DIVINCI: Dissection of Influenza Vaccination and Infection for Childhood Immunity

摘要 在全球范围内，流感病毒是一个主要的公共卫生负担。证据表明，一个人最早的 接触流感对人一生中对病毒的免疫力有深远的影响。精心策划的，婴儿 队列，用于询问针对早期流感暴露的全谱免疫反应，以及 缺乏对后续暴露的检查。我们这个提议的前提是抗原型 (毒株、感染与疫苗接种)接触流感病毒会导致不同的免疫记忆 特征，特别是在B和T细胞谱系中。具体地说，我们将研究流感感染--以及 疫苗介导的印迹调节B细胞和抗体的广度、寿命和功能质量 反应并决定T细胞的特异性、受体特征、功能活性和表观遗传状态 对随后的流感暴露的反应。此外，我们还将研究这些参数是如何受到影响的 因为反复暴露在流感中。我们将通过全面评估B和T来解决这些问题 三项独特的出生队列研究中流感感染和疫苗接种诱导的细胞免疫反应：1) 尼加拉瓜马那瓜；2)新西兰惠灵顿；3)加利福尼亚州洛杉矶。通过三个地点，选择 由于我们在进行队列研究和婴儿登记方面的丰富经验，不同的季节性 流感的传播，以及多样化的人口结构，我们将建立一个约3100名儿童的队列，其中2100名 在U01课程期间登记的新生儿和另外1,000名已经被跟踪的儿童 出生以来长达8年的有症状的流感感染，并有现有的血液样本银行。我们的 中心假设是，最初和随后接触流感的年表持续了很长时间 对抗流感反应的影响(“印记”)，使婴儿处于不同的免疫轨迹 通过招募不同的B和T细胞的特异性和功能能力。我们将测试 这一假设通过建立队列(目标1)，检查对初始暴露的反应(目标2)， 审查对后续暴露的反应(目标3)和评估保护的相关性(目标4)。我们 已经组成了一个由世界知名调查人员组成的联盟，他们有着长期的合作历史(&gt；150 出版物)。结合在临床、免疫学和病毒学方面的丰富经验和正在进行的计划 研究确保了高质量、成功的研究计划。这一U01将导致：1)对 印记机制；2)在早期和早期提高了对什么是保护性免疫的理解 随后的流感感染，包括接种疫苗的影响；以及3)鉴定天然和疫苗-- 诱导的B细胞/抗体和CD4/CD8T细胞的保护作用相关。这些调查提供了一种新的 将独特的队列与详尽的免疫分析相结合的机会，为新的 疫苗策略，以诱导对流感病毒的广泛保护性免疫。

SUMMARY Globally, influenza virus is a major public health burden. Evidence suggests that an individual’s earliest exposures to influenza have profound effects on immunity against the virus throughout life. Well-curated, infant cohorts, used to interrogate the full spectrum of immune responses against early influenza exposures, and examined for subsequent exposures have been lacking. Our premise of this proposal is that the antigenic form (strain, infection vs. vaccination) of an encounter with influenza virus results in disparate immunological memory profiles, particularly in B and T cell repertoires. Specifically, we will examine how influenza infection- and vaccination-mediated imprinting modulates the breadth, longevity, and functional quality of B cell and antibody responses and dictates the specificity, receptor profiles, functional activity and epigenetic state of the T cell responses to subsequent influenza exposures. In addition, we will examine how these parameters are impacted by repeated exposure to influenza. We will address these questions by comprehensively assessing the B and T cell immune responses induced by influenza infection and vaccination in three unique birth cohort studies: 1) Managua, Nicaragua; 2) Wellington, New Zealand; and 3) Los Angeles, CA. Through the three sites, chosen because of our extensive experience with conduct of cohort studies and enrollment of infants, distinct seasonal transmission of influenza, and diverse demographics, we will establish a cohort of ~3,100 children, with 2,100 newborns enrolled over the course of the U01 and an additional ~1,000 children who have already been followed since birth for up to 8 years for symptomatic influenza infection and have existing banked blood samples. Our central hypothesis is that the chronology of initial and subsequent influenza exposures has long lasting effects on anti-influenza responses (“imprinting”), setting infants on diverse immunological trajectories mediated by the recruitment of distinct B and T cell specificities and functional capabilities. We will test this hypothesis through establishment of the cohort (Aim 1), examining the response to initial exposures (Aim 2), examining the response to subsequent exposures (Aim 3) and evaluating correlates of protection (Aim 4). We have formed a Consortium of world-renowned investigators who have a long history of collaboration (>150 publications). Combining extensive experience and on-going programs in clinical, immunological, and virological research ensures a high-quality, successful research program. This U01 will result in: 1) New insight on the mechanisms of imprinting; 2) Improved understanding of what constitutes protective immunity in early and subsequent influenza infections, including the effects of vaccination; and 3) Identification of natural and vaccine- induced B cell/antibody and CD4+/CD8+ T cell correlates of protection. These investigations provide a novel opportunity to combine unique cohorts with exhaustive immune profiling, generating critical insights for new vaccine strategies to induce broadly protective immunity to influenza virus.