Antibody Durability Dynamics

抗体耐久性动力学

• 批准号: 10654056
• 负责人: Duane R. Wesemann
• 金额: $ 68.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654056
• 关键词: Affinity; Animal Model; Antibodies; Antibody Response; Antigens; Attenuated Vaccines; Automobile Driving; B cell repertoire; B-Cell Activation; B-Lymphocytes; Binding; COVID-19; COVID-19 pandemic; Cell Communication; Communicable Diseases; Coronavirus; Cues; Data; Disease; Dose; Engineering; Epitopes; Evolution; Frequencies; Future; Generations; Goals; Human; Human Papilloma Virus Vaccine; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunologics; Immunology; Infection; Invaded; Light; Link; Longevity; Lymphocyte; Memory; Memory B-Lymphocyte; Modernization; Mus; Mutation; Pathogenicity; Plasma Cells; Proteins; Public Health; RNA vaccination; Recovery; Research; SARS-CoV-2 antibody; SARS-CoV-2 infection; Sampling; Somatic Mutation; Speed; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Time; Vaccination; Vaccine Design; Vaccinee; Vaccines; Variant; Viral; Virus; Work; antigen binding; cohort; cross reactivity; improved; insight; neutralizing antibody; particle; pathogen; plasma cell differentiation; polyclonal antibody; post SARS-CoV-2 infection; prophylactic; protective efficacy; response; time interval; vaccine access; vaccine strategy

Project Summary Antibodies specific for pathogenic threats can provide immediate protection from infectious disease but longevity of an antibody responses after vaccination or infection can be highly variable. Responses induced by some live vaccines can persist for a lifetime, whereas protein-based vaccines are in general shorter lasting. However, antibody durability is not necessarily linked to the use of live virus as long-lived antibody responses have been shown to be induced by the human papilloma virus (HPV) vaccine, a non-live viral-like particle- based platform. This suggests that distinct immunological cues can be engineered to result in the generation of longer-lived antibody responses. While memory lymphocytes also provide a system of protective efficacy, strategies to maximize robust levels of protective secreted antibodies that are stable over time is an important goal in modern immunology. Understanding the capabilities of the immune system in this context, and how available vaccines can elicit durable secreted antibody responses will be important to decipher. This is relevant to the ongoing SARS-CoV-2 pandemic and for vaccine strategies more broadly. Preliminary data suggest that antibodies induced by natural infection harbor robust long-term stability at modest levels and greater polyclonal neutralizing breadth across viral variants compared to infection-naïve vaccinees. In addition, differential antibody durability trajectories tend to favor COVID-19 convalescent subjects with dual memory B cell features of greater antibody somatic mutation and cross-coronavirus reactivity. These findings support a hypothesis that high somatical mutation and cross-reactivity in antigen-binding memory B cell repertoires early after recovery predicts antibody durability and that recalled immunity may confer greater longevity of differentiated plasma cells. This hypothesis will be examined in two aims, (i) to illuminate factors influencing anti-SARS-CoV-2 antibody durability, and (ii) to chart the functional evolution of anti-CoV memory B cell over time. For aim 1, human and mouse studies will be used to illuminate potential mechanistic insights and features connected to durable antibody responses. For aim 2, the durability and evolution of memory B cell repertoire antigen recognition capacity will be charted over time to assess the evolving relationship between secreted polyclonal and memory B cell repertoires. This work is expected to shed light on factors that influence longevity and evolution of antibody responses, which will be important for ongoing improvement of vaccine strategies.

项目摘要 针对病原体威胁的特异性抗体可以提供对传染病的直接保护， 疫苗接种或感染后抗体应答的寿命可以是高度可变的。诱导的反应 一些活疫苗可以持续一生，而蛋白质疫苗通常持续时间较短。 然而，抗体持久性不一定与使用活病毒作为长寿命抗体应答有关 已被证明是由人乳头瘤病毒（HPV）疫苗诱导的，HPV疫苗是一种非活的病毒样颗粒， 基于平台。这表明，不同的免疫学线索可以被工程化以导致产生免疫应答。 寿命更长的抗体反应。虽然记忆淋巴细胞也提供了一种保护功效系统， 最大化随时间稳定的保护性分泌抗体的稳健水平的策略是重要的 现代免疫学的目标。了解免疫系统在这种情况下的能力，以及如何 现有的疫苗能否引发持久的分泌性抗体应答将是重要的。这是相关 对正在进行的SARS-CoV-2大流行和更广泛的疫苗战略。初步数据显示， 由自然感染诱导的抗体在适度水平和更高的多克隆水平下具有稳健的长期稳定性。 与未感染过的疫苗接种者相比，此外，差分 抗体持久性轨迹倾向于有利于具有双重记忆B细胞特征的COVID-19恢复期受试者 更强的抗体体细胞突变和交叉冠状病毒反应性。这些发现支持了一个假设， 恢复后早期抗原结合记忆B细胞库中高度体细胞突变和交叉反应性 预测抗体的持久性，并且召回的免疫可能赋予分化的血浆更长的寿命。 细胞这一假设将在两个目标进行检验，（i）阐明影响抗SARS-CoV-2的因素 抗体耐久性，和（ii）绘制抗CoV记忆B细胞随时间的功能进化。对于目标1， 人类和小鼠的研究将用于阐明潜在的机制见解和特征， 持久的抗体反应。目的2：记忆B细胞库抗原的持久性和进化 随着时间的推移，识别能力将被绘制成图表，以评估分泌的多克隆抗体之间的演变关系。 和记忆B细胞库。这项工作有望揭示影响寿命的因素， 抗体反应的演变，这将是重要的不断改进的疫苗战略。