Novel Vaccine Immunogens for Pandemic H5 Influenza

针对大流行性 H5 流感的新型疫苗免疫原

• 批准号: 7538182
• 负责人: Robert G. Whalen
• 金额: $ 30万
• 依托单位: MAXYGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538182
• 关键词: Amino Acid Sequence; Antibodies; Antigens; Ants; Attention; Avian Influenza; Biological Assay; Birds; Budgets; Case Fatality Rates; Cessation of life; Collection; Country; Coupled; Cultured Cells; DNA; DNA Sequence; Directed Molecular Evolution; Disease Outbreaks; Flu virus; Future; Genes; Genetic Recombination; Genetic Variation; H5 hemagglutinin; Hemagglutination; Hemagglutinin; Human; Immune Sera; Immunity; Immunization; In Vitro; Individual; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Libraries; Life; Measures; Membrane Glycoproteins; Methods; Mus; Nature; Numbers; Peptide Sequence Determination; Phase; Population; Proteins; Public Health; Published Comment; Reporting; Scientist; Screening procedure; Serum; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Technology; Testing; Transfection; United States; Vaccinated; Vaccination; Vaccines; Variant; Virus; Virus Diseases; Work; World Health Organization; base; chimeric gene; immunogenic; immunogenicity; improved; novel; novel vaccines; pandemic disease; pandemic influenza; pathogen; prophylactic; vaccine evaluation

DESCRIPTION (provided by applicant): Influenza pandemics occur when an abrupt change in the composition of the circulating viruses results in a strain to which individuals have little or no immunity. The three pandemic outbreaks that occurred in the 20th century in 1918, 1957, and 1968 represent three different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2, respectively. The concern of a future pandemic has focused attention on the avian H5N1 virus, which has demonstrated not only the possibility of infecting humans but to do so with a high case-fatality rate. Vaccinating populations to protect them from a future pandemic virus poses an obvious problem. David Nabarro, UN senior coordinator for avian and human influenza, stated: "We cannot have a vaccine against a pandemic virus until the pandemic virus appears and then there will be an interval of perhaps six months until we have a reasonable quantity of vaccine." Efforts are underway to create pre-pandemic vaccines to H5N1 viruses that can confer broad protection against different strains. However, the divergence of highly pathogenic H5N1 viruses into distinct clades has increased the complexity of developing a prophylactic vaccine against multiple H5N1 subtypes. We propose here a novel way to approach this problem, using the power of directed molecular evolution. This technology encompasses a method for creating novel protein sequences coupled with a means of screening the protein variants. In vitro homologous DNA recombination can create libraries of high-quality functional diversity from pathogen genes encoding the proteins needed to create a vaccine. Libraries of the variant proteins can then be screened for improved immunogenicity. The only major correlate of protection against influenza is antibody to its surface glycoproteins, primarily the hemagglutinin (HA). We hypothesize that variants of the H5 HA protein can be created that are more immunogenic than the wild-type proteins, and will induce immune sera with potentially broad neutralization potency. Genes encoding the variants to test this hypothesis will be created by in vitro DNA recombination of wildtype H5 HA-encoding genes. The specific product that is being targeted by this work is an HA-based vaccine with broad neutralization activity against many H5N1 viruses. The creation of a stockpile of variants and the sera induced by them will nonetheless provide a means to rapidly choose the immunogen needed to prepare a vaccine once a pandemic strain has appeared. The current proposal will assess the feasibility of this idea. A study by the Congressional Budget Office estimates that the consequences of a severe pandemic could include 200 million people infected, 90 million clinically ill, and 2 million dead in the United States alone. If a pandemic is caused by H5N1, the numbers of deaths could be considerably higher given the observed >50% case-fatality rate for infection by this virus. A strategy such as that proposed here could - if successful - provide a measure of protection against a pandemic H5 influenza strain and potentially save millions of lives. PUBLIC HEALTH RELEVANCE: Influenza pandemics occur when individuals are poorly protected from the virus. We propose to create a collection of vaccine candidates that can rapidly be tested against an emerging pandemic. A strategy such as that proposed here could provide protection against a pandemic flu virus and save millions of lives.

描述（由申请人提供）：当循环病毒组成的突然变化导致个体几乎没有免疫力或没有免疫力的压力时，流感大流感会发生。 1918年，1957年和1968年在20世纪发生的三场大流行爆发分别代表了流感病毒的三种不同的抗原亚型：H1N1，H2N2和H3N2。未来大流行的关注点集中在鸟类H5N1病毒上，该病毒不仅证明了感染人类的​​可能性，而且还以高病态效率率这样做。疫苗接种人群以保护他们免受未来的大流行病毒的侵害提出了一个明显的问题。联合国鸟类和人类流感的联合国高级协调员戴维·纳巴罗（David Nabarro）表示：“直到出现大流行病毒之前，我们不能对大流行病毒进行疫苗，然后将有六个月的时间间隔，直到我们有合理数量的疫苗。”正在进行努力为H5N1病毒创建流行前疫苗，从而对不同的菌株进行广泛的保护。然而，高度致病的H5N1病毒对不同的进化枝的差异增加了针对多种H5N1亚型开发预防性疫苗的复杂性。我们在这里提出了一种新的方法来解决这个问题，利用定向分子进化的力量。该技术涵盖了一种创建新型蛋白质序列以及筛选蛋白质变体的方法的方法。体外同源DNA重组可以从编码创建疫苗所需的蛋白质的病原体基因创建高质量功能多样性的文库。然后可以筛选变体蛋白的文库以提高免疫原性。唯一的针对流感保护的主要相关性是其表面糖蛋白的抗体，主要是血凝集素（HA）。我们假设可以产生比野生型蛋白更免疫原性的H5 HA蛋白的变体，并且会诱导具有潜在宽的中和效力的免疫血清。编码变体以检验该假设的基因将通过野生型H5 HA编码基因的体外DNA重组而产生。这项工作针对的特定产品是一种基于HA的疫苗，具有针对许多H5N1病毒的广泛中和活性。尽管出现大流血菌株，因此创建了一种变体库存和由它们引起的血清的储备提供一种方法，以迅速选择准备疫苗所需的免疫原。当前的建议将评估这一想法的可行性。国会预算办公室的一项研究估计，严重大流行的后果可能包括2亿人感染，9000万临床病，仅在美国死亡200万人。如果大流行是由H5N1引起的，那么由于该病毒感染了> 50％的病例拟合率，死亡人数可能会更高。这样的策略可以 - 如果成功的话，可以提供针对大流行性流感菌株的保护，并有可能挽救数百万的生命。公共卫生相关性：当个人受到不受病毒的保护时，会发生流感流感。我们建议创建一系列候选疫苗，可以迅速针对新兴的大流行进行测试。这样的策略在这里提出的策略可以保护对大流传病毒的保护，并挽救数百万的生命。