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

初次接触流感对流感免疫的质量、程度、广度、效力和持久性的影响

基本信息

批准号：
10614959
负责人：
MARY A STAAT
金额：
$ 434.66万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614959
关键词：
Address Antibodies Antigens B-Lymphocytes Blood Breast Feeding Child Childhood Cities Clinical Collection Communicable Diseases Effectiveness Elderly Enrollment Epidemiology Epitopes Evaluation Exposure to Frequencies Future Genetic Programming Genetic Variation Goals Human Immune Immune response Immunity Immunization Immunologic Memory Immunologics Immunology Individual Infant Infection Influenza Influenza A virus Influenza vaccination Infrastructure Knowledge Life Maintenance Maternally-Acquired Immunity Memory Mexico Milk Mothers Nature Pediatric Hospitals Population Predisposition Pregnant Women Primary Infection Reporting Research Personnel Sampling Schedule Seasons Shapes Site Symptoms T memory cell T-Lymphocyte Umbilical Cord Blood Vaccination Vaccines Variant Viral Viral Antigens Virus cohort imprint improved infancy influenza infection influenza virus strain influenza virus vaccine influenzavirus nasal swab postnatal recruit response seasonal influenza secondary infection stem universal influenza vaccine vaccine strategy virology virus genetics

项目摘要

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).

项目摘要摘要迫切需要一种更普遍的针对影响病毒感染的疫苗。但是，一个主要障碍将更有效和耐用的疫苗限制为影响技术员感染，源于迅速转移的性质病毒免疫显性表位。进一步困惑的障碍是功能差异对疫苗接种和个体对自然感染的易感性的免疫反应能力事先暴露于影响抗原。这种免疫印迹可能解释了广泛的不和谐当前季节性影响疫苗的有效性。考虑到几乎无处不在的暴露个体会影响Za病毒，以及从无症状到临床症状的广泛差异严重的感染以及季节性免疫抑制的普遍使用，免疫印记到在婴儿期开始时，流感病毒可能是在首次暴露于自然感染或免疫的过程中开始的。重要的是，关于个体如何应对主要影响力的主要影响力暴露的关键知识差距早期生活，在自然感染或疫苗接种的背景下，以及缺乏预先存在的免疫效应主宿主影响力的病毒多样性。目前尚不清楚第一次接触影响力如何影响随后对抗原相同，相似或不一致的影响者的免疫学反应。对于婴儿，垂直转移的孕产妇免疫的影响，或通过后产后获得的影响母乳喂养，关于随之而来的影响特定免疫反应的质量，尚不清楚。填充这些知识差距，辛辛那提儿童医院持续招募孕产妇的队列扩大了墨西哥城的平行努力。这两个站点都进行了持续的监视有症状的原发性感染病例。随着2000多名孕妇的拟议入学率鉴于我们已建立的每周鼻腔基础设施拭子和症状报告，预定的血液收集以检测不对称和症状影响，母体和脐带血和牛奶样本分析以及易感性和详细评估对母亲和婴儿的影响力感染和疫苗接种的免疫学反应。我们的总体假设是早期生命中的主要影响力会影响免疫学的幅度，耐用性和广度记忆到影响力抗原的进化范围，这种初始烙印将对随后的影响。一组研究人员，在小儿感染方面具有完全专业知识疾病，流行病学，产妇群体，人类B和T细胞免疫学和影响力病毒学通过研究婴儿对原发性的免疫反应来解决我们的假设与免疫化相比，流感病毒自然感染（AIM 1）比较免疫反应反对最初暴露于通过自然感染或婴儿免疫接触病毒（AIM 2），并且研究了先前存在的影响力免疫学对个体内病毒遗传多样性的影响（AIM 3）。