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

项目摘要/摘要 近年来，百日咳(百日咳，PT)在全球范围内重新出现，尽管 接种疫苗。在20世纪90年代中期，对疫苗相关副作用的担忧促使广泛的 取代全细胞百日咳(WP)疫苗，支持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 对应于上世纪90年代中期作为新生儿接种AP疫苗的第一批儿童，它是 怀疑改用AP疫苗可能是发病率上升的原因，这进一步得到了 不同地区甲型肝炎疫苗接种与PT病例回升的流行病学证据比较 国家。这项提议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年前出生的婴儿接种疫苗的个体。 对于WP，出生于1996年或以后的人在婴儿时期接种了AP疫苗。这些年轻人 与注意到疾病发病率增加的人口和年龄组相对应。值得注意的是， 我们发现这两个群体的免疫表型在质量上存在显著差异，尽管事实是 最初的AP或WP启动发生在18年前。甲状旁腺素特异性T细胞的体外分析 提示原始AP激发主要与IL-4、转化生长因子-β和IL-9反应有关，而原始WP 启动与IFNG和IL-17的反应有关。此外，在反复接种AP疫苗后，T细胞 最初被AP激活的细胞变得与体内对增强的反应能力减弱有关，并且 已经改变了增殖能力。在这里，我们计划定义对疫苗增强的转录反应 从最初用AP和WP启动的捐赠者的PBMC中鉴定与分化相关的细胞类型 答复(目标1)。在这个最初的“广泛的网”描述之后，我们将磨练 AP和WP供者(AIM2)PT特异性记忆T细胞反应的差异及其分子特征 AP和WP疫苗接种供者T细胞APC启动差异的机制(目标3)。我们的研究将 是第一个表征APC和T细胞反应的相互作用的人，将预充的结果与 两种疫苗具有不同的保护效力。这一结果将对具体的 了解与百日咳疫苗接种相关的免疫学机制，以及更广泛的 确定持久疫苗效力的机制。

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.