Optimizing the generation of long-lived plasma cells

项目摘要 理想的流感疫苗必须具备两个基本属性：一是能够广泛诱导 交叉反应抗体，可以中和不同的流感病毒株;和第二，它必须诱导长寿命的 抗体应答，以维持长时间的保护性免疫。已获许可的灭活流感病毒 病毒疫苗两者都没有-抗体反应的广度有限，疫苗诱导的免疫出现 是短暂的。我们的初步结果表明，目前使用的季节性灭活三价 流感疫苗（TIV）不能有效地在人体内产生长寿命的骨髓浆细胞， 这种细胞缺陷是流感疫苗接种后免疫力下降的基础。另外我们 最近的数据表明，在免疫后流感特异性B细胞中存在最小的体细胞高突变 关于TIV这表明疫苗不能引起被认为是 是产生长寿命浆细胞所必需的。当我们朝着发展一个“普遍”的目标前进时， 流感疫苗，迫切需要一种产品，将提供持久的保护， 许多不同的流感病毒株。以前的研究表明，一些减毒活病毒 疫苗或感染能够诱导抗体反应，在人类中持续终生， 对蛋白质疫苗的反应通常下降得更快。这表明存在质的差异 活疫苗和灭活疫苗引起的浆细胞中的差异。我们的建议涉及根本问题 关于流感特异性长寿浆细胞的产生及其在骨髓中的持久性 在接种疫苗或感染后的人类和小鼠中。建议的具体目标如下： 具体目标1：确定在儿童中对流感病毒感染的体液免疫与疫苗接种的持续时间。 具体目标2：优化使用佐剂和开发的候选疫苗的策略 在这个项目中，在小鼠体内产生长寿的骨髓浆细胞。我们的研究将是高度 与本计划项目赠款中的其他项目和核心协同。

Project Summary An ideal influenza vaccine must have two essential attributes: one, it should be capable of inducing broadly cross-reactive antibodies that can neutralize diverse influenza virus strains; and two, it must induce long-lived antibody responses to maintain protective immunity for extended periods. The licensed inactivated influenza virus vaccine does neither – the antibody response is of limited breadth and vaccine-induced immunity appears to be of short duration. Our preliminary results show that the currently used seasonal inactivated trivalent influenza vaccine (TIV) is not efficient in generating long-lived bone marrow plasma cells in humans and that this is the cellular defect that underlies the waning immunity seen after influenza vaccination. In addition, our recent data suggest that there is minimal somatic hypermutation in influenza-specific B cells after immunization with TIV. This suggests that the vaccine fails to elicit the robust germinal center responses that are thought to be required for generating long-lived plasma cells. As we move towards the goal of developing a “Universal” influenza vaccine, there is a compelling need for a product that will provide long-lasting protection against many different strains of influenza viruses. Previous studies have shown that some live attenuated viral vaccines or infections are able to induce antibody responses that persist for a lifetime in humans, while responses to protein vaccines typically decline much faster. This suggests that there are qualitative differences in the plasma cells elicited by live versus inactivated vaccines. Our proposal addresses fundamental questions about the generation of influenza-specific long-lived plasma cells and their persistence in the bone marrow both in humans and in mice following vaccination or infection. The following specific aims are proposed: Specific Aim 1; To determine the duration of humoral immunity to influenza virus infection versus vaccination in humans; and Specific Aim 2: To optimize strategies for using adjuvants and the vaccine candidates developed in this program project to generate long lived bone marrow plasma cells in mice. Our studies will be highly synergistic with other projects and cores in this Program Project grant.