Dynamics of the protective vaccine-induced human influenza neuraminidase B cell response

保护性疫苗诱导的人流感神经氨酸酶 B 细胞反应的动态

基本信息

批准号：
9765486
负责人：
James J Kobie
金额：
$ 75.01万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2019-09-16 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765486
关键词：
Adjuvant Adult Animals Antibodies Antibody Repertoire Antibody Response Antibody Specificity Antiviral Agents B-Lymphocytes Blood Circulation Bone Marrow Cavia Cell Lineage Cells Characteristics Clone Cells Dependence Development Epitopes Evolution Frequencies Future Genetic Glycoproteins Hemagglutinin Human Immune response Immunity Immunization Immunoglobulin G In Vitro Infection Influenza Influenza B Virus Influenza Hemagglutinin Intramuscular Lung Inflammation MF59 Mediating Modality Monoclonal Antibodies Mus Mutation Neuraminidase Phagocytosis Plasma Cells Prevention Process Production Property Proteins Receptors, Antigen, B-Cell Research Resolution Seasons Serum Severity of illness Site Source Specificity Surface Testing Therapeutic Translating Vaccination Vaccines Viral Viral Physiology Virion Virus Virus Shedding antibody-dependent cell cytotoxicity complement pathway deep sequencing flu transmission human monoclonal antibodies immunogenic in vivo influenza virus vaccine insight novel vaccines pandemic influenza peripheral blood prevent resistant strain response transcriptomics transmission process universal vaccine vaccine development

项目摘要

PROJECT SUMMARY The human immune response against influenza is dominated by the production of hemagglutinin (HA)-specific antibodies (Abs). The yearly mutation rate in influenza HA proteins is 1-2% leading to development of new viral strains that are resistant to previous immunity. The other most predominant glycoprotein on the virion surface is neuraminidase (NA). Although immunogenic, predominance of human NA-specific Abs is much lower than HA, probably because NA expression is only one fourth the amount of HA on the virion surface. The yearly rate of mutation of NA is about half that of HA while part of the enzymatic site remains conserved across type A (IAV) and B (IBV) influenza viruses, making NA a potentially effective target for universal vaccine and therapeutic human monoclonal Ab (hmAb) development. Antibody responses targeting NA have demonstrated protective and therapeutic activity against influenza infection in animals, and in humans NA-inhibiting serum Abs have been correlated with effective protection, reduced disease severity, and duration of viral shedding, independent of or more strongly than HA-specific Ab responses, substantiating NA as a valuable target for the prevention and treatment of influenza in humans. Although seasonal human inactivated influenza vaccines (IIV) contain NA, the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Our research has demonstrated that IIV in humans does induce both IAV and IBV NA- specific B cells, and that the Ab clonal lineages they encode for include those that have broad and potent ability to protect and treat influenza infection. Further, we have demonstrated that these protective NA-specific B cell clonal lineages are present in long-lived bone marrow plasma cells in humans following IIV and are the likely source for their sustained presence in circulation. We posit that NA-mediated universal humoral protection, like HA, is dependent on B cell receptor/Ab specificity, however, to a greater extent than HA is also highly dependent on the precise Fc/IgG subclass composition of the NA-specific Ab repertoire. Our central hypothesis is that human IIV induces NA-specific B cell responses with broad protective potential, however, those with both the proper specificity and anti-viral activity to confer universal protection are subdominant and sporadically induced, hence at insufficient abundance to confer optimal protection. Through precisely defining the dynamics of those protective human NA-specific B cell clonal lineages, including their induction, frequency, persistence, precise specificity, and mechanisms of action, we expect to obtain insight on how to optimally stimulate them for future human universal vaccine strategies. To that end, we propose 1) define the evolution of human NA-specific B cell clonal lineages in response to seasonal IIV 2) assess the ability of IIV-induced human NA B cell lineages to inhibit infection and transmission and 3) evaluate the Fc-dependence of NA-specific hmAb protection. The process for the development of protective human NA-specific B cell clonal lineages will be defined and strategies to translate this to universal human vaccine-mediated protection from influenza infection identified.

项目概要人体针对流感的免疫反应主要是产生特定的血凝素 (HA) 抗体（Ab）。流感HA蛋白每年的突变率为1-2%，导致新病毒的发展对先前的免疫有抵抗力的菌株。病毒粒子表面的另一种最主要的糖蛋白是神经氨酸酶（NA）。尽管人类 NA 特异性抗体的免疫原性优势远低于 HA，可能是因为 NA 表达量仅为病毒颗粒表面 HA 量的四分之一。每年的比率为 NA 的突变约为 HA 的一半，而部分酶位点在 A 型 (IAV) 中保持保守和 B (IBV) 流感病毒，使 NA 成为通用疫苗和治疗的潜在有效靶点人单克隆抗体 (hmAb) 开发。针对 NA 的抗体反应已被证明具有保护作用 NA抑制血清抗体对动物和人类流感感染的治疗活性与有效保护、疾病严重程度降低和病毒脱落持续时间相关，独立于或比 HA 特异性抗体反应更强烈，证实 NA 作为预防和预防的有价值的目标治疗人类流感。尽管季节性人类灭活流感疫苗 (IIV) 含有 NA，但疫苗接种诱导的保护性人类 NA 特异性体液反应的程度和作用机制都不好解决。我们的研究表明，人类 IIV 确实会诱发 IAV 和 IBV NA- 特定的 B 细胞，并且它们编码的 Ab 克隆谱系包括那些具有广泛而有效能力的抗体谱系保护和治疗流感感染。此外，我们还证明这些保护性 NA 特异性 B 细胞克隆谱系存在于人类 IIV 后的长寿骨髓浆细胞中，并且可能是它们在流通中持续存在的来源。我们假设 NA 介导的普遍体液保护，例如 HA 依赖于 B 细胞受体/抗体特异性，但在更大程度上比 HA 也高度依赖 NA 特异性抗体库的精确 Fc/IgG 亚类组成。我们的中心假设是人 IIV 诱导 NA 特异性 B 细胞反应，具有广泛的保护潜力，然而，那些同时具有赋予普遍保护的适当特异性和抗病毒活性是次显性的和零星诱导的，因此丰度不足以提供最佳保护。通过精确定义这些因素的动态保护性人类 NA 特异性 B 细胞克隆谱系，包括其诱导、频率、持久性、精确性特异性和作用机制，我们希望深入了解如何在未来最佳地刺激它们人类通用疫苗策略。为此，我们建议 1) 定义人类 NA 特异性 B 细胞的进化响应季节性 IIV 的克隆谱系 2) 评估 IIV 诱导的人 NA B 细胞谱系的能力抑制感染和传播，3) 评估 NA 特异性 hmAb 保护的 Fc 依赖性。这将定义保护性人类 NA 特异性 B 细胞克隆谱系的开发过程和策略将其转化为通用的人类疫苗介导的流感感染保护作用。