Features of Broad T Cell Coronavirus Immunity

广泛 T 细胞冠状病毒免疫的特点

基本信息

批准号：
10328120
负责人：
ANDREW D LUSTER
金额：
$ 257.29万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10328120
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 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 Proteins Research Personnel Respiratory Mucosa Route SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 variant Severe Acute Respiratory Syndrome Somatic Mutation Structure Structure of germinal center of lymph node T cell response T memory cell T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Transgenic Mice Vaccinated Vaccination Vaccine Design Vaccines base betacoronavirus vaccine cross reactivity design efficacy evaluation global health human coronavirus human subject improved innovation mouse model novel vaccines pandemic disease programs response screening universal coronavirus vaccine vaccine candidate vaccine delivery vaccine efficacy zoonotic coronavirus

项目摘要

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总结由 SARS-CoV-2 冠状病毒引起的 2019 冠状病毒病 (COVID-19) 已迅速成为全球性流行病史无前例的健康危机。这次大流行以及 2002 年的 SARS-CoV 和 MERS-CoV 2012年的流行病凸显了新出现的新冠病毒对人类构成的极其危险的持续威胁人类热带冠状病毒正在从蝙蝠和其他野生动物物种转移到人类身上。因此，虽然 SARS-CoV-2 的早期疫苗已经表现出显着的功效，下一代疫苗应针对多种冠状病毒提供广泛的保护并提高稳健性对抗威胁免疫逃逸的新出现的 SARS-CoV-2 变体。本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冠状病毒疫苗策略 SARS-CoV-2 感染产生的抗体反应（项目 1）和 T 细胞反应（项目 2）疫苗接种采用先进的结构设计和疫苗输送策略（项目 3）。这个协同计划寻求设计一种具有保护性、持久性的疫苗，能够在人类和各种人群中诱导免疫力人畜共患冠状病毒。为此，需要更好地了解靶向的免疫显性表位 B 细胞和 T 细胞的反应以及这些反应针对保守细胞的交叉反应程度跨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器子集（包括 T 辅助细胞类型）的强大交叉反应反应 1 (TH1)、滤泡辅助 T 细胞 (TFH) 和循环和呼吸系统中产生的细胞毒性 T 细胞 (CTL) 粘膜组织驻留区室。该项目的总体目标是应用从我们对恢复期 COVID-19 患者和疫苗接种者以及 SARS-CoV-2 特异性 T 细胞的研究小鼠模型中的创新实验设计为疫苗免疫原的设计提供信息 3 将最大限度地提高交叉反应性，但持久且功能多样的 T 细胞免疫力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表位而异泛冠状病毒疫苗设计应结合基于免疫优势的表位，功能多样性和交叉反应的广度。该项目的研究将确定最佳表位这个目的。具体来说，我们建议：1) 从以下研究中鉴定 SARS-CoV-2 CD4+ T 细胞表位表现出最大程度免疫优势的恢复期 COVID-19 患者和疫苗接种者，耐久性和交叉反应性； 2) 评估新型疫苗中交叉反应CD4+ T细胞表位的功效免疫原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确定表位并评估其产生保护性 CD8+ T 细胞的能力小鼠的反应。