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

Alexander T. Baker, Ryan J. Boyd, Daipayan Sarkar, Alicia Teijeira-Crespo, Chun Kit Chan, Emily Bates, Kasim Waraich, John Vant, Eric Wilson, Chloe D. Truong, Magdalena Lipka-Lloyd, Petra Fromme, Josh Vermaas, Dewight Williams, Lee Ann Machiesky, Meike Heurich, Bolni M. Nagalo, Lynda Coughlan, Scott Umlauf, Po Lin ChiuPierre J. Rizkallah, Taylor S. Cohen, Alan L. Parker, Abhishek Singharoy, Mitesh J. Borad

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereabl8213
JournalScience Advances
Volume7
Issue number49
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • General

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