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列为其重点研究之一 目标，而传统的疫苗设计无法满足这一需求。全球范围内的设计 由于缺乏明确和可定义的疫苗，预防流感的保护性疫苗受到阻碍 流感免疫力的相关性。目前流感防护的相关性 感染，用于评估季节性流感疫苗，是血凝抑制（HAI） 滴度，抗体中和病毒的间接量度。然而，HAI 并不完全 解释了人类免受季节性流感感染的保护。反之，超中和 抗体依赖性先天免疫效应功能，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）均与小鼠的保护作用有关。然而，它是 不确定非中和功能是否有助于保护人类。因此，在这里我们 旨在开发一种全面的、不可知的、样本保留的体液分析工具——广泛地 在前所未有的深度捕获 Fc 谱多样性 - 定义额外中和谱 追踪人类流感保护的抗体。两个独特的井群 将对特征化的疫苗接种者进行分析，以确定保护的相关性和疫苗接种的相关性。 中和抗体宽度的演变。与小鼠的机械解剖有关，相关 将进行剖析以确定机械联系以指导下一代疫苗的开发 旨在诱导针对流感的功能性广泛中和抗体的策略。