Transfer of COVID-19 Immunity Between

总结 严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是目前正在进行的 2019冠状病毒病（COVID-19）大流行。的 联合患者 严重的基础疾病，包括免疫功能低下的癌症患者， 造血细胞移植患者因COVID-19而患严重疾病的风险更高。沿着调查 冠状病毒的流行正在逐步增加， 美国和其他国家的全球病例和死亡人数仍在攀升。 了解SARS-CoV-2的病毒学，了解COVID-19的基本免疫力对于理性的 设计有效的治疗方法。细胞疗法代表了治疗患者的一种新的免疫疗法 严重的新型冠状病毒感染在大多数COVID-19患者中检测到SARS-CoV-2特异性T细胞; 然而，缺乏对病毒特异性T细胞在治疗中的有效性和寿命的详细分析。 保护患者免受随后的SARS-CoV-2感染。此外，免疫原性T细胞表位没有 然而，还没有描述，特别是对于连接细胞和体液免疫应答的关键的CD 4 + T细胞。 该项目的总体目标是分离、表征和扩增SARS-CoV-2特异性T细胞， 为严重COVID-19感染患者提供有效的免疫治疗。我们 假设SARS-CoV-2特异性T细胞过继转移将a）激发CD 4+和CD 8+细胞 当前COVID-19感染患者的免疫力; B）在过继转移后持续存在; c）可用于 以HLA依赖性方式作为现成产品立即使用。在我们的具体目标中，我们建议 广泛研究了从患有SARS-CoV-2的患者中分离的SARS-CoV-2特异性T细胞的细胞免疫， 通过测量先前感染COVID-19的人血液中病毒特异性T细胞的水平， COVID-19感染，表征记忆和耗竭T细胞表型，并评估功能 在体外和体内抗病毒抗原。我们团队在过继免疫方法方面的经验 使用针对巨细胞病毒（CMV）和其他病毒的病毒特异性T细胞，结合我们建立的 用于分离和扩增CMV特异性T细胞的平台，将允许快速大规模产生 SARS-CoV-2特异性T细胞与HLA类型的阵列，并提供了现成的T细胞产品， 立即使用。此外，通过使用新的MHC-PepSeq技术，我们将鉴定免疫原性表位， 这将有助于候选疫苗的设计和促进疫苗的评价 候选免疫原性。我们提出的研究将为SARS-CoV-2细胞 免疫力，这可能对COVID-19患者产生广泛影响。此外，我们建议 制造平台将使我们能够开发具有不同HLA的现成SARS-CoV-2特异性T细胞 类型，这将对COVID-19重症患者的治疗产生重大临床影响。

SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. The United Patients with serious underlying medical conditions, including immunocompromised cancer patients undergoing hematopoietic cell transplantation, are at higher risk of severe illness from COVID-19. Along with investigations coronavirus epidemic is progressively increasing in the States and other countries with the number of global cases and deaths still climbing. into the virology of SARS-CoV-2, understanding the fundamental immunity of COVID-19 is vital for the rational design of effective therapies. Cellular therapy represents a novel immunotherapeutic modality to treat patients with severe COVID-19 infections. SARS-CoV-2 specific T cells have been detected in most COVID-19 patients; however, there is lack of detailed analysis of the effectiveness and longevity of the virus specific T cells in protecting patients from subsequent SARS-CoV-2 infection. Moreover, immunogenic T cell epitopes have not yet been described, especially for CD4+ T cells critical for linking the cellular and humoral immune responses. The overall goal of this project is to isolate, characterize, and expand SARS-CoV-2 specific T cells to therapeutic doses to provide effective immunotherapy for patients with severe COVID-19 infections. We hypothesize that adoptive transfer of SARS-CoV-2 specific T cells will a) elicitCD4+ and CD8+cellular immunity in patients with current COVID-19 infections; b) persist following adoptive transfer; c) be available for immediate use as off-the-shelf products in an HLA-dependent manner. In our Specific Aims, we propose to extensively investigate the cellular immunity of SARS-CoV-2 specific T cells isolated from patients with previous COVID-19 infections by measuring levels of virus-specific T cells in blood of people with previous COVID-19 infections, characterizing the memory and exhaustion T cell phenotype, and evaluating function against viral antigen in vitro and in vivo. Our team's experience with adoptive immunotherapeutic approaches using virus specific T cells against cytomegalovirus (CMV) and other viruses combined with our established platform for the isolation and expansion of CMV specific T cells, will allow for the rapid large-scale generation of SARS-CoV-2 specific T cells with an array of HLA types and provide an off-the-shelf T cell product for immediate use. Further, by using the novel MHC-PepSeq technology, we will identify immunogenic epitopes restricted by MHC II molecules, which will assist candidate vaccine design and facilitate evaluation of vaccine candidate immunogenicity. Our proposed studies will provide scientific insights into SARS-CoV-2 cellular immunity, which may have broad implications for patients with COVID-19. Moreover, our proposed manufacturing platform will allow us to develop off-the-shelf SARS-CoV-2 specific T cells with different HLA types, which will have a major clinical impact on treatment of patients with severe illness from COVID-19.