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

产生高亲和力的类转换抗体是消除病毒和引起免疫的关键 通过接种疫苗。接种疫苗导致了一些疾病的根除，但在某些情况下并没有提供 足够的保护，例如对老年人或免疫功能受损的个人。抗体反应受到控制 通过体液免疫调节途径，包括抑制B细胞效应器功能的TFR细胞的抑制。 疫苗应答中与年龄相关的缺陷部分是由于TFR细胞增强的体液免疫调节。 由于COVID19大流行对老年人等高危人群的影响不成比例，新的疫苗 需要制定战略，加强对这一群体的保护。然而，一个基本的理解是 目前尚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。我们 TFR细胞在衰老过程中增强体液免疫调节的假设改变了SARS-CoV-2疫苗 限制转铁蛋白受体细胞可以提高疫苗效力。我们还假设限制幽默 免疫调节导致产生新的独特的治疗性抗体。为了检验这些假设，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， 广度、病毒中和潜力和抗体序列/克隆性。我们将使用新的TfR-deleter小鼠来 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 增龄过程中体液免疫调节改变SARS-CoV-2期间中和抗体的克隆选择 疫苗接种，以及2)确定消除体液免疫调节如何增强克隆选择 中和抗体。我们的目标是详细确定体液免疫调节如何改变抗体。 疫苗接种后控制效应者抗体反应的选择。

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.