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.

项目概要 针对病原体威胁的特异性抗体可以提供针对传染病的立即保护，但 疫苗接种或感染后抗体反应的持续时间可能存在很大差异。 一些活疫苗可以持续一生，而基于蛋白质的疫苗通常持续时间较短。 然而，抗体耐久性并不一定与使用活病毒作为长效抗体反应有关 已被证明是由人乳头瘤病毒 (HPV) 疫苗（一种非活病毒样颗粒）诱导的 这表明可以设计不同的免疫线索来产生 更长寿命的抗体反应虽然记忆淋巴细胞也提供保护功效系统， 最大限度地提高随时间稳定的保护性分泌抗体的强大水平的策略是一个重要的 了解免疫系统在这方面的能力以及如何实现这一目标。 现有的疫苗能否引发持久的分泌性抗体反应对于破译这一点很重要。 针对正在进行的 SARS-CoV-2 大流行以及更广泛的疫苗策略，初步数据表明： 自然感染诱导的抗体在适度水平和更高的多克隆性下具有强大的长期稳定性 与未感染疫苗相比，中和病毒变体的广度。 抗体持久性轨迹倾向于有利于具有双记忆 B 细胞特征的 COVID-19 恢复期受试者 这些发现支持了一个假设：更大的抗体体细胞突变和交叉冠状病毒反应性。 恢复后早期抗原结合记忆 B 细胞库中存在高体细胞突变和交叉反应性 预测抗体的耐久性，并且回忆的免疫力可能会赋予分化血浆更长的寿命 该假设将通过两个目的进行检验，(i) 阐明影响抗 SARS-CoV-2 的因素。 抗体耐久性，以及 (ii) 绘制抗 CoV 记忆 B 细胞随时间的功能演变图。 对于目标 1， 人类和小鼠研究将用于阐明潜在的机制见解和相关特征 对于目标 2，记忆 B 细胞库抗原的持久性和进化。 识别能力将随着时间的推移绘制图表，以评估分泌的多克隆之间不断变化的关系 这项工作有望揭示影响寿命和记忆的因素。 抗体反应的演变，这对于疫苗策略的持续改进非常重要。