ANTIBODY DIVERSITY, AGE AND INFLUENZA VACCINE EFFICACY

在这份提案中，提出了一个将促进职业生涯的计划 最近完成奖学金的斯特凡·格雷文斯坦的发展 在老年医学方面的培训，并被任命为 医学。最初，这个职业发展奖将允许他 有机会开发和应用基本的板凳技能来学习 提出研究问题。从长远来看，这项研究将极大地 增强他在自己感兴趣的重点领域的研究能力，免疫 衰老和疫苗。这项奖励中的资金将帮助他发展一种 独立实验室。 尽管市场上有疫苗，但流感仍然是导致 老年人的发病率和死亡率。有几个建议 对此进行了定量和定性的解释。许多较旧的疫苗 受者(可能有50%)的抗体水平没有达到四倍的增长。 通常被认为是“保护性”的滴度。在其他国家，流感 尽管有可测量的抗体反应，但仍会发生感染。在这些 个体在抗体质量上可能存在差异。 流感疫苗含有纯化的血凝素(HA)分子 它们是在病毒颗粒表面发现的糖蛋白。这个 HA分子结构已经得到了很好的表征，现在 认识到有四个抗原域。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，大多数抗体只产生一种或一种抗体 四个域中的两个。我们还提出，抗体多样性较少。 虚弱老年人比健康老年人更健康。最后，我们建议后- 疫苗接种抗体多样性，即对每一种疫苗的抗体特异性 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的单抗 抗HA上四个免疫优势抗原域的抗体。这个 这方面的培训和开发将在威斯康星州大学的杂交瘤设施进行。 我们将使用这些抗体来选择HA变异病毒。血凝素核糖核酸 这些病毒将被测序以确定mAb的特异性。 接受检测的是700多名患有流感的虚弱老年人 纽约指导下的临床试验中的疫苗。健康人血清 同时抽样的青年(n=50)或老年(n&gt；35)受试者 将会被比较。如果我们的假设是真的，我们应该证明 随着年龄的增长，对疫苗的抗体反应变得不那么多样化， 而这种多样性在虚弱的老年人中比健康的老年人要少。最后， 我们想要证明抗体多样性之间的联系 接种流感疫苗和随后的流感疾病后的曲目。

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.