aim 4. To determine how the vaccine impact susceptibility to secondary bacterial infection. These studies will provide a comprehensive pre-clinical evaluation of the efficacy and safety of the M2SR vaccine.

描述(申请人提供)：以前的流感大流行已导致全球5000-1亿人死亡，而季节性流感病毒仅在美国每年就导致3000-5万人死亡和20万人住院。最近出现的高致病性禽流感H5N1和H7N9毒株以及2009年H1N1流感大流行凸显了大流行性流感对人类健康和国家安全构成的持续威胁。为了应对这一威胁，建议美国所有6个月以上的儿童每年普遍接种疫苗。目前的疫苗包括灭活的三价裂解或亚单位疫苗和减毒活疫苗，这两种疫苗的缺点都是必须使用繁琐的方法在鸡蛋中培养，并根据预计将在下一个流感季节流行的流感毒株每年重新配制疫苗。然而，这些疫苗的主要缺点是令人惊讶地缺乏有效性，这在最近对美国流感疫苗(活的和灭活的)的荟萃分析中得到了强调。即使在最近的2012-13赛季，疫苗与流行毒株很好地匹配，也只达到了59%的效果，这让人对长期以来的信念产生了怀疑，即疫苗和传播毒株之间的紧密匹配会带来高效。迫切需要开发高效和交叉保护的流感疫苗和新的快速制造方法。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(M2SR)。病毒基因组中的这种缺失允许疫苗病毒在宿主中单次复制并产生病毒蛋白，从而在不产生后代病毒粒子(脱落)的情况下诱导强大的交叉保护免疫，这是当前疫苗策略无法实现的目标。M2SR是一种平台主干病毒，可以修改为编码任何流感病毒株的病毒抗原，并在一种新的细胞培养系统中生产，避免使用鸡蛋。我们假设M2SR将对流感提供安全、高效、广谱、持久的保护。我们的初步数据支持这一假设，并表明该疫苗可引发强烈的系统和粘膜免疫反应，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4个具体目标上检验这一假设：目的1.确定M2SR疫苗的效力和保护范围。我们将进一步研究针对同源和异种病毒攻击的保护效果和寿命。目的2.评价疫苗的安全性。接种和激发后将对肺组织学和炎症反应进行评估。我们还将进行毒理学研究，并确定先前存在的流感感染对疫苗的影响。目的3.确定异源保护的机制。我们将研究病毒特异性T和B细胞反应在交叉保护中的作用。目的4.确定疫苗如何影响继发性细菌感染的易感性。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。