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，出现了几种能够引起严重呼吸道疾病的冠状病毒，但没有疫苗可以预防这些快速传播的病原体。由于我们对这些病原体的免疫相关性缺乏了解，疫苗设计特别滞后。细胞和体液免疫应答都与疾病的消退有关，但迄今为止，只有抗体的被动转移才能在小鼠中提供完全的保护。有趣的是，“中和”和非中和抗体的转移都显示出保护功效，凸显了多种体液机制在限制病毒感染/传播中的作用。这些对限制疾病影响最深远的抗体的确切作用机制目前尚不清楚，但如果得到阐明，可以为开发针对COVID-19和其他冠状病毒的有效疫苗提供关键见解。因此，在这里，我们的目标是采取一种系统的方法来剖析和定义抗体赋予针对COVID-19的保护的多克隆和单克隆机制。具体而言，将使用系统血清学对来自DNA-和腺病毒26（Ad 26）- COVID-19刺突蛋白（S）免疫动物（将用COVID-19攻毒）的样本进行全面分析，以确定与小鼠、雪貂和猕猴中感染/疾病保护相关的功能性体液免疫应答。机器学习建模将用于识别在这些不同动物环境中有效翻译的关键免疫反应特征。这些研究不仅将确定疫苗和物种之间的免疫相关性，而且还将为抗体在未来疫苗中提供保护的精确机制提供机制见解。