Defining humoral correlates of immunity against COVID-19

定义 COVID-19 免疫力的体液相关性

• 批准号: 10265799
• 负责人: Galit Alter
• 金额: $ 35.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265799
• 关键词: Adenoviruses; Animal Model; Animals; Antibodies; Antibody Response; COVID-19; Coronavirus; DNA; Development; Disease; Ferrets; Future; Immune; Immune response; Immunity; Immunize; Infection; Lead; Link; Lung diseases; Macaca; Macaca mulatta; Machine Learning; Modeling; Mus; Passive Transfer of Immunity; Resolution; Role; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Sampling; Serology; System; Translating; Vaccination; Vaccine Design; Vaccines; Virus Diseases; Work; immunoregulation; insight; novel therapeutics; pathogen; prevent; protective efficacy; vaccine development

Since 2002, several coronaviruses have emerged able to cause severe respiratory disease, however no vaccine is available to prevent these rapidly spreading pathogens. Vaccine design has specifically lagged due to our lack of understanding of the correlates of immunity against these pathogens. Both cellular and humoral immune responses have been implicated in resolution of disease, but to date only the passive transfer of antibodies has been shown to confer complete protection in mice. Interestingly, the transfer of both “neutralizing” and nonneutralizing antibodies have shown protective efficacy, highlighting the role of multiple humoral mechanisms in limiting viral infection/spread. The precise mechanism of action of these antibodies that have the most profound impact on limiting disease is currently unclear, but if elucidated could provide critical insights for the development of effective vaccines against COVID-19 and other coronaviruses. Thus, here we aim to take a systematic approach to dissect and define both the polyclonal and monoclonal mechanisms by which antibodies confer protection against COVID-19. Specifically, samples from DNA- and adenovirus 26 (Ad26)- COVID-19 Spike protein (S) immunized animals, that will be challenged with COVID-19, will be comprehensively profiled using Systems Serology, to define the functional humoral immune responses linked to protection from infection/disease in mice, ferrets, and macaques. Machine learning modeling will be employed to discern key immune response features that translate usefully across these diverse animal contexts. These studies will not only define correlates of immunity across vaccines and species, but also provide mechanistic insights into the precise mechanisms by which antibodies may confer protection in the context of future vaccines.

自2002年以来，已经出现了几种冠状病毒来引起严重的呼吸道疾病，但是没有疫苗可防止这些快速传播的病原体。由于我们对这些病原体的免疫学相关性缺乏了解，因此疫苗设计特别滞后。在疾病的解决方案中，均暗示了细胞和体液免疫调查，但迄今为止，仅显示抗体的被动转移已显示以会议在小鼠中完全保护。有趣的是，“中和”和非中和抗体的转移均显示出受保护的有效性，突出了多种体液机制在限制病毒感染/扩散中的作用。目前尚不清楚这些对限制疾病产生最深远影响的抗体的确切作用机制，但是如果阐明，可以为开发有效的疫苗开发对Covid-19和其他冠状病毒的有效疫苗提供关键见解。在这里，我们旨在采用一种系统的方法来剖析和定义抗体允许对COVID-19的保护的多克隆和单克隆机制。具体而言，来自DNA-和腺病毒26（AD26）的样品 - Covid-19-Spike蛋白（S）免疫抑制的动物将受到COVID-19的挑战，它将使用Systems Serology进行全面介绍，以定义功能性的体验，以定义功能性的体液，与MACAECE和MACAQU链接到感染/疾病中的感染/疾病链接到感染/疾病中，并具有MACA的保护。机器学习建模将用于辨别关键的免疫响应特征，这些特征在这些潜水动物的环境中方便地翻译。这些研究不仅将定义跨疫苗和物种的免疫学相关性，而且还提供了对抗体在未来疫苗中允许保护的确切机制的机械见解。