Defining the Fc-correlates of protection against influenza

摘要 NIAID已将通用流感疫苗的开发命名为其关键研究之一 目标，而传统的疫苗设计不能满足这一需求。一种全球化的设计 由于缺乏明确和可定义的疫苗，针对流感的保护性疫苗一直受到阻碍 流感免疫力的相关性。当前预防流感的相关性 感染，用来评价季节性流感疫苗，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 解释了对人类季节性流感感染的保护。相反，超中和 抗体依赖的先天免疫效应功能，包括抗体依赖的细胞 细胞毒性(ADCC)、抗体依赖吞噬作用(ADCP)和抗体依赖 补体激活(ADC)，都被认为与小鼠的保护有关。然而，它是 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、节省样本的体液侧写工具--它广泛地 以前所未有的深度捕捉FC-配置文件多样性-以定义额外的中和配置文件 追踪对人类流感的保护作用的抗体。两个独特的油井队列 将对特化的疫苗接种者进行概况分析，以确定保护的相关性和 中和抗体广度的进化。与小鼠的机械性解剖有关 将被解剖以定义指导下一代疫苗开发的机械环节 旨在诱导针对流感的功能性广谱中和抗体的策略。

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.