Features of Broad T Cell Coronavirus Immunity

项目2摘要 由SARS-CoV-2冠状病毒引起的2019冠状病毒病（COVID-19）已迅速成为全球性的疾病， 巨大的健康危机这场大流行，沿着2002年的SARS-CoV流行和MERS-CoV 2012年的流行病，突出了新出现的艾滋病毒/艾滋病对人类构成的极其危险的持续威胁， 人类嗜热带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的早期疫苗已经显示出显著的疗效，下一代疫苗 应提供广泛的保护，以抵御各种冠状病毒，并提高稳健性 针对新出现的威胁免疫逃逸的SARS-CoV-2变体。该计划的总体目标是 通过结合B细胞的关键免疫学信息， 以及SARS-CoV-2感染的抗体应答（项目1）和T细胞应答（项目2）， 疫苗接种到先进的结构设计和疫苗输送策略（项目3）。这个协同计划 旨在设计一种保护性的、持久的疫苗，能够在一系列人类中诱导免疫， 人畜共患冠状病毒。要做到这一点，需要更好地了解靶向的免疫显性表位 由B细胞和T细胞以及交叉反应的程度，这些反应对保守的 冠状病毒物种的表位。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子亚群（包括T辅助细胞类型）的强交叉反应性应答 1（TH 1），T滤泡辅助细胞（TFH）和细胞毒性T细胞（CTL）在循环和呼吸道中产生 粘膜组织驻留隔室。该项目的总体目标是应用从 我们在恢复期COVID-19患者和疫苗接种者以及 在小鼠模型中进行创新的新实验设计，为疫苗免疫原的设计提供信息 3，这将最大限度地提高交叉反应，但持久和功能多样的T细胞免疫，将保护免受 多种冠状病毒。我们假设T细胞对冠状病毒的免疫质量因表位而异 并且泛冠状病毒疫苗设计应该整合基于免疫优势的表位， 功能多样性和交叉反应性的广度。该项目的研究将确定最佳表位， 这个目的。具体而言，我们提出：1）从SARS-CoV-2的研究中鉴定SARS-CoV-2的CD 4 + T细胞表位。 恢复期COVID-19患者和表现出最大程度免疫优势的疫苗接种者， 2）评价交叉反应性CD 4 + T细胞表位在新型疫苗中的功效 在动物模型中诱导保护性免疫应答的免疫原;和3）发现新的I类MHC 表位，并评估其产生保护性CD 8 + 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.