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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：
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
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/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

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.

项目二总结