Lovatt, Charlotte, Frängsmyr, Lars, Swift, Emma A., Mundy, Rosie M. and Parker, Alan L.  ORCID: https://orcid.org/0000-0002-9302-1761
2025.
Investigating endothelial cell transduction and hexon:PF4 binding of ChAdOx1 in the context of VITT.
Journal of Thrombosis and Haemostasis
10.1016/j.jtha.2025.06.006
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Abstract
Background Vaccines against SARS-CoV2 have been essential in controlling COVID-19 related mortality and have saved millions of lives. Adenoviral (Ad) based vaccines been integral part in this vaccine campaign, with licensed vaccines based on the simian Y25 isolate (Vaxzevria, Astrazeneca) and human Ad type 26 (Jcovden, Janssen) widely adopted. As part of the largest global vaccination programme ever undertaken, cases of vaccine-induced thrombotic thrombocytopenia (VITT) have been described in approximately 1:200,000 vaccinees administered with Ad based SARS-CoV2 vaccines. Objectives The mechanism underpinning these adverse events remain to be completely delineated, but is characterised by elevated autoantibodies against PF4 which, in complex with PF4, cluster, bind FcγRIIa on platelets and induce thrombus formation. Here we investigated the ability of ChAdOx1 to transduce and activate endothelial cells (EC). Methods Using protein sequence alignment tools and in vitro transduction assays, the ability of ChAdOx1 to infect EC was assessed. Furthermore, the ability of ChAdOx1 infection to activate EC was determined. Finally, using surface plasmon resonance we assessed the electrostatic interactions between the ChAdOx1 hexon and PF4. Results and Conclusions Despite lacking the primary cell entry receptor, Coxsackie and Adenovirus Receptor (CAR), ChAdOx1 efficiently transduced EC in a CAR-independent manner. This transduction did not result in EC activation. Purified hexon protein from ChAdOx1 preps did, however, bind PF4 with a similar affinity to that previously reported for the whole ChAdOx1 capsid. These data confirm the need to develop non-PF4 binding adenoviral capsids and assess their potential to mitigate adverse events associated with VITT.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Medicine |
| Publisher: | Elsevier |
| ISSN: | 1538-7836 |
| Funders: | National Institute for Health Research |
| Date of First Compliant Deposit: | 27 June 2025 |
| Date of Acceptance: | 2 June 2025 |
| Last Modified: | 04 Jul 2025 21:30 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/179348 |
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