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，但由于我们对细胞和体液免疫的相关性缺乏了解，因此没有疫苗可以预防这些快速传播的病原体。免疫反应与疾病的解决有关，但迄今为止，只有抗体的被动转移被证明可以在小鼠身上提供完全的保护，“中和”和非中和抗体的转移都显示出保护功效。强调多种体液机制在限制病毒感染/传播中的作用目前尚不清楚这些对限制疾病具有最深远影响的抗体的确切作用机制，但如果得到阐明，可以为开发有效的新冠疫苗提供重要见解。 -19 和其他冠状病毒。因此，我们的目标是采用系统方法来剖析和定义抗体提供针对 COVID-19 的保护的多克隆和单克隆机制，特别是来自 DNA 和腺病毒 26 的样本。 (Ad26)- 将使用系统血清学对将受到 COVID-19 挑战的 COVID-19 尖峰蛋白 (S) 免疫动物进行全面分析，以确定与小鼠、雪貂免受感染/疾病相关的功能性体液免疫反应和猕猴将用于识别关键的免疫反应特征，这些特征可以在这些不同的动物环境中有效转化，这些研究不仅可以定义疫苗和物种之间免疫的相关性，还可以提供机制见解。研究抗体在未来疫苗中提供保护的精确机制。