Virus-cell interactions of the ChAdOx1 viral vector give insights into vaccine-induced immune thrombotic thrombocytopenia

ABSTRACT

The ChAdOx1 nCoV-19 vaccine (AZD1222/Vaxzervia) adapted from the chimpanzee adenovirus Y25 (ChAd-Y25) has been critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. However, as part of the largest vaccination campaign in history, a potentially lifethreatening clotting disorder, thrombosis with thrombocytopenia, resembling heparin-induced thrombocytopenia (HIT), has been observed in a minority of AZD1222 patients following the first but not the second dose. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterised by development of thromboses at uncommon sites such as the cerebral venous sinuses and the splanchnic veins, with concomitant thrombocytopaenia. Therefore, to determine how ChAdOx1 may contribute to this novel disorder, it is critical to investigate the vector-host interactions of ChAdOx1. Structural and in vitro analysis of the fiber knob responsible for the primary virus-cell interaction suggests that coxsackie and adenovirus receptor (CAR) is the primary ChAdOx1 receptor. However, ChAdOx1 infection of CAR(-) human vascular endothelial cells has been demonstrated in vitro, suggesting ChAdOx1 may be using additional receptors. Dual tropism has been demonstrated in other human adenoviruses, with HAdV-D26 and HAdV-D37 both using sialic acid and CAR for transduction. Furthermore, coagulation factor X (FX), a factor demonstrated to bind to the hexon and facilitate human adenovirus type 5 (HAdV-C5) transduction via a CARindependent pathway does not increase ChAdOx1 infection, with amino acid alignment between the hexon proteins suggesting ChAdOx1 is unable to bind FX. Taken together, these findings suggest ChAdOx1 uses additional as yet unknown mechanisms for transduction, which may further contribute to the pathogenesis of VITT.