Antibody Durability Dynamics

项目摘要 针对致病威胁的抗体可以提供对传染病的即时保护，但 接种疫苗或感染后抗体反应的寿命可能有很大的变数。由以下因素引起的响应 一些活疫苗可以持续一生，而基于蛋白质的疫苗通常有效期较短。 然而，抗体持久性并不一定与使用活病毒作为长期抗体反应有关。 已被证明是由人乳头瘤病毒(HPV)疫苗诱导的，HPV是一种非活的病毒样颗粒- 基于平台。这表明，不同的免疫学信号可以被改造成导致 更持久的抗体反应。虽然记忆淋巴细胞也提供了一种保护效能的系统， 最大限度地提高保护性分泌抗体的强健水平并随着时间的推移保持稳定的策略是重要的 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 可用的疫苗可以引起持久的分泌型抗体反应，这对破译将是重要的。这是相关的 对于正在进行的SARS-CoV-2大流行和更广泛的疫苗战略。初步数据显示， 自然感染诱导的抗体在中等水平和更多的多克隆水平上具有强大的长期稳定性 与感染天真的疫苗接种者相比，中和病毒变异的广度。此外，差分 抗体持久性轨迹倾向于具有双记忆B细胞特征的新冠肺炎恢复期患者 更强的抗体体细胞突变和交叉冠状病毒反应性。这些发现支持这样一种假设 恢复早期抗原结合记忆B细胞库的高体细胞突变和交叉反应 预测抗体的持久性，召回的免疫可能赋予分化的血浆更长的寿命 细胞。这一假说将从两个方面进行检验：(一)阐明影响抗SARS-CoV-2的因素 抗体持久性，以及(Ii)绘制抗冠状病毒记忆B细胞随时间的功能演变图。对于目标1， 人类和老鼠的研究将被用来阐明潜在的机械洞察力和与 持久的抗体反应。对于目标2，记忆B细胞谱系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的演变关系 和记忆B细胞库。这项工作有望阐明影响长寿的因素和 抗体反应的进化，这对于疫苗策略的持续改进将是重要的。

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.