Improved Vaccines for Influenza B Virus

改进的乙型流感病毒疫苗

• 批准号: 8007330
• 负责人: Robert G. Whalen
• 金额: $ 29.84万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007330
• 关键词: Address; Affect; Antigens; Biological Assay; Cell surface; Cercopithecine Herpesvirus 1; Cessation of life; Child; Code; Complication; DNA Vaccines; Directed Molecular Evolution; Elderly; Epidemic; Epitopes; Flu virus; Genes; Genetic Recombination; 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; public health relevance; 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）：流感是世界各地发病率和死亡率的主要原因。在美国，流感的季节性流行病是从秋末到早春会影响所有年龄段，但儿童感染率尤其高。严重的疾病和死亡是老年人，幼儿和患有其他疾病的人的流感感染的后果，这些疾病使它们造成了流感并发症。疫苗接种是抵抗流感感染和疾病的有效方法，但是几种科学和技术考虑因素可能会对目前针对该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倾向的抗原漂移，每个季节的疫苗中包括的病毒菌株经常会改变以反映当前的循环病毒。抗原漂移的问题可能是生产“普遍”或广泛跨保护性疫苗的最重要的障碍。克服流感菌株多样性的尝试一直是许多努力的重点。 在此提案中，我们将尝试解决与季节性疫苗的流感B病毒成分相关的FDA确定的特定问题。与流感A病毒不同，流感B感染了人类几乎完全感染了人类，并且负责严重的流行病，幼儿住院率很高。多年来已经认可了两个流感B的谱系。尽管每个谱系内都有抗原漂移，但序列多样性相对有限。但是，事实证明，很难预测哪些谱系将主导给定的流感季节，而FDA建议两种菌株都包含在季节性疫苗中，因此需要开发四二价疫苗。 一个简单的解决方案是创建一种流感B免疫原，该免疫原诱导两种谱系的交叉保护免疫。我们建议使用定向的分子进化方法来解决这个问题。流感B血凝素的许多变体将使用编码以前疫苗中使用的各种血凝素蛋白的基因的体外DNA重组创建。具有许多这些变体的小鼠的免疫和对所得血清中和能力的分析将用于筛选符合所需标准的免疫原子。尽管我们意识到这样一个事实，即流感脑血凝集素序列的变化在很大程度上是通过点突变引起的，但几种可能性支持这样一种观念，即通过重组创造新的多样性可以改善免疫原性。重组可能将来自不同病毒变体的表位结合起来，或将中和表位暴露为一种能够引起更广泛保护性反应的免疫原。我们的主要目标是具有新型流感B免疫原的完全交叉反应性中和反应。但是，次要目标是扩大涵盖一个谱系病毒的反应。 公共卫生相关性：年度流感季节是造成大量疾病和死亡的原因，尤其是在较脆弱的人群中。由于流感菌株每年都会发生变化，因此一种广泛作用的疫苗将具有很大的价值。我们建议创建改进的季节性疫苗组成部分之一的版本，以更好地保护某些流感病毒。