Transfer of COVID-19 Immunity Between

摘要 严重急性呼吸综合征冠状病毒2(SARS-CoV-2)是正在进行的 冠状病毒病2019年(新冠肺炎)大流行。这个 联合患者与 严重的潜在医疗状况，包括免疫功能低下的癌症患者正在接受 造血细胞移植后，患新冠肺炎严重疾病的风险更高。随着调查一起进行 冠状病毒在中国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。 深入了解SARS-CoV-2的病毒学，了解新冠肺炎的基本免疫机制对于理性 设计有效的治疗方法。细胞疗法代表了一种治疗患者的新的免疫治疗方式 患有严重的新冠肺炎感染。大多数新冠肺炎患者体内已检测到SARS-CoV-2特异性T细胞； 然而，缺乏对病毒特异性T细胞在体内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细胞表位还没有 然而，已经被描述，特别是对于连接细胞和体液免疫反应的关键的CD4+T细胞。 该项目的总体目标是分离、鉴定和扩展SARS-CoV-2特异性T细胞，以 治疗剂量，为严重新冠肺炎感染患者提供有效的免疫治疗。我们 假设过继转移SARS-CoV-2特异性T细胞将a)诱导CD4+和CD8+细胞 当前新冠肺炎感染患者的免疫力；b)在收养转移后持续；c)可用于 以依赖于人类白细胞抗原的方式立即作为现成产品使用。在我们的具体目标中，我们建议 SARS-CoV-2特异性T细胞免疫功能的研究 通过检测既往新冠肺炎感染者血液中病毒特异性T细胞水平来研究 新冠肺炎感染、记忆力衰竭T细胞表型特征及功能评价 在体外和体内抗病毒抗原。我们团队在过继免疫治疗方面的经验 利用病毒特异性T细胞对抗巨细胞病毒(CMV)等病毒与我们建立的 用于分离和扩增CMV特异性T细胞的平台，将允许快速大规模生成 具有多种人类白细胞抗原类型的SARS-CoV-2特异性T细胞并提供现成的T细胞产品 即刻使用。此外，通过使用新的MHC-PepSeq技术，我们将识别免疫原性表位 受MHC II分子的限制，这将有助于候选疫苗的设计和促进疫苗的评估 候选免疫原性。我们提出的研究将为研究SARS-CoV-2细胞提供科学见解 免疫，这可能对新冠肺炎患者有广泛的影响。此外，我们的建议 制造平台将允许我们开发具有不同人类白细胞抗原的现成SARS-CoV-2特异性T细胞 类型，这将对来自新冠肺炎的大病患者的治疗产生重大的临床影响。

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.