Impact of the Initial Influenza Exposure on the Quality, Magnitude, Breadth, Potency and Durability of Influenza Immunity

项目总结摘要 迫切需要一种更普遍的流感病毒感染疫苗。然而，一个主要的障碍是 限制针对流感感染的更有效和更持久的疫苗源于 病毒免疫优势表位。进一步混淆这一障碍的是 疫苗接种的免疫反应性和个体对自然感染的易感性 以前接触过流感抗原。这种类型的免疫印记很可能解释了广泛的不一致 目前季节性流感疫苗的有效性。考虑到几乎无处不在的曝光 个体对流感病毒的感染，以及临床症状从无症状到 严重感染和日益广泛使用的季节性免疫，免疫印记 流感病毒很可能是在婴儿首次接触自然感染或免疫时开始感染的。 重要的是，关于个人如何应对#年的初级流感暴露，关键的知识缺口仍然存在。 早期生命，在自然感染或接种疫苗的背景下，以及缺乏先前存在的免疫系统如何产生影响 宿主内流感病毒多样性。目前也不清楚首次接触流感会对 随后对抗原性相同、相似或不一致的流感表位的免疫应答。 对于婴儿，垂直转移的母体免疫的影响，或通过出生后获得的 母乳喂养对随之而来的流感的质量的特异性免疫反应仍不清楚。为了填满这些 知识差距，辛辛那提儿童医院正在进行的母婴队列招募工作将是 扩大了，同时在墨西哥城开展了类似的努力。这两个地点都有持续的监控，提供了更多 有症状的原发感染4例。随着2000多名孕妇的建议招生，我们的 考虑到我们每周鼻腔基础设施的建立，双部位队列非常适合拟议的研究 拭子和症状报告，定期采血以检测无症状和有症状的流感， 孕妇、脐带血和乳汁样本分析和详细评估 母婴对流感感染和疫苗接种的免疫学反应。我们的总体假设 早期接触原发流感会影响免疫学的大小、持久性和广度吗？ 对一系列进化的流感病毒抗原的记忆和这一最初的印记将对 随后接触到流感。在儿科感染性疾病方面具有互补专业知识的调查团队 疾病、流行病学、母婴队列、人类B和T细胞免疫学以及流感病毒学 通过研究婴儿对初发疾病的免疫反应来验证我们的假设 流感病毒自然感染与免疫比较(目标1)，比较免疫学反应 通过婴儿自然感染或免疫首次接触流感病毒(目标2)；以及 调查先前存在的流感免疫对个体内病毒遗传多样性的影响(目标3)。

PROJECT SUMMARY ABSTRACT A more universal vaccine against influenza virus infection is urgently needed. However, a major obstacle limiting more effective and durable vaccines against influenza infection stem from the rapidly shifting nature of viral immune dominant epitopes. Further confounding this obstacle are functional differences in the immunological responsiveness to vaccination and susceptibility of individuals to natural infection primed by prior exposure to influenza antigens. This type of immunological imprinting likely explains the wide discordance in effectiveness of current seasonal influenza vaccines. Considering the near ubiquitous exposure of individuals to influenza virus, together with the wide variability in clinical symptoms from asymptomatic to severe infection and increasingly widespread use of seasonal immunization, immunological imprinting to influenza virus is likely initiated during infancy with the first exposure to natural infection or immunization. Importantly, critical knowledge gaps remain regarding how individuals respond to primary influenza exposure in early life, in the context of natural infection or vaccination, and how a lack of pre-existing immunity effects within-host influenza viral diversity. It is also unclear how this first exposure to influenza impacts the subsequent immunological responsiveness to antigenically identical, similar or discordant influenza epitopes. For infants, the impact of vertically transferred maternal immunity, or that acquired postnatally through breastfeeding, on the quality of ensuing influenza specific immune responses remain unclear. To fill these knowledge gaps, ongoing recruitment of a maternal-infant cohort at Cincinnati Children’s Hospital will be expanded, along with parallel efforts in Mexico City. Both sites have ongoing surveillance providing additional cases of symptomatic primary infection. With the proposed enrollment of more than 2000 pregnant women, our two-site cohort is ideally suited for the proposed studies given our established infrastructure of weekly nasal swabs and symptom reporting, scheduled blood collection to detect asymptomatic and symptomatic influenza, maternal and cord blood and milk sample analyses and detailed evaluations of susceptibility and immunological responses to influenza infection and vaccination in mothers and infants. Our overall hypothesis is that primary influenza exposure in early life impacts the magnitude, durability and breadth of immunological memory to an evolving range of influenza virus antigens and this initial imprint will have a profound effect on subsequent influenza exposures. A team of investigators with complementary expertise in pediatric infectious diseases, epidemiology, maternal-infant cohorts, human B and T cell immunology and influenza virology have been assembled to address our hypothesis by investigating the immunological response of infants to primary influenza virus natural infection compared with immunization (Aim 1), compare the immunological response against an initial exposure to influenza virus via natural infection or immunization in infants (Aim 2), and investigating the impact of pre-existing influenza immunity on virus genetic diversity within individuals (Aim 3).