ANTIBODY DIVERSITY, AGE AND INFLUENZA VACCINE EFFICACY

抗体多样性、年龄和流感疫苗功效

• 批准号: 2048296
• 负责人: Stefan Gravenstein
• 金额: $ 8.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-27 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2048296
• 关键词: Orthomyxoviridae; active immunization; age difference; aging; antibody formation; antibody neutralization test; antibody specificity; ascites; chemical structure; complementary DNA; diphtheria; enzyme linked immunosorbent assay; epitope mapping; frail elderly; hemagglutinin; high performance liquid chromatography; human therapy evaluation; human tissue; immunoconjugates; influenza vaccines; laboratory mouse; mixed tissue /cell culture; monoclonal antibody; neutralizing antibody; nucleic acid sequence; serum; thymosin; virus RNA

In this proposal, a program is presented that will facilitate the career development of Stefan Gravenstein who has recently completed fellowship training in Geriatrics and has been appointed Assistant Professor of Medicine. Initially, this career development award will allow him the opportunity to develop and apply essential bench skills to study the proposed research question. Over the long term, this study will greatly enhance his research capabilities in his focused area of interest, immune senescence and vaccines. The funds in this award will help him develop an independent laboratory. Despite commercially available vaccine, influenza remains a major cause of morbidity and mortality in elderly people. There are several proposed quantitative and qualitative explanations for this. Many older vaccine recipients (perhaps 50%) do not achieve the fourfold increase in antibody titer that is conventionally considered "protective". In others, influenza infection occurs despite a measurable antibody response. In these individuals there may a qualitative difference in antibody. The influenza vaccine in comprised of purified hemagglutinin (HA) molecules which are glycoproteins found on the surface of the viral particle. The structure of the HA molecule has been well characterized and it is now appreciated that there are four antigenic domains. The domains are not equivalent in their immuno-genicity and it is our hypothesis that with advancing age the majority of antibody is made increasingly to only one or two of the four domains. We also propose that antibody diversity is less in frail elderly than in healthy elderly. Finally, we propose that post- vaccination antibody diversity, i.e., antibody specificity to each of the HA antigenic domains, is reduced in those individuals who eventually succumb to influenza. In this research we plan to develop a panel of epitope-specific monoclonal antibodies (mAb) to the four immunodominant antigenic domains on HA. The training and development for this will occur at the UW Hybridoma Facility. We will use these antibodies to select HA-variant viruses. The HA RNA from these viruses will be sequenced to determine the mAb specificity.The sera to be tested are from over 700 frail elderly people receiving influenza vaccine in clinical trials under ny direction. Sera from healthy vaccinated young (n=50) or elderly (n>35) subjects sampled at the same time will be compared. If our hypothesis is true, we should demonstrate that with advancing age there is a less diverse antibody response to vaccine, and that diversity is less in frail elderly than healthy elderly. Finally, we would like to show an association between diversity of antibody repertoire after influenza vaccination and subsequent influenza illness.

在该提案中，提出了一项将促进职业生涯的计划 最近完成奖学金的斯特凡·格拉文斯坦 (Stefan Gravenstein) 的发展 老年病学培训并被任命为助理教授 药品。 最初，这个职业发展奖将使他能够 有机会发展和应用基本的基础技能来研究 提出的研究问题。 从长远来看，这项研究将极大地促进 增强他在他感兴趣的重点领域免疫方面的研究能力 衰老和疫苗。 该奖项的资金将帮助他发展 独立实验室。 尽管有商业疫苗，流感仍然是导致流感的主要原因 老年人的发病率和死亡率。 有几种建议 对此进行定量和定性解释。 许多较旧的疫苗 接受者（大约 50%）的抗体未达到四倍增加 滴度通常被认为是“保护性的”。 在其他情况下，流感 尽管有可测量的抗体反应，感染仍然发生。 在这些 个体之间的抗体可能存在质的差异。 流感疫苗由纯化的血凝素 (HA) 分子组成 它们是在病毒颗粒表面发现的糖蛋白。 这 HA 分子的结构已经得到很好的表征，现在 认识到有四个抗原结构域。 域不是 它们的免疫原性相当，我们的假设是 随着年龄的增长，大多数抗体越来越多地只产生一种或 四个域中的两个。 我们还提出抗体多样性较低 体弱老年人的比例高于健康老年人。 最后，我们建议后期 疫苗接种抗体多样性，即抗体对每种疫苗的特异性 HA 抗原域在那些最终 死于流感。 在这项研究中，我们计划开发一组表位特异性单克隆抗体 针对 HA 上四个免疫显性抗原域的抗体 (mAb)。 这 这方面的培训和开发将在华盛顿大学杂交瘤设施进行。 我们将使用这些抗体来选择 HA 变体病毒。 HA RNA 来自 这些病毒将被测序以确定单克隆抗体的特异性。血清 接受检测的是700多名患有流感的体弱老人 疫苗在任何指导下进行临床试验。 健康血清 同时取样的已接种疫苗的年轻 (n=50) 或老年 (n>35) 受试者 将会被比较。 如果我们的假设成立，我们应该证明 随着年龄的增长，对疫苗的抗体反应越来越不多样化， 体弱老年人的多样性低于健康老年人。 最后， 我们想展示抗体多样性之间的关联 流感疫苗接种后和随后的流感疾病后的曲目。