Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany.
Department of Medicine II, University Hospital Munich, and German Centre for Infection Research (DZIF) (partner site Munich), Munich, Germany.
Blood. 2021 Oct 7;138(14):1269-1277. doi: 10.1182/blood.2021012938.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.
疫苗诱导的免疫性血栓性血小板减少症（VITT）是 ChAdOx1 nCoV-19 COVID-19 疫苗（Vaxzevria）和 Janssen Ad26.COV2.S COVID-19 疫苗的一种严重不良反应，与不寻常的血栓形成有关。VITT 是由抗血小板因子 4（PF4）抗体通过其 FcγRIIa 受体激活血小板引起的。在 COVID-19 患者中也发现了通过 FcγRIIa 受体激活血小板的抗体。这些发现引起了人们的关注，即针对 SARS-CoV-2 刺突蛋白的疫苗诱导抗体通过与 PF4 交叉反应引起血栓形成。使用计算机预测工具和 3D 建模比较了 PF4 和 SARS-CoV-2 刺突蛋白的免疫原性表位。SARS-CoV-2 刺突蛋白和 PF4 至少共享 1 个相似表位。用 VITT 患者的纯化抗 PF4 抗体测试了针对重组 SARS-CoV-2 刺突蛋白的反应性。然而，14 名 VITT 患者中经亲和纯化的抗 PF4 抗体均未与 SARS-CoV-2 刺突蛋白发生交叉反应。来自 5 个欧洲中心的 222 名经聚合酶链反应（PCR）确诊的 COVID-19 患者的血清通过 PF4-肝素酶联免疫吸附测定（ELISA）和 PF4 依赖性血小板激活测定进行了检测。我们发现 222 名 COVID-19 患者的血清中有 19 例（8.6%）存在抗 PF4 抗体。然而，只有 4 例在存在 PF4 的情况下表现出弱至中度的血小板激活，且这些患者均未发生血栓并发症。在 10 名（4.5%）COVID-19 合并血栓形成的患者中，均未发现 PF4 依赖性血小板激活抗体。总之，疫苗诱导的针对 PF4 的抗体与 SARS-CoV-2 刺突蛋白不发生交叉反应，表明针对 SARS-CoV-2 刺突蛋白的预期疫苗诱导免疫反应不是 VITT 的触发因素。在本研究中，COVID-19 患者中发现的 PF4 反应性抗体与血栓并发症无关。
