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

摘要-总体 流感病毒在群体免疫力的压力下进化，导致进行性变异 病毒抗原性和限制疫苗功效。该计划的目标是建立一个 为可能提供持久免疫力的新型疫苗接种策略奠定可靠的机制基础 面对目前流行亚型的快速抗原变异， 将人畜共患病亚型引入人群。我们四个领域的专业知识广度 合作项目和三个科学核心和结果，从目前和以前的赠款 我们的目标是实现以下几个具体目标。(1)一个合适的疫苗接种策略能改变 或重定向免疫“印记”--观察到的个人感染史的影响， 疫苗接种对他们对抗原漂移毒株或新亚型的反应有什么影响？我们将确定 所有年龄段的个体（婴儿至 老年人），因此不同的暴露，我们将进行，在非人类灵长类动物（NHP）， 通过感染和接种来比较印迹的实验。(2)我们发现， 蛋白抗原免疫的解剖学位置对随后免疫应答的影响 次免疫我们将确定这种影响是否延伸到感染，以及在感染中是否也是如此。 NHP。小鼠实验将确定TFH细胞记忆的组成部分是否类似于 定位并测试保守的T细胞表位对体液印迹的贡献。(3)我们将 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）对流感神经氨酸酶（NA）的作用，并确定T细胞表位的重要性 优化免疫原设计的多样性。我们还将建立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.