ANTIBODY DIVERSITY, AGE AND INFLUENZA VACCINE EFFICACY

在这个建议中，提出了一个计划，将促进职业生涯 Stefan Gravenstein最近完成了奖学金， 在老年医学培训，并已被任命为助理教授 药 最初，这个职业发展奖将使他 有机会发展和应用基本的板凳技能，以研究 提出研究问题。 从长远来看，这项研究将大大 增强他在他感兴趣的重点领域的研究能力，免疫 衰老和疫苗 该奖项的资金将帮助他开发一个 独立实验室 尽管有市售疫苗，但流感仍然是导致儿童死亡的主要原因。 老年人的发病率和死亡率。 有几个建议 定量和定性的解释。 许多老疫苗 接受者（约50%）的抗体水平没有达到4倍的增加， 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应答，仍会发生感染。 在这些 个体间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 其是在病毒颗粒表面上发现的糖蛋白。 的 HA分子的结构已经得到很好的表征，现在 应当理解，存在四个抗原结构域。 域不是 它们的免疫原性相当，我们假设， 随着年龄的增长，大多数抗体越来越多地只产生一种或多种抗体。 四个领域中的两个。 我们还提出，抗体多样性较少 体弱老年人比健康老年人多。 最后，我们建议后- 疫苗接种抗体多样性，即，抗体特异性，以每一个 HA抗原结构域，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上的四个免疫显性抗原结构域的抗体（mAb）。 的 这方面的培训和发展将在华盛顿大学的杂交植物研究所进行。 我们将使用这些抗体来选择HA变异病毒。 HA RNA来自 这些病毒将被测序以确定mAb特异性。 超过700名体弱长者接受流感测试 疫苗在纽约的指导下进行临床试验。 健康人血清 同时采样的年轻（n=50）或老年（n>35）受试者 将被比较。 如果我们的假设是正确的，我们应该证明， 随着年龄的增长，对疫苗的抗体应答的多样性减少， 而这种多样性在体弱的老年人中比健康的老年人要少。 最后， 我们想展示抗体多样性 流感疫苗接种和随后的流感疾病后的所有谱。

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.