Potential Anionic Substances Binding to Platelet Factor 4 in Vaccine-Induced Thrombotic Thrombocytopenia of ChAdOx1-S Vaccine for SARS-CoV-2

Abstract

Recent reports of rare ChAdOx1-S vaccine-related venous thrombosis led to the suspension of its usage in several countries. Vaccine-induced thrombotic thrombocytopenia (VITT) is characterized by thrombocytopenia and thrombosis in association with anti-platelet factor 4 (PF4) antibodies. Herein, we propose five potential anionic substances of the ChAdOx1-S vaccine that can combine with PF4 and trigger VITT, including (1) the proteins on the surface of adenovirus, e.g., negative charged glycoprotein, (2) the adjuvant components of the vaccine, e.g., Tween 80, (3) the DNA of adenovirus, (4) the S protein antigen expressed by the vaccine, and (5) the negatively charged impurity proteins expressed by the vaccine, e.g., adenovirus skeleton proteins. After analysis of each case, we consider the most possible trigger to be the negatively charged impurity proteins expressed by the vaccine. Then, we display the possible extravascular route and intravascular route of the formation of PF4 autoantibodies triggered by the negatively charged impurity proteins, which is accordant with the clinical situation. Accordingly, the susceptible individuals of VITT after ChAdOx1-S vaccination may be people who express negatively charged impurity proteins and reach a certain high titer.

Reverse Engineering of a Pathogenic Antibody Reveals the Molecular Mechanism of Vaccine-Induced Immune Thrombotic Thrombocytopenia

“…Above and beyond being capable of binding PF4, RVT1 can be readily cross-linked by this protein (as confirmed by native MS and molecular modeling), giving rise to macromolecular assemblies capable of clustering FcγRIIa receptors on the platelet surface, which is a key step triggering their activation (Figure ). This is another important distinction of VITT, whichunlike HIT, and contrary to the earlier suggestions − , does not require a polyanionic scaffold to enable antigen clustering as a prerequisite for assembling large pathogenic immune complexes. Indeed, the electrostatic nature of the epitope/paratope interaction and the presence of the extended polycationic segment on the PF4 surface allow it to cross-link at least two VITT antibodies, as confirmed by both DLS measurements and native MS measurements, where abundant complexes as large as (RVT1) 3 (PF4) 2 have been identified (Figure ).…”

“…The critical importance of heparin in the etiology of HIT and its notable irrelevance to VITT despite the striking similarity of the two pathologies prompted several groups to propose scenarios where heparin’s dual role of (i) the scaffold of the immune complex assembly and (ii) the effector of PF4 conformational change is assumed by other anionic biopolymers, such as polyanionic impurities, the viral DNA – the Ad vector cargo, or indeed the surface of the Ad capsid . However, mapping the VITT antibodies’ epitopes on the PF4 surface revealed their significant overlap with the heparin-binding sites, lending credibility to the notion of the immune complex formation via cross-linking of antibodies by polyvalent (tetrameric) protein antigens and unassisted by any polyanionic scaffolds/effectors.…”

A Narrative Review of Neurological Complications of SARS-CoV-2 Vaccination

“…22 It is likely that the negatively charged components of vaccines such as glycoprotein of adenovirus, adjuvants components, and/or adenovirus deoxyribonucleic acid (DNA) are also able to bind PF4 similar to heparin. 23…”

Impfstoffe gegen „coronavirus disease 2019“ (COVID-19)

“…Da Coronaviren zu den RNA-Viren zählen, ist davon auszugehen, dass beim Spleißen der transkribierten RNA wiederum Proteinvarianten entstehen können, die keinen Membrananker mehr aufweisen und deren weiteres Schicksal bzw. mögliches immunmodulierendes Potenzial unklar bleibt [ 16 , 17 ].…”