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Integrated Analysis of SARS-CoV-2 Vaccine Responses During Aging

衰老过程中 SARS-CoV-2 疫苗反应的综合分析

基本信息

批准号：
10175583
负责人：
Peter The Sage
金额：
$ 25.59万
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：
2021-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175583
关键词：
2019-nCoV Affect Affinity Aging Animal Model Antibodies Antibody Repertoire Antibody Response Antibody Specificity Antigens B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes COVID-19 pandemic COVID-19 vaccination COVID-19 vaccine Cell Culture Techniques Cells Clonality Clone Cells Data Defect Disease Effector Cell Elderly Equilibrium Goals HIV Helper-Inducer T-Lymphocyte Humoral Immunities Immune system Immunity Immunocompromised Host Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Individual Influenza Lead Memory B-Lymphocyte Modeling Mus Pathway interactions Population Populations at Risk Pre-Clinical Model Process Production Role SARS-CoV-2 antibody Signal Transduction Specificity System Testing Therapeutic antibodies Vaccination Vaccines Viral Virus age related base genetic approach immunoregulation mouse model neutralizing antibody novel novel strategies novel vaccines response tool vaccination strategy vaccine candidate vaccine effectiveness vaccine efficacy vaccine response

项目摘要

Production of high-affinity class-switched antibodies is essential for elimination of viruses and immunity elicited by vaccination. Vaccination has led to the eradication of some diseases, but in some settings do not provide sufficient protection, such as in elderly or immunocompromised individuals. Antibody responses are controlled by humoral immunoregulatory pathways, including inhibition by Tfr cells, which suppress B cell effector functions. Aged-related defects in vaccine responses are partially due to enhanced humoral immunoregulation by Tfr cells. Since the COVID19 pandemic disproportionally affects at-risk populations such as the elderly, new vaccine strategies need to be developed to enhance protection for this group. However, a fundamental understanding of how humoral immunoregulation associated with aging alters SARS-CoV-2 vaccine responses is lacking. We hypothesize that augmented humoral immunoregulation by Tfr cells during aging alters SARS-CoV-2 vaccine responses, and that limiting Tfr cells can enhance vaccine efficacy. We also hypothesize that limiting humoral immunoregulation results in production of new and unique therapeutic antibodies. To test these hypotheses, we will use a novel systems-based approach to integrate, on a per cell basis, SARS-CoV-2 antibody specificity, breadth, viral neutralization potential, and antibody sequence/clonality. We will use novel Tfr-deleter mice to assess how humoral immunoregulation alters these responses. Our aims are to 1) determine how augmented humoral immunoregulation in aging alters clonal selection of neutralizing antibodies during SARS-CoV-2 vaccination, and 2) determine how eliminating humoral immunoregulation enhances clonal selection of neutralizing antibodies. Our goals are to determine, in detail, how humoral immunoregulation alters antibody selection to control effector antibody responses after vaccination.

高亲和力类别转换抗体的生产对于消除病毒和引发免疫至关重要通过接种疫苗。疫苗接种导致了一些疾病的根除，但在某些情况下，足够的保护，如在老年人或免疫功能低下的人。抗体反应得到控制通过体液免疫调节途径，包括Tfr细胞的抑制，其抑制B细胞效应子功能。疫苗应答中的免疫缺陷部分是由于Tfr细胞增强的体液免疫调节。由于COVID-19大流行对老年人等高危人群产生了预防性影响，需要制定战略，加强对这一群体的保护。然而，一个基本的理解缺乏与衰老相关的体液免疫调节如何改变SARS-CoV-2疫苗反应的研究。我们假设衰老过程中Tfr细胞增强体液免疫调节改变SARS-CoV-2疫苗限制Tfr细胞可以增强疫苗的效力。我们还假设，限制体液免疫调节导致产生新的和独特的治疗性抗体。为了验证这些假设，我们将使用一种新的基于系统的方法，在每个细胞的基础上整合SARS-CoV-2抗体特异性，宽度、病毒中和潜力和抗体序列/克隆性。我们将使用新的Tfr-删除小鼠，评估体液免疫调节如何改变这些反应。我们的目标是1）确定如何增强衰老中的体液免疫调节改变SARS-CoV-2中和抗体的克隆选择疫苗接种，和2）确定消除体液免疫调节如何增强克隆选择，中和抗体我们的目标是详细地确定体液免疫调节如何改变抗体，选择以控制疫苗接种后的效应抗体应答。