ABSTRACT
In this study we investigated a link between adenovirus-based vaccines, deployed to fight the SARS-CoV-2 pandemic, and lifethreatening thromboembolisms after vaccination. Post-marketing surveillance showed that, following vaccination, Vaxzevria (ChAdOx1 based, AstraZeneca) and Jcovden (Adenovirus type 26 based, Johnson & Johnson) are associated with reduced platelet counts (thrombocytopenia) and blood clots (thrombosis) in some individuals. This extremely rare condition, with a rate between 1:50,000 - 1:350,000 cases per vaccinated individual, is above background rates of thrombosis in the population and can lead to fatal ischemic events including cerebral venous thrombosis, intracranial haemorrhage, and pulmonary embolism. It has been termed vaccine induced thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome (TTS). Heparin induced thrombocytopenia (HIT) is another condition with a similar clinical presentation to TTS. In HIT, immunoaggregates are formed due to the presence of strong anti-selfantibodies directed against Platelet Factor 4 (PF4). When similar anti-PF4 antibodies were detected in TTS patients, we investigated whether there could be a link between the adenovirus vectors used in the vaccines and PF4. This study demonstrates a direct interaction between adenovirus capsids and PF4 using surface plasmon resonance. We then utilized an integrative structural biology workflow including cryo-electron microscopy and molecular dynamics to characterize and demonstrate the mechanism of this interaction. These results demonstrate a previously unknown adenovirushost interaction and provide critical clues as to the underlying mechanism which causes TTS, including how these pathogenic anti-PF4 antibodies may be induced. We are therefore able to present a hypothesis as to the route of pathogenesis in TTS.