ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome

Baker, Alexander T., Boyd, Ryan J., Sarkar, Daipayan, Teijeira Crespo, Alicia, Chan, Chun Kit, Bates, Emily, Waraich, Kasim, Vant, John, Wilson, Eric, Truong, Chloe D., Lipka-Lloyd, Magdalena, Fromme, Petra, Vermaas, Josh, Williams, Dewight, Machiesky, LeeAnn, Heurich, Meike ORCID: https://orcid.org/0000-0003-0105-2702, Nagalo, Bolni M., Coughlan, Lynda, Umlauf, Scott, Chiu, Po-Lin, Rizkallah, Pierre J. ORCID: https://orcid.org/0000-0002-9290-0369, Cohen, Taylor S., Parker, Alan L. ORCID: https://orcid.org/0000-0002-9302-1761, Singharoy, Abhishek and Borad, Mitesh J. 2021. ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome. Science Advances 7 (49) , eabl8213. 10.1126/sciadv.abl8213

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Abstract

Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences
Additional Information:	Distributed under a Creative Commons Attribution License 4.0 (CC BY).
Publisher:	American Association for the Advancement of Science
ISSN:	2375-2548
Funders:	Cancer Research UK
Date of First Compliant Deposit:	2 December 2021
Date of Acceptance:	19 October 2021
Last Modified:	06 Mar 2024 02:09
URI:	https://orca.cardiff.ac.uk/id/eprint/145867

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