Features of Broad T Cell Coronavirus Immunity

广泛 T 细胞冠状病毒免疫的特点

• 批准号: 10842889
• 负责人: ANDREW D LUSTER
• 金额: $ 198.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842889
• 关键词: 2019-nCoV; Alleles; Animal Model; Antibody Response; Antigens; B-Lymphocytes; Binding; Biological Assay; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 patient; COVID-19 vaccine; Cell Line; Chiroptera; Coronavirus; Coupling; Cytotoxic T-Lymphocytes; Dangerousness; Development; Epidemic; Epitopes; Exhibits; Experimental Designs; Frequencies; Generations; Goals; Human; Humanities; Immune; Immune response; Immunity; Immunodominant Epitopes; Immunologic Memory; Immunologics; Individual; Infection; Intramuscular; K-18 conjugate; Knowledge; Libraries; Link; MHC Class I Genes; MHC binding peptide; Memory B-Lymphocyte; Methods; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Mucous Membrane; Mus; Patients; Peptide/MHC Complex; Peptides; Phenotype; Physical assessment; Proteins; Research Personnel; Respiratory Mucosa; Route; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 variant; Severe Acute Respiratory Syndrome; Somatic Mutation; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Transgenic Mice; Vaccinated; Vaccination; Vaccine Design; Vaccinee; Vaccines; betacoronavirus vaccine; cross reactivity; design; efficacy evaluation; global health; human coronavirus; human subject; improved; innovation; mouse model; novel vaccines; pandemic disease; programs; response; screening; tissue resident memory T cell; universal coronavirus vaccine; vaccine candidate; vaccine delivery; vaccine efficacy; vaccine strategy; zoonotic coronavirus

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.

项目2摘要 由SARS-COV-2冠状病毒引起的冠状病毒疾病2019年（COVID-19）已迅速成为全球 史诗比例的健康危机。这种大流行，以及2002年的SARS-COV流行和MERS-COV 2012年流行病强调了新兴的危险危险持续威胁 从蝙蝠和其他野生动植物物种过渡到人类的人类热带冠状病毒。因此， SARS-COV-2的早期疫苗已经表现出显着的功效，下一代疫苗 应为广泛的冠状病毒提供广泛的保护以及改善的鲁棒性 针对威胁免疫逃脱的新兴新兴SARS-COV-2变体。该计划的总体目标 是通过耦合有关B细胞的关键免疫学信息来设计泛氧化病毒疫苗策略 与SARS-COV-2感染的T细胞反应（项目2）和抗体反应（项目1）和 高级结构设计和疫苗输送策略的疫苗接种（项目3）。这个协同程序 试图设计一种能够诱导人类和人类范围内免疫的保护性耐用疫苗 人畜共努性冠状病毒。这样做将需要更好地了解针对的免疫主导表位 通过B细胞和T细胞以及交叉反应的程度，这些反应对保守 冠状病毒物种的表位。对于T细胞，这是项目2的焦点，耐用的泛氧化病毒 免疫力可能需要多个效应子集（包括T辅助）类型的鲁棒交叉反应反应 1（Th1），T卵泡辅助器（TFH）和循环和呼吸中产生的细胞毒性T细胞（CTL） 粘膜组织居民室。该项目的总体目标是运用从中获得的知识 我们对康复covid Covid-19患者和疫苗的SARS-COV-2特异性T细胞的研究以及 鼠标模型中创新的新实验设计，以告知项目的疫苗免疫剂的设计 3将最大化交叉反应性，但耐用且功能多样的T细胞免疫力，可以预防 多个冠状病毒。我们假设T细胞对冠状病毒的免疫质量随表位而变化 而且泛氧化病毒疫苗的设计应统称基于免疫主持的表位， 功能多样性和交叉反应性的广度。该项目中的研究将确定最佳的表位 这个目的。具体而言，我们建议：1）从研究中鉴定SARS-COV-2 CD4+ T细胞表位 疗养者199患者和疫苗表现出最大程度的免疫主持程度， 耐用性和交叉反应性； 2）评估新型疫苗中交叉反应性CD4+ T细胞表位的功效 免疫原子在动物模型中诱导保护性免疫反应； 3）发现新的MHC I类 使用创新筛选技术的表位并评估其产生保护性CD8+ T细胞的能力 小鼠的反应。