Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, George Papanikolaou Hospital, Thessaloniki, Greece.
Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Clin Infect Dis. 2021 Dec 6;73(11):2073-2082. doi: 10.1093/cid/ciab371.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an urgent need for the development of effective therapies for coronavirus disease 2019 (COVID-19).
We first tested SARS-CoV-2-specific T-cell (CοV-2-ST) immunity and expansion in unexposed donors, COVID-19-infected individuals (convalescent), asymptomatic polymerase chain reaction (PCR)-positive subjects, vaccinated individuals, non-intensive care unit (ICU) hospitalized patients, and ICU patients who either recovered and were discharged (ICU recovered) or had a prolonged stay and/or died (ICU critical). CoV-2-STs were generated from all types of donors and underwent phenotypic and functional assessment.
We demonstrate causal relationship between the expansion of endogenous CoV-2-STs and the disease outcome; insufficient expansion of circulating CoV-2-STs identified hospitalized patients at high risk for an adverse outcome. CoV-2-STs with a similarly functional and non-alloreactive, albeit highly cytotoxic, profile against SARS-CoV-2 could be expanded from both convalescent and vaccinated donors generating clinical-scale, SARS-CoV-2-specific T-cell products with functional activity against both the unmutated virus and its B.1.1.7 and B.1.351 variants. In contrast, critical COVID-19 patient-originating CoV-2-STs failed to expand, recapitulating the in vivo failure of CoV-2-specific T-cell immunity to control the infection. CoV-2-STs generated from asymptomatic PCR-positive individuals presented only weak responses, whereas their counterparts originating from exposed to other seasonal coronaviruses subjects failed to kill the virus, thus disempowering the hypothesis of protective cross-immunity.
Overall, we provide evidence on risk stratification of hospitalized COVID-19 patients and the feasibility of generating powerful CoV-2-ST products from both convalescent and vaccinated donors as an "off-the shelf" T-cell immunotherapy for high-risk patients.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）大流行迫切需要开发针对 2019 年冠状病毒病（COVID-19）的有效疗法。
我们首先测试了未接触过 SARS-CoV-2 的供体、COVID-19 感染者（恢复期）、无症状聚合酶链反应（PCR）阳性受试者、接种疫苗的个体、非重症监护病房（ICU）住院患者以及从 ICU 康复出院（ICU 康复）或在 ICU 停留时间延长和/或死亡（ICU 危重）的患者的 SARS-CoV-2 特异性 T 细胞（CοV-2-ST）免疫和扩增情况。从所有类型的供体中生成 CoV-2-ST，并进行表型和功能评估。
我们证明了内源性 CoV-2-ST 扩增与疾病结果之间存在因果关系；循环 CoV-2-ST 扩增不足可识别出住院患者发生不良结局的风险较高。从恢复期和接种疫苗的供体中均可扩增出具有相似功能且非同种异体反应性的 CoV-2-ST，尽管其对 SARS-CoV-2 具有高度细胞毒性，但可从临床规模生成 SARS-CoV-2 特异性 T 细胞产品，对未突变病毒及其 B.1.1.7 和 B.1.351 变体均具有功能活性。相比之下，危重 COVID-19 患者来源的 CoV-2-ST 无法扩增，这反映了 CoV-2 特异性 T 细胞免疫无法控制感染的体内失败。来自无症状 PCR 阳性个体的 CoV-2-ST 仅表现出微弱的反应，而来自接触其他季节性冠状病毒的供体的 CoV-2-ST 则无法杀死病毒，从而削弱了保护性交叉免疫的假设。
总的来说，我们提供了住院 COVID-19 患者风险分层的证据，并证明了从恢复期和接种疫苗的供体中生成强大的 CoV-2-ST 产品的可行性，可作为高危患者的“现成”T 细胞免疫疗法。
