Identifying mechanisms and correlates of long-lasting vaccine-induced immunity to whooping cough

项目总结/摘要 近年来，尽管百日咳在世界范围内广泛流行， 预防针在20世纪90年代中期，对疫苗相关副作用的担忧引发了广泛的 全细胞百日咳（wP）疫苗替代更安全的无细胞百日咳（aP）疫苗。 出乎意料的是，百日咳病例最近有所增加，特别是在青少年中。因为这个年龄段 对应于20世纪90年代中期新生儿接种AP疫苗的第一批儿童， 怀疑改用aP疫苗可能是发病率上升的原因，这一点得到了以下方面的进一步支持： 流行病学证据比较了在不同地区引入aP疫苗和PT病例的复发， 国家该提案的目标是确定长效疫苗的机制和相关因素- 诱导免疫。我们的方法是比较1995年之前出生的人在婴儿期接种疫苗 与1996年或以后出生的在婴儿期接种aP的个体相比，这些年轻人 与注意到发病率增加的人口和年龄组相对应。值得注意的是， 我们检测到两个群体的免疫表型存在巨大的质的差异， 最初的aP或wP启动发生在18年前。PT特异性T细胞的离体分析 结果表明，原始aP启动主要与IL-4、TGF-β和IL-9反应相关，而原始wP启动主要与IL-4、TGF-β和IL-9反应相关， 引发与IFNg和IL-17应答相关。此外，在重复aP疫苗接种加强后，T 最初用aP致敏的细胞变得与对体内加强免疫应答的能力降低有关， 有改变的增殖能力。在这里，我们计划定义转录反应，疫苗加强， 来自最初用aP与wP致敏的供体的PBMC，并鉴定与差异表达相关的细胞类型。 答案（目标1）。在这个最初的“广泛的网络”特征描述之后，我们将磨练 在aP与wP供体（Aim 2）中PT特异性记忆T细胞应答的差异，并表征了在aP与wP供体中PT特异性记忆T细胞应答的分子特征。 aP-与wP-接种供体中T细胞的APC-引发的差异机制（目的3）。我们的研究将 是第一个表征APC和T细胞应答的相互作用的人，将引发的结果与 这两种疫苗具有不同的保护效力。这些结果将对特定的 了解与百日咳疫苗接种相关的免疫机制， 定义疫苗持久效力的机制。

Project Summary/Abstract Recent years witnessed a worldwide reemergence of Pertussis (whooping cough, PT) despite widespread vaccination. In the mid-1990s, concerns over vaccine-related side effects prompted the widespread replacement of the whole-cell Pertussis (wP) vaccine in favor of a safer acellular Pertussis (aP) vaccine. Unexpectedly, whooping cough cases recently increased, particularly in teenagers. As this age bracket corresponds to the first cohorts of children that were aP-vaccinated in the mid-1990s as newborns, it is suspected that the switch to the aP vaccine may underlie this rise in morbidity, which is further supported by epidemiologic evidence comparing introduction of the aP vaccine and resurgence of PT cases across different countries. The goal of this proposal is identifying the mechanisms and correlates of long-lasting vaccine- induced immunity. Our approach is to compare individuals born before 1995 that were vaccinated in infancy with wP, with individuals born in 1996 or later that were vaccinated with aP in infancy. These young adults correspond to the population and age group in which the increased disease incidence is noted. Remarkably, we detect drastic qualitative differences in the immune phenotypes of the two populations despite the fact that the original aP- or wP-priming occurred more than 18 years ago. Ex vivo analysis of PT-specific T cells revealed that original aP priming is mostly associated with IL-4, TGF-β and IL-9 responses while original wP priming is associated with IFNg and IL-17 responses. Furthermore, after repeated aP vaccination boosts, T cells originally primed with aP become associated with diminished capacity to respond to a boost in vivo and have altered proliferative capacity. Here, we plan to define the transcriptional response to vaccine boost in PBMC from donors originally primed with aP vs. wP and identify the cell types associated with differential responses (Aim 1). Following this initial “broad net” characterization, we will hone in the characterization of differences in PT-specific memory T cell responses in aP vs. wP donors (Aim2) and characterize the molecular mechanisms of differences in APC-priming of T cells in aP- vs. wP-vaccinated donors (Aim 3). Our study will be the first to characterize the interplay of APC and T cell response, comparing the outcome of priming with two vaccines associated with differential protective efficacy. The results will have implications for specifically understanding the immunological mechanisms associated with Pertussis vaccination and more generally defining the mechanisms of durable vaccine efficacy.