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.

摘要 NIAID已将开发通用流感疫苗列为其重点研究之一 这一需求将无法通过传统的疫苗设计来满足。设计一个全球 由于缺乏一个明确和可定义的疫苗， 与流感免疫力相关。当前预防流感的相关因素 用于评估季节性流感疫苗的血凝抑制（HAI） 滴度，抗体中和病毒的间接量度。然而，HAI不完全 解释保护人类免受季节性流感感染。相反， 抗体依赖性先天免疫效应子功能，包括抗体依赖性细胞免疫效应子功能， 细胞毒性（ADCC）、抗体依赖性吞噬作用（ADCP）和抗体依赖性吞噬作用（ADCC）。 补体激活（ADC）都与小鼠的保护作用有关。但据 不确定非中和功能是否有助于人类的保护。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-以定义额外的中和谱 追踪保护人类免受流感侵害的抗体。两组独特的油井 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 中和抗体宽度的演变。与小鼠的机械解剖有关， 将进行剖析，以确定机制环节，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。