Defining the Fc-correlates of protection against influenza

定义流感保护的 Fc 相关因素

• 批准号: 10599256
• 负责人: Daniel Lingwood
• 金额: $ 60.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-11 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599256
• 关键词: Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody-mediated protection; Antigen Presentation; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Automobile Driving; B-Lymphocytes; Binding; Biology; Cells; Characteristics; Complement; Complement Activation; Complement Receptor; Data; Deposition; Development; Dissection; Evolution; Failure; Fc Receptor; Future; Goals; Hemagglutination; Human; Humoral Immunities; Immune; Immunity; Individual; Infection; Infection prevention; Inflammation; Influenza; Innate Immune System; Link; Measures; Mediating; Mus; Names; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Phagocytes; Phagocytosis; Play; Reaction; Research; Role; Sampling; Seasons; Shapes; Structure of germinal center of lymph node; T-Lymphocyte; Vaccination; Vaccine Design; Vaccinee; Vaccines; Variant; Viral Physiology; Virus; antibody-dependent cell cytotoxicity; case control; cohort; cytotoxicity; design; epidemiology study; global health; glycosylation; immune activation; immunoregulation; influenza infection; influenza virus vaccine; innate immune function; insight; mouse model; neutralizing antibody; next generation; novel; novel vaccines; pathogen; recruit; seasonal influenza; tool; universal influenza vaccine; vaccine development; vaccine response; vaccine strategy; vaccine-induced antibodies; vaccine-induced immunity

Abstract The NIAID has named the development of a universal influenza vaccine as one if its key research goals, and this need will not be met with traditional vaccine design. The design of a globally protective vaccine against influenza has been hampered by the lack of a clear and definable correlate of immunity against influenza. The current correlate of protection from influenza infection, used to evaluate seasonal influenza vaccines, is the hemagglutination inhibition (HAI) titer, an indirect measure of virus neutralization by antibodies. However, HAI incompletely explains protection from seasonal influenza infection in humans. Conversely, extra-neutralizing antibody-dependent innate immune effector functions, including antibody dependent cellular cytotoxicity (ADCC), antibody dependent phagocytosis (ADCP), and antibody dependent complement activation (ADC), have all been implicated in protection in mice. However, it is uncertain whether non-neutralizing functions contribute to protection in humans. Thus, here we aim to exploit a comprehensive, agnostic, sample-sparing humoral profiling tool - that broadly captures Fc-profile diversity at unprecedented depths - to define the extra-neutralizing profiles of antibodies that track with protection against influenza in humans. Two unique cohorts of well characterized vaccinees will be profiled to define correlates of protection and correlates of the evolution of neutralizing antibody breadth. Linked to mechanistic dissection in mice, correlates will be dissected to define mechanistic links to guide the development of next generation vaccine strategies aimed at inducing functional-broadly neutralizing antibodies against influenza.

抽象的 NIAID将通用流感疫苗的开发命名为一种主要研究 目标，传统疫苗设计将不会满足这种需求。全球设计 缺乏明确可确定的保护性疫苗，阻碍了针对流感的影响 对流感的免疫相关。当前保护免受流感的保护 用于评估季节性流感疫苗的感染是血凝抑制（HAI） 滴度，一种通过抗体中和病毒中和的间接度量。但是，海并不完全 解释了免受人类季节性流感感染的保护。相反，除外 抗体依赖性的先天免疫效应子功能，包括抗体依赖性细胞 细胞毒性（ADCC），抗体依赖性吞噬作用（ADCP）和抗体依赖性 补体激活（ADC）都与小鼠的保护有关。但是，是 不确定非中和功能是否有助于人类的保护。因此，我们在这里 旨在利用一种全面的，不可知论的，分类的幽默分析工具 - 广泛地 捕获前所未有的深度捕获FC-Profile多样性 - 定义除外的轮廓 通过保护人类流感的保护的抗体。两个独特的人群 特征的疫苗将被介绍以定义保护的相关性和相关性 中和抗体宽度的演变。与小鼠的机械解剖有关，相关性 将解剖以定义机械链接以指导下一代疫苗的开发 旨在诱导对流感的功能性中和抗体的策略。