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

摘要--总体 流感病毒在群体免疫的压力下进化，导致渐进性变异。 病毒的抗原性和有限的疫苗效力。该计划项目的目标是建立一个 为可能提供持久免疫力的新型疫苗接种策略奠定坚实的机制基础 面对当前流通亚型的快速抗原变异和潜在的 将人畜共患病亚型引入人类群体。我们四家公司的专业知识广度 合作项目和三个科学核心以及来自当前和以前赠款的成果 周期使我们能够追求以下具体目标。(1)合适的疫苗接种策略是否可以修改 或重定向免疫“印记”--观察个体感染史的影响 根据他们对抗原漂移的菌株或新亚型的反应接种疫苗？我们将决定 所有年龄段的人(婴儿到婴儿)对接种疫苗的全部体液反应 老年人)，因此暴露在不同的环境中，我们将在非人类灵长类动物(NHP)中进行， 比较感染和接种的印记的实验。(2)我们发现(在老鼠身上)有很强的 蛋白质抗原免疫的解剖位置对后续免疫应答的影响 免疫接种。我们将确定这种影响是否延伸到感染，以及在 国家卫生保健计划。在小鼠身上的实验将确定TFH细胞记忆的成分是否类似 定位并测试保守的T细胞表位对体液印记的贡献。(3)我们会 设计新的疫苗抗原以扩展先前对人类免疫反应的研究(重点是 血凝素)与流感神经氨酸酶(NA)结合，并确定T细胞表位的重要性 优化免疫原设计的多样性。我们还将创建一个病毒共同进化的模型 (免疫逃逸)和体液免疫(抗体亲和力成熟) 实验室里的进化。

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.