Improved Vaccines for Influenza B Virus

改进的乙型流感病毒疫苗

• 批准号: 8082724
• 负责人: Robert G. Whalen
• 金额: $ 30万
• 依托单位: ALTRAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082724
• 关键词: Address; Affect; Antigens; Biological Assay; Cell surface; Cessation of life; Child; Code; Complication; DNA Vaccines; Directed Molecular Evolution; Elderly; Epidemic; Epitopes; Flu virus; Genes; Genetic Recombination; Health; Hemagglutinin; Hospitalization; Human; Immunity; Immunization; In Vitro; Individual; Infection; Influenza; Influenza A virus; Influenza B virus; Influenza Hemagglutinin; Libraries; Manufacturer Name; Monoclonal Antibodies; Morbidity - disease rate; Mus; Phase; Point Mutation; Population; Production; Proteins; Reporting; Research; Risk; Screening procedure; Seasons; Serum; Site; Small Business Innovation Research Grant; Solutions; T cell response; TimeLine; United States; Vaccination; Vaccine Production; Vaccines; Variant; Viral; Viral Proteins; Virus; Virus-like particle; age group; design; egg; falls; flu; immunogenicity; improved; in vivo; influenza epidemic; influenzavirus; meetings; member; mortality; neutralizing antibody; novel; pandemic disease; peptide based vaccine; protein B; research study; response; vaccination strategy

DESCRIPTION (provided by applicant): Influenza is a major cause of morbidity and mortality around the world. In the United States, seasonal epidemics of flu occur from late fall to early spring affecting all age groups but with especially high rates of infection in children. Serious illness and death are consequences of influenza infection among the elderly, young children, and individuals with other illnesses that predispose them form complication of influenza. Vaccination is an effective way to counter influenza infection and illness, but several scientific and technical considerations can negatively impact the current strategies for vaccination against this virus. Because of the antigenic drift for which the influenza virus has a considerable propensity, the strain of virus included in each season's vaccine is frequently change to reflect the current circulating virus. The issue of antigenic drift is perhaps the most significant impediment to the production of a "universal" or broadly cross- protective vaccine to influenza. Attempts to overcome the diversity of influenza strains have been the focus of many efforts. In this proposal we will attempt to solve a particular problem that has been identified by the FDA related to the influenza B virus component of the seasonal vaccine. Unlike influenza A viruses, influenza B infects almost exclusively humans and has been responsible for severe epidemics with high rates of hospitalization for young children. Two lineages of influenza B have been recognized for many years. Although there is antigenic drift within each lineage, the sequence diversity is relatively limited. However, it has proven to be difficult to forecast which lineage will dominate a given flu season and the FDA has suggested that both strains be included in the seasonal vaccine, thus requiring a quadrivalent vaccine to be developed. A simpler solution would be to create an influenza B immunogen that induces cross-protective immunity to both lineages. We propose to use a directed molecular evolution approach to address this problem. Many variants of influenza B hemagglutinin will be created using in vitro DNA recombination of the genes encoding the various hemagglutinin proteins that have been used in previous vaccines. Immunization of mice with many of these variants and analysis of the neutralizing capability of the resulting serum will be used to screen for immunogens that meet the desired criteria. Although we are cognizant of the fact that changes in influenza hemagglutinin sequences arise largely through point mutation, several possibilities support the idea that creation of novel diversity by recombination can improve immunogenicity. Recombination might combine epitopes from different viral variants or expose conserved neutralizing epitopes into one immunogen capable of eliciting broader protective responses. Our primary objective is to have a fully cross-reactive neutralizing response from a novel influenza B immunogen; however, a secondary objective is to broaden the response to cover all viruses of one lineage. PUBLIC HEALTH RELEVANCE: The annual influenza season is responsible for considerable sickness and death, especially among the more vulnerable members of the population. Since flu strains change from year to year, a vaccine that acts broadly would be of great value. We propose to create an improved version of one of the components of the seasonal vaccine that can provide better protection against some of the flu viruses.

描述（由申请人提供）：流感是全世界发病和死亡的主要原因。在美国，季节性流感流行从秋末到早春，影响所有年龄段，但儿童感染率尤其高。老年人、幼儿和患有其他易患流感并发症的疾病的人感染流感会导致严重疾病和死亡。疫苗接种是对抗流感感染和疾病的有效方法，但一些科学和技术因素可能会对当前针对这种病毒的疫苗接种策略产生负面影响。 由于流感病毒具有相当大的抗原漂移倾向，每个季节的疫苗中包含的病毒株经常发生变化，以反映当前流行的病毒。抗原漂移问题可能是生产“通用”或广泛交叉保护性流感疫苗的最大障碍。尝试克服流感毒株的多样性一直是许多努力的重点。 在本提案中，我们将尝试解决 FDA 发现的与季节性疫苗中的乙型流感病毒成分相关的特定问题。与甲型流感病毒不同，乙型流感病毒几乎只感染人类，并导致了严重的流行病，幼儿住院率很高。多年来人们已认识到乙型流感的两个谱系。尽管每个谱系内存在抗原漂移，但序列多样性相对有限。然而，事实证明很难预测哪个谱系将在特定的流感季节中占主导地位，FDA 建议将这两种毒株都包含在季节性疫苗中，因此需要开发四价疫苗。 一个更简单的解决方案是创造一种乙型流感免疫原，诱导对两个谱系的交叉保护性免疫。我们建议使用定向分子进化方法来解决这个问题。乙型流感血凝素的许多变体将通过编码先前疫苗中使用的各种血凝素蛋白的基因进行体外 DNA 重组而产生。用许多这些变体对小鼠进行免疫并对所得血清的中和能力进行分析将用于筛选满足所需标准的免疫原。尽管我们认识到流感血凝素序列的变化主要是通过点突变引起的，但有几种可能性支持这样的观点：通过重组创造新的多样性可以提高免疫原性。重组可能会组合来自不同病毒变体的表位，或将保守的中和表位暴露到一种能够引发更广泛保护反应的免疫原中。我们的主要目标是从新型乙型流感免疫原中获得完全交叉反应的中和反应；然而，第二个目标是扩大应对范围，以覆盖某一谱系的所有病毒。 公共卫生相关性：每年的流感季节导致大量疾病和死亡，特别是在人群中较脆弱的成员中。由于流感毒株每年都会发生变化，因此一种作用广泛的疫苗将具有巨大的价值。我们建议创建季节性疫苗成分之一的改进版本，可以更好地预防某些流感病毒。