Features of Broad T Cell Coronavirus Immunity

项目2摘要 由SARS-CoV-2冠状病毒引起的2019年冠状病毒病(新冠肺炎)迅速成为全球性的 史诗般的健康危机。这场大流行与2002年的SARS-CoV疫情和MERS-CoV一起 2012年的流行病，突显了新兴经济体对人类构成的巨大危险的持续威胁 嗜人冠状病毒正在从蝙蝠和其他野生动物物种过渡到人类。因此，虽然 SARS-CoV-2早期疫苗已经显示出显著的疗效，下一代疫苗 应提供针对多种冠状病毒的广泛保护以及增强的健壮性 对抗新出现的威胁免疫逃逸的SARS-CoV-2变种。这项计划的总体目标是 是通过结合关于B细胞的关键免疫学信息来设计泛冠状病毒疫苗策略 和抗体反应(项目1)和来自SARS-CoV-2感染的T细胞反应(项目2)和 疫苗接种到先进的结构设计和疫苗交付战略(项目3)。这一协同计划 寻求设计一种保护性的、持久的疫苗，能够诱导一系列人类以及 人畜共患冠状病毒。要做到这一点，需要更好地了解目标免疫优势表位。 通过B细胞和T细胞以及交叉反应的程度来对抗保守的 冠状病毒物种间的表位。对于T细胞，这是项目2的重点，持久的泛冠状病毒 免疫可能需要多个效应器子集的强大交叉反应，包括T辅助类型 1(TH1)、T滤泡辅助细胞(TFH)和细胞毒性T细胞(CTL)在循环和呼吸中产生 粘膜组织驻留的隔室。这个项目的总体目标是应用从 新冠肺炎恢复期患者、疫苗接种者及成人血清中SARS-CoV-2特异性T细胞的研究 创新的小鼠模型实验设计，为疫苗免疫原的设计提供信息 3它将最大限度地提高交叉反应，但持久的和功能多样化的T细胞免疫将防止 多种冠状病毒。我们假设T细胞对冠状病毒的免疫质量因抗原表位而异 而泛冠状病毒疫苗的设计应该包括基于免疫优势的共同表位， 功能多样性和交叉反应的广度。这个项目中的研究将确定最好的表位 这就是目的。具体地说，我们建议：1)通过对SARS-CoV-2 CD4+T细胞表位的研究确定SARS-CoV-2 正在康复的新冠肺炎患者和表现出最大程度免疫优势的疫苗接种者， 持久性和交叉反应性；2)评价交叉反应性CD4+T细胞表位在新型疫苗中的有效性 在动物模型中诱导保护性免疫反应的免疫原；以及3)发现新的MHC I类 利用创新的筛选技术筛选表位并评估其产生保护性CD8+T细胞的能力 小鼠的反应。

Project 2 Summary Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 coronavirus, has quickly become a global health crisis of epic proportion. This pandemic, along with the SARS-CoV epidemic of 2002 and MERS-CoV epidemic of 2012, highlights the tremendously dangerous ongoing threat to humanity posed by emerging human-tropic coronaviruses that are transitioning from bats and other wildlife species into humans. Thus, while early vaccines for SARS-CoV-2 have already demonstrated remarkable efficacy, next generation vaccines should deliver broad protection against a wide spectrum of coronaviruses as well as improved robustness against newly emerging SARS-CoV-2 variants that threaten immune escape. The overall goal of this program is to design a pan-coronavirus vaccine strategy by coupling key immunological information regarding the B cell and antibody response (Project 1) with the T cell response (Project 2) from SARS-CoV-2 infection and vaccination to advanced structural design and vaccine delivery strategies (Project 3). This synergistic program seeks to design a protective, durable vaccine able to induce immunity across a spectrum of human as well as zoonotic coronaviruses. To do so will require a better understanding of the immunodominant epitopes targeted by B cells and T cells as well as the extent of cross-reactivity these responses have against conserved epitopes across coronavirus species. For T cells, which is the focus of Project 2, durable pan-coronavirus immunity will likely require robust cross-reactive responses by multiple effector subsets, including T helper type 1 (TH1), T follicular helper (TFH), and cytotoxic T cells (CTL) generated in both circulating and respiratory mucosal tissue-resident compartments. The overall goal of this project is to apply the knowledge gained from our studies of SARS-CoV-2-specific T cells in convalescent COVID-19 patients and vaccinees as well as innovative new experimental designs in mouse models to inform the design of vaccine immunogens by Project 3 that will maximize cross-reactive, yet durable and functionally diverse T cell immunity that will protect against multiple coronaviruses. We hypothesize that the quality of T cell immunity to coronaviruses varies by epitope and that pan-coronavirus vaccine design should incorporate epitopes based collectively on immunodominance, functional diversity, and breadth of cross-reactivity. The studies in this project will identify the best epitopes for this purpose. Specifically, we propose: 1) To identify SARS-CoV-2 CD4+ T cell epitopes from studies of convalescent COVID-19 patients and vaccinees that exhibit the greatest extent of immunodominance, durability, and cross-reactivity; 2) Evaluate the efficacy of cross-reactive CD4+ T cell epitopes in novel vaccine immunogens to induce protective immune responses in animal models; and 3) Discover new MHC class I epitopes using innovative screening technologies and evaluate their ability to generate protective CD8+ T cell responses in mice.