Human and mouse antibodies against influenza virus

人类和小鼠抗流感病毒抗体

• 批准号: 7025662
• 负责人: Gillian M Air
• 金额: $ 32.19万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025662
• 关键词: Orthomyxoviridae; adult human (21+); aging; antigen antibody reaction; antiviral antibody; clinical research; enzyme linked immunosorbent assay; exo alpha sialidase; genetic manipulation; hemagglutination test; hemagglutinin; human subject; immunologic substance development /preparation; influenza; influenza vaccines; laboratory mouse; microorganism immunology; monoclonal antibody; neutralizing antibody; patient oriented research; serology /serodiagnosis; vaccine development; virus antigen; virus genetics

DESCRIPTION (provided by applicant): Influenza vaccines have variable efficacy and protection is often low in the elderly. One hypothesis is that low effectiveness of vaccine in the elderly may be due to a preponderance of influenza-specific but non-neutralizing antibodies. These non-neutralizing antibodies may be against earlier influenza viruses, against denatured or internal viral proteins, or of low avidity. The long-term goal of this research is to develop more effective influenza vaccines by maximizing induction of neutralizing antibodies against the vaccine strain and minimizing the response to denatured glycoproteins, internal proteins, and earlier viruses. Qualitative and quantitative studies of neutralizing and non-neutralizing antibodies in sera of multiply-vaccinated or infected subjects will be undertaken in three Specific Aims. Aim 1: What antibody specificities are present in serum after repeated flu vaccination or infection? Measurement of serum antibodies in vaccinees and infected subjects against the major antigenic drift variants of H3N2 viruses, and in competition assays against monoclonal antibodies specific to those viruses will provide quantitative information on neutralizing versus non-neutralizing, cross-reactive versus strain-specific antibodies, and if the non-neutralizing antibody response is primarily directed against older viruses or against denatured virions. Aim 2: Do the major antigenic regions change in dominance during antigenic drift? The major antigenic sites on the hemagglutinin (HA) have changed in relative dominance over the years. The relative immunodominance of epitopes on the HA and the relative avidity of antibodies will be measured by competition assays, and the results refined by constructing recombinant HA genes engineered to express only one of the major antigenic sites. Aim 3: Devise a vaccine strategy to optimize production of neutralizing antibodies. The results of Aims 1 and 2 will provide a measure of the origins of non-neutralizing antibodies in serum, and allow development of a vaccine strategy to maximize neutralizing antibodies. These experiments are designed to fill a large gap in knowledge of the breadth of human antibody response to influenza vaccines, and to apply this knowledge to vaccine production to improve the ratio of protective, neutralizing antibodies. This may be of particular help in protecting the elderly from influenza.

描述（由申请人提供）：流感疫苗具有不同的疗效，老年人的保护作用通常较低。一种假设是，老年人中疫苗的低有效性可能是由于流感特异性但非中和抗体的优势。这些非中和抗体可以是针对早期流感病毒的，针对变性或内部病毒蛋白的，或具有低亲合力的。这项研究的长期目标是通过最大限度地诱导针对疫苗株的中和抗体，并最大限度地减少对变性糖蛋白、内部蛋白和早期病毒的反应，开发更有效的流感疫苗。将在三个特定目的中对多次接种疫苗或感染受试者血清中的中和和非中和抗体进行定性和定量研究。 目的1：重复接种流感疫苗或感染后，血清中存在哪些抗体特异性？测量疫苗接种者和感染受试者针对H3 N2病毒主要抗原漂移变体的血清抗体，以及针对这些病毒特异性单克隆抗体的竞争测定，将提供有关中和与非中和、交叉反应与毒株特异性抗体的定量信息抗体，以及非中和抗体反应是否主要针对较旧的病毒或变性病毒粒子。 目的2：在抗原漂移过程中，主要抗原区域的优势是否发生变化？血凝素（HA）上的主要抗原位点多年来在相对优势方面发生了变化。HA上表位的相对免疫优势和抗体的相对亲合力将通过竞争测定来测量，并且通过构建经工程改造以仅表达主要抗原位点之一的重组HA基因来精炼结果。 目的3：设计疫苗策略以优化中和抗体的产生。目的1和2的结果将提供血清中非中和抗体来源的量度，并允许开发疫苗策略以最大化中和抗体。 这些实验旨在填补人类抗体对流感疫苗反应广度的知识空白，并将这些知识应用于疫苗生产，以提高保护性中和抗体的比例。这可能对保护老年人免受流感特别有帮助。