DIVINCI: Dissection of Influenza Vaccination and Infection for Childhood Immunity

DIVINCI：剖析流感疫苗和感染对儿童免疫的影响

• 批准号: 10614457
• 负责人: AUBREE L GORDON
• 金额: $ 486.23万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-02 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614457
• 关键词: Address; Affect; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Biological Assay; Birth; Blood Banks; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Assay; Child; Childhood; Chronology; Clinical; Cohort Studies; Collaborations; Development; Disease; Disparate; Dissection; Elderly; Enrollment; Ensure; Epigenetic Process; Exposure to; Head; Hemagglutinin; Human; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunologics; Individual; Infant; Infection; Influenza; Influenza vaccination; Investigation; Joints; Life; Longevity; Longitudinal cohort; Los Angeles; Mediating; Memory; Methods; Neuraminidase; New Zealand; Newborn Infant; Nicaragua; Nicaraguan; Post-Translational Protein Processing; Predisposition; Productivity; Public Health; Publications; Recording of previous events; Recovery; Research; Research Personnel; Sampling; Seasons; Serology; Site; Specificity; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Vaccinated; Vaccination; Vaccines; Virus; anti-influenza; cohort; demographics; design; experience; flu transmission; imprint; improved; influenza infection; influenza virus vaccine; influenzavirus; innovation; insight; member; novel; novel vaccines; programs; receptor; recruit; response; unvaccinated; vaccine effectiveness; vaccine strategy; vaccine-induced antibodies

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.

概括 在全球范围内，流感病毒是一个主要的公共卫生负担。 接触流感对婴儿一生对病毒的免疫力产生深远影响。 队列，用于询问针对早期流感暴露的全方位免疫反应，以及 我们提出这一建议的前提是缺乏抗原形式。 接触流感病毒（毒株、感染与疫苗接种）会导致不同的免疫记忆 具体而言，我们将研究流感病毒感染和传播的方式。 疫苗介导的印记调节 B 细胞和抗体的宽度、寿命和功能质量 反应并决定 T 细胞的特异性、受体谱、功能活性和表观遗传状态 此外，我们将研究这些参数是如何受到影响的。 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；以及 3) 加利福尼亚州洛杉矶 通过这三个地点。 由于我们在进行队列研究和婴儿入组方面拥有丰富的经验，因此不同的季节性 由于流感传播和不同的人口统计数据，我们将建立一个由约 3,100 名儿童组成的队列，其中 2,100 在 U01 课程中登记的新生儿以及另外约 1,000 名已接受跟踪的儿童 自出生起长达 8 年内有症状的流感感染并且已有储存的血液样本。 中心假设是，最初和随后的流感暴露的时间顺序是长期持续的 对抗流感反应（“印记”）的影响，使婴儿处于不同的免疫轨迹 我们将测试通过招募不同的 B 细胞和 T 细胞特异性和功能能力来介导。 通过建立队列（目标 1）、检查对初始暴露的反应（目标 2）来实现这一假设， 检查对后续暴露的反应（目标 3）并评估保护的相关性（目标 4）。 已经成立了一个由世界知名的研究人员组成的联盟，这些研究人员有着悠久的合作历史（> 150 出版物）结合了临床、免疫学和病毒学方面的丰富经验和正在进行的项目。 研究确保了高质量、成功的研究计划。该 U01 将带来： 1) 对以下问题的新见解。 2) 更好地理解早期和晚期保护性免疫的构成； 随后的流感感染，包括疫苗接种的影响；以及 3) 天然和疫苗的鉴定 诱导 B 细胞/抗体和 CD4+/CD8+ T 细胞的保护相关性这些研究提供了一种新颖的方法。 有机会将独特的队列与详尽的免疫分析相结合，为新的研究产生重要的见解 诱导对流感病毒的广泛保护性免疫力的疫苗策略。