Department of Immunology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Transplant Unit and Hematological Intensive Care Unit, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Leuk Res. 2023 Jul;130:107314. doi: 10.1016/j.leukres.2023.107314. Epub 2023 May 16.
Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are at high risk of complications associated with COVID-19 infection due to dysfunction of their immune system. Vaccination can protect from the adverse consequences of COVID-19. However, studies on the efficacy of COVID-19 vaccines in HSCT recipients with insufficient post-HSCT immune reconstitution are still scarce. In our study, we determined how immunosuppressive medication and the reconstitution of the cellular immune system influenced T cell responses specific for the surface glycoprotein of SARS-CoV-2 virus (S antigen) after two doses of mRNA vaccine against COVID-19 in patients with myeloid malignancies treated with HSCT.
Vaccination outcomes were followed in 18 (allo-HSCT) recipients and 8 healthy volunteers. The IgG antibodies against SARS-CoV-2 spike (S) and nucleocapsid (NCP) protein were determined in ELISA and S-specific T cells were detected using a sensitive ELISPOT-IFNγ based on in vitro expansion and restimulation of T cells in pre- and post-vaccination blood samples. Multiparametric flow cytometry analysis of peripheral blood leukocyte differentiation markers was employed for determination of reconstitution of the main subpopulations of T cells and NK cells at month 6 after HSCT.
S- specific IgG antibody response detected in 72% of the patients was lower than in healthy vaccinees (100%). Vaccine-induced T-cell responses to S1 or S2 antigen were significantly reduced in HSCT recipients, which were treated with corticosteroids in dose 5 mg of prednisone- equivalents or higher during the vaccination period or in preceeding 100 days in comparison with recipients un-affected with corticosteroids. A significant positive correlation was found between the level of anti-SARS-Cov-2 spike protein IgG antibodies and the number of functional S antigen-specific T cells. Further analysis also showed that the specific response to vaccination was significantly influenced by the interval between administration of vaccine and transplantation. Vaccination outcomes were not related to age, sex, type of mRNA vaccine used, basic diagnosis, HLA match between HSC donor and recipient, and blood counts of lymphocytes, neutrophils, and monocytes at the time of vaccination. Multiparametric flow cytometry analysis of peripheral blood leukocyte differentiation markers showed that good humoral and cellular S-specific immune responses induced by vaccination were associated with well-reconstituted CD4 T cells, mainly CD4 effector memory subpopulation at six months after HSCT.
The results showed that both humoral and cellular adaptive immune responses of HSCT recipients to the SARS-CoV-2 vaccine were significantly suppressed by corticosteroid therapy. Specific response to the vaccine was significantly affected by the length of the interval between HSCT and vaccination. Vaccination as early as 5 months after HSCT can lead to a good response. Immune response to the vaccine is not related to age, gender, HLA match between HSC donor and recipient, or type of myeloid malignancy. Vaccine efficacy was dependent on well-reconstituted CD4 T cells, at six months after HSCT.
由于免疫系统功能障碍，异基因造血干细胞移植（allo-HSCT）受者罹患 COVID-19 感染相关并发症的风险很高。疫苗接种可预防 COVID-19 的不良后果。然而，对于接受 HSCT 后免疫重建不足的 HSCT 受者，关于 COVID-19 疫苗疗效的研究仍然很少。在我们的研究中，我们确定了免疫抑制药物和细胞免疫重建如何影响骨髓恶性肿瘤接受 HSCT 治疗的患者在接受两剂 mRNA COVID-19 疫苗后针对 SARS-CoV-2 病毒表面糖蛋白（S 抗原）的 T 细胞反应。
在 18 名（allo-HSCT）受者和 8 名健康志愿者中观察疫苗接种结果。通过 ELISA 测定针对 SARS-CoV-2 刺突（S）和核衣壳（NCP）蛋白的 IgG 抗体，并使用基于体外扩增和在接种前和接种后血液样本中 T 细胞再刺激的敏感 ELISPOT-IFNγ检测 S 特异性 T 细胞。采用多参数流式细胞术分析外周血白细胞分化标志物，以确定 HSCT 后 6 个月时主要 T 细胞和 NK 细胞亚群的重建情况。
在 72%的患者中检测到的 S-特异性 IgG 抗体反应低于健康疫苗接种者（100%）。与未接受皮质类固醇治疗的受者相比，接受皮质类固醇治疗（泼尼松等效剂量为 5mg 或更高）或在接种前 100 天内接受皮质类固醇治疗的 HSCT 受者的疫苗诱导的 S1 或 S2 抗原 T 细胞反应显著降低。发现抗 SARS-CoV-2 刺突蛋白 IgG 抗体水平与功能性 S 抗原特异性 T 细胞数量之间存在显著正相关。进一步分析还表明，疫苗接种的特异性反应受疫苗接种和移植之间间隔的显著影响。疫苗接种结果与年龄、性别、使用的 mRNA 疫苗类型、基础诊断、HSC 供体和受者之间的 HLA 匹配以及接种时淋巴细胞、中性粒细胞和单核细胞的计数无关。外周血白细胞分化标志物的多参数流式细胞术分析表明，良好的体液和细胞 S 特异性免疫反应与 HSCT 后 6 个月时重建良好的 CD4 T 细胞有关，主要是 CD4 效应记忆亚群。
结果表明，HSCT 受者对 SARS-CoV-2 疫苗的体液和细胞适应性免疫反应均受到皮质类固醇治疗的显著抑制。疫苗的特异性反应受 HSCT 和接种之间间隔长度的显著影响。HSCT 后 5 个月即可进行疫苗接种，可获得良好的反应。疫苗接种效果与年龄、性别、HSC 供体和受者之间的 HLA 匹配或骨髓恶性肿瘤类型无关。疫苗疗效取决于 HSCT 后 6 个月时重建良好的 CD4 T 细胞。
