Understanding Human B Cell Responses to Influenza to Improve the Influenza

了解人类 B 细胞对流感的反应以改善流感

• 批准号: 8667697
• 负责人: Patrick Christopher Wilson
• 金额: $ 41.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8667697
• 关键词: Accounting; Affect; Antibodies; Antibody Formation; Antigens; B cell differentiation; B-Lymphocytes; Binding; Cell physiology; Cells; Data; Development; Epidemic; Epitopes; Exposure to; Frequencies; Future; Genes; Glean; Head; Hemagglutinin; Human; Humoral Immunities; Immune Sera; Immunity; Immunology; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Masks; Mediating; Memory; Memory B-Lymphocyte; Monoclonal Antibodies; Nature; Neuraminidase; Phenotype; Population; Recording of previous events; Resources; Role; Serum; Shadowing (Histology); Short-Term Memory; Specificity; Staging; Therapeutic; Training; Vaccination; Vaccines; Variant; Virus; anti-influenza; base; cohort; improved; influenza virus vaccine; influenzavirus; inhibiting antibody; member; new technology; novel; novel strategies; pandemic disease; pandemic influenza; precursor cell; programs; research study; response; screening; vaccine efficacy

We have compelling new data demonstrating that providing the influenza vaccine in different contexts can induce dramatic shifts in long-term B cell memory to influenza. This important proof of concept suggests that human B cell responses can be re-trained as needed to improve vaccine efficacy. In this project we will explore the mechanism of these observations. The principles gleaned will be important in the development of an improved influenza vaccine. First, in Aim 1, we will explore the role of B cell memory and immune sera in redirecting antibody responses to particular epitopes upon re-exposure to variant influenza strains. Secondly, in Aim 2 we will determine if, like the response to hemagglutinin, a predominance of broadly cross-reactive B cells were activated against neuraminidase upon first exposure to the 2009 pandemic strain of influenza. We will also use novel approaches to determine how stable previously observed biased influenza epitope targeting in human populations is. Finally, we have identified what we believe is an "epidemic-memory" B cell differentiation that we hypothesize persists at high numbers for months rather than permanently, and provides immediate protection due to the highly likely re-exposure that will occur during an epidemic. We believe that these memory cells, when induced by vaccination with relevant or irrelevant strains, can substantially impact responses to variant influenza strains occurring in the near future in an original-antigenic sin (OAS) fashion. In fact, these cells may account for the dramatic shifts that we observed for some but not all members of our cohort, leading to responses with either greater breadth or more strain-specific responses. We will explore the phenotype and function of these cells. Further, by determining the specificity of the B cells from this population we will directly determine the impact of these memory cells upon re-exposure to a divergent influenza strain. Understanding the types and stages of B cell memory will allow better targeting of the influenza vaccine response. Finally, in the context of these studies we will develop new technologies such as our "epitope-shadowing" approach using our novel mAb microarray platform to allow rapid and global screening of both monoclonal and polyclonal (serum) epitope targeting. We will also generate a large panel of human mAbs against influenza. These antibodies may identify epitopes important for developing a broadly protective vaccine or the mAbs themselves may have therapeutic potential.

我们有令人信服的新数据表明，在不同的环境下提供流感疫苗可以诱导长期B细胞记忆向流感的戏剧性转变。这一重要的概念证明表明，可以根据需要重新训练人类B细胞反应，以提高疫苗效力。在这个项目中，我们将探索这些观测的机制。收集到的原则将在改进的流感疫苗的开发中发挥重要作用。首先，在目标1中，我们将探索B细胞记忆和免疫血清在再次暴露于不同的流感毒株时，将抗体反应重定向到特定表位的作用。其次，在目标2中，我们将确定是否像对血凝素的反应一样，在首次暴露于2009年流感大流行毒株时，针对神经氨酸酶激活了广泛交叉反应的优势B细胞。我们还将使用新的方法来确定之前观察到的偏向流感表位靶向在人类群体中的稳定性。最后，我们已经确定了我们认为是一种“流行病--记忆”B细胞分化，我们假设这种分化会以高数量持续数月而不是永久存在，并由于在流行病期间极有可能再次暴露而提供即时保护。我们相信，当这些记忆细胞通过接种相关或无关的毒株而被诱导时，可以以原始抗原SIN(OAS)的方式实质上影响对在不久的将来发生的变异流感毒株的反应。事实上，这些细胞可能解释了我们在队列中观察到的一些但不是所有成员的戏剧性变化，导致了更广泛的反应或更具菌株特异性的反应。我们将探索这些细胞的表型和功能。此外，通过确定该人群中B细胞的特异性，我们将直接确定这些记忆细胞在再次暴露于一种不同的流感毒株时的影响。了解B细胞记忆的类型和阶段将有助于更好地针对流感疫苗反应。最后，在这些研究的背景下，我们将开发新的技术，如使用我们的新型单抗微阵列平台的“表位跟踪”方法，以实现对单克隆和多克隆(血清)表位靶向的快速和全球筛选。我们还将产生一大批人类抗流感单抗。这些抗体可能识别对开发广泛保护性疫苗重要的表位，或者单抗本身可能具有治疗潜力。