Optimizing the generation of long-lived plasma cells

项目摘要 一种理想的流感疫苗必须具备两个基本属性：第一，它应该能够广泛诱导 能够中和不同流感病毒株的交叉反应抗体；第二，它必须诱导长寿 抗体反应，以维持较长时期的保护性免疫。领有牌照的灭活流感 病毒疫苗两者都没有--抗体反应的广度有限，出现了疫苗诱导的免疫。 持续时间短。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)在人类体内产生长寿骨髓浆细胞的效率不高，而且 这就是接种流感疫苗后免疫力减弱的细胞缺陷。此外，我们的 最近的数据表明，免疫后流感特异性B细胞存在极小的体细胞超突变 使用TIV。这表明，疫苗未能引发生发中心的强大反应，而这种反应被认为是 是产生长寿浆细胞所必需的。当我们朝着发展一种“普遍的”目标前进时 流感疫苗，迫切需要一种能够长期预防流感的产品。 许多不同的流感病毒株。以前的研究表明，一些活的减毒病毒 疫苗或感染能够诱导在人类体内持续终生的抗体反应，而 对蛋白质疫苗的反应通常下降得更快。这表明两者之间存在质的差异。 在活疫苗和灭活疫苗引发的浆细胞中。我们的建议解决了根本问题 流感特异性长寿命浆细胞的产生及其在骨髓中的存留 在接种疫苗或感染后，在人类和小鼠身上都是如此。提出了以下具体目标： 具体目标1；确定对流感病毒感染的体液免疫持续时间与疫苗接种的持续时间 人类；和具体目标2：优化使用佐剂的战略和开发的候选疫苗 在这个计划中，项目是在小鼠身上产生长寿的骨髓浆细胞。我们的研究将高度重视 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.