Structure-function analysis of infection- and vaccine-induced B-cell repertoires

感染和疫苗诱导的 B 细胞库的结构功能分析

基本信息

批准号：
10549602
负责人：
STEPHEN COPLAN HARRISON
金额：
$ 299.48万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549602
关键词：
2019-nCoV Affect Affinity Age Anatomy Antibodies Antibody Affinity Antigenic Variation Antigens B cell repertoire B-Lymphocyte Epitopes B-Lymphocytes Binding Sites Blood Cell Compartmentation Cells Coupling Directed Molecular Evolution Distant Epitopes Evolution Face Foundations Goals Grant Hemagglutinin Herd Immunity Human Humoral Immunities Immune Immune response Immunity Immunization In Vitro Individual Infant Infection Influenza Laboratories Location Memory Memory B-Lymphocyte Modeling Molecular Mus Neuraminidase Plasma Cells Plasmablast Population Property Proteins Recording of previous events Role Sampling Secure Serum Specificity Structure T-Lymphocyte Epitopes Testing Update Vaccination Vaccine Antigen Vaccines Variant Viral Virus Zoonoses age group cohort design exhaustion experimental study future pandemic imprint influenzavirus lymph nodes movie nonhuman primate novel novel vaccines pandemic virus pressure programs protective efficacy receptor binding response vaccination strategy vaccine development vaccine efficacy vaccine response viral resistance

项目摘要

Abstract - Overall Influenza virus evolves in response to pressure from herd immunity, resulting in progressive variation of viral antigenicity and limiting vaccine efficacy. The goal of this Program project is to establish a secure mechanistic foundation for novel vaccination strategies that might confer long-lasting immunity in face of rapid antigenic variation of currently circulating subtypes and in anticipation of potential introduction of zoonotic subtypes into the human population. The breadth of expertise in our four collaborative Projects and three scientific Cores and Results from the current and previous grant cycles allow us to pursue the following Specific Aims. (1) Can a suitable vaccination strategy modify or redirect immune "imprinting" -- the observed influence of an individual's history of infection of vaccination on their response to an antigenically drifted strain or novel subtype? We will determine the full scope of the human humoral response to vaccination in individuals of all ages (infants to seniors) and hence of varying exposures, and we will carry out, in non-human primates (NHPs), experiments to compare imprinting by infection and vaccination. (2) We have found (in mice) a strong effect of the anatomical location of immunization with protein antigen on the response to a subsequent immunization. We will determine whether this effect extends to infection and whether it is also true in NHPs. Experiments in mice will determine whether components of TFH cell memory are similarly localized and test the contribution of conserved T-cell epitopes to humoral imprinting. (3) We will design novel vaccine antigens to extend previous studies of human immune responses (focused on hemagglutinin) to influenza neuraminidase (NA) and to determine the importance of T-cell epitope diversity for design of optimized immunogens. We will also create a model for co-evolution of virus (immune escape) and humoral immunity (antibody affinity maturation) using directed molecular evolution in the laboratory.

摘要 - 总体流感病毒会响应牛群免疫力的压力而演变，从而导致进行性变化病毒抗原性和限制疫苗功效。该计划项目的目标是建立一个新型疫苗接种策略的安全机械基础，可能赋予长期免疫力面对当前循环亚型的快速抗原变异，并预期潜力将人畜共队亚型引入人口。我们四个的专业知识广度合作项目和三个科学核心以及当前和上一个赠款的结果周期使我们能够追求以下特定目标。（1）可以修改合适的疫苗接种策略或重定向免疫“印迹” - 个人感染病史的影响他们对抗原漂移菌株或新型亚型的反应的疫苗接种？我们将确定人类对所有年龄段个人疫苗接种的人体体液反应的全部范围（婴儿老年人），因此有不同的暴露，我们将在非人类灵长类动物（NHP）中进行实验比较感染和疫苗接种的印迹。（2）我们发现（在小鼠中）很强用蛋白质抗原免疫的解剖位置对随后的反应的影响免疫。我们将确定这种影响是否扩展到感染以及它是否在 NHP。小鼠中的实验将确定TFH细胞存储器的组件是否相似局部并测试保守的T细胞表位对体液印迹的贡献。（3）我们会的设计新型疫苗抗原，以扩展对人免疫反应的先前研究（重点是血凝素）至流感神经氨酸酶（NA）并确定T细胞表位的重要性设计优化免疫原的多样性。我们还将创建一个用于病毒共同进化的模型（免疫逃逸）和使用定向分子的体液免疫（抗体亲和力成熟）实验室的进化。