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Int J Mol Sci ; 22(19)2021 Oct 06.
Article in English | MEDLINE | ID: covidwho-1457948


Novel coronavirus SARS-CoV-2 has resulted in a global pandemic with worldwide 6-digit infection rates and thousands of death tolls daily. Enormous efforts are undertaken to achieve high coverage of immunization to reach herd immunity in order to stop the spread of SARS-CoV-2 infection. Several SARS-CoV-2 vaccines based on mRNA, viral vectors, or inactivated SARS-CoV-2 virus have been approved and are being applied worldwide. However, the recent increased numbers of normally very rare types of thromboses associated with thrombocytopenia have been reported, particularly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The statistical prevalence of these side effects seems to correlate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the exact molecular mechanisms are still not clear. The present review summarizes current data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis indicating that coagulopathies, including thromboses, thrombocytopenia, and other related side effects, are correlated to an interplay of the two components in the vaccine, i.e., the spike antigen and the adenoviral vector, with the innate and immune systems, which under certain circumstances can imitate the picture of a limited COVID-19 pathological picture.

COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Thrombocytopenia/etiology , Thrombosis/etiology , Adenoviridae/immunology , Animals , COVID-19/immunology , COVID-19 Vaccines/immunology , Genetic Vectors/adverse effects , Genetic Vectors/immunology , Humans , Purpura, Thrombocytopenic, Idiopathic/etiology , Purpura, Thrombocytopenic, Idiopathic/immunology , Spike Glycoprotein, Coronavirus/adverse effects , Thrombocytopenia/immunology , Thrombosis/immunology , Vaccination/adverse effects
Blood ; 138(22): 2256-2268, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1443788


SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.

Antigen-Antibody Complex/immunology , Autoantibodies/immunology , COVID-19/prevention & control , Capsid Proteins/adverse effects , Drug Contamination , Genetic Vectors/adverse effects , HEK293 Cells/immunology , Immunoglobulin G/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/etiology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/adverse effects , Adenoviridae/immunology , Animals , Antigen-Antibody Complex/ultrastructure , Autoantibodies/biosynthesis , Capillary Leak Syndrome/etiology , Capsid Proteins/immunology , Cell Line, Transformed , /immunology , Dynamic Light Scattering , Epitopes/chemistry , Epitopes/immunology , Extracellular Traps/immunology , Extravasation of Diagnostic and Therapeutic Materials/etiology , Genetic Vectors/immunology , HEK293 Cells/chemistry , Humans , Imaging, Three-Dimensional , Immunoglobulin G/biosynthesis , Inflammation , Mice , Microscopy/methods , Platelet Activation , Proteomics , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/immunology , Sinus Thrombosis, Intracranial/diagnostic imaging , Sinus Thrombosis, Intracranial/immunology , Spike Glycoprotein, Coronavirus/immunology , Virus Cultivation