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 Chiu; Pierre J. Rizkallah; Taylor S. Cohen; Alan L. Parker; Abhishek Singharoy; Mitesh J. Borad

doi:10.1126/sciadv.abl8213

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

Molecular Sciences, School of (SMS)

Research output: Contribution to journal › Article › peer-review

100 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 language	English (US)
Article number	eabl8213
Journal	Science Advances
Volume	7
Issue number	49
DOIs	https://doi.org/10.1126/sciadv.abl8213
State	Published - Dec 2021

ASJC Scopus subject areas

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10.1126/sciadv.abl8213

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Baker, A. T., Boyd, R. J., Sarkar, D., Teijeira-Crespo, A., Chan, C. K., Bates, E., Waraich, K., Vant, J., Wilson, E., Truong, C. D., Lipka-Lloyd, M., Fromme, P., Vermaas, J., Williams, D., Machiesky, L. A., Heurich, M., Nagalo, B. M., Coughlan, L., Umlauf, S., ... Borad, M. J. (2021). ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome. Science Advances, 7(49), Article eabl8213. https://doi.org/10.1126/sciadv.abl8213

Baker, AT, Boyd, RJ, Sarkar, D, Teijeira-Crespo, A, Chan, CK, Bates, E, Waraich, K, Vant, J, Wilson, E, Truong, CD, Lipka-Lloyd, M, Fromme, P, Vermaas, J, Williams, D, Machiesky, LA, Heurich, M, Nagalo, BM, Coughlan, L, Umlauf, S, Chiu, PL, Rizkallah, PJ, Cohen, TS, Parker, AL, Singharoy, A & Borad, MJ 2021, 'ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome', Science Advances, vol. 7, no. 49, eabl8213. https://doi.org/10.1126/sciadv.abl8213

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title = "ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome",

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved;",

year = "2021",

month = dec,

doi = "10.1126/sciadv.abl8213",

language = "English (US)",

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AU - Baker, Alexander T.

AU - Boyd, Ryan J.

AU - Sarkar, Daipayan

AU - Teijeira-Crespo, Alicia

AU - Chan, Chun Kit

AU - Bates, Emily

AU - Waraich, Kasim

AU - Vant, John

AU - Wilson, Eric

AU - Truong, Chloe D.

AU - Lipka-Lloyd, Magdalena

AU - Fromme, Petra

AU - Vermaas, Josh

AU - Williams, Dewight

AU - Machiesky, Lee Ann

AU - Heurich, Meike

AU - Nagalo, Bolni M.

AU - Coughlan, Lynda

AU - Umlauf, Scott

AU - Chiu, Po Lin

AU - Rizkallah, Pierre J.

AU - Cohen, Taylor S.

AU - Parker, Alan L.

AU - Singharoy, Abhishek

AU - Borad, Mitesh J.

PY - 2021/12

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N2 - 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.

AB - 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.

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

Abstract

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The Capsid Structure of the ChAdOx1 viral vector/chimpanzee adenovirus Y25

Chadox1/ Chimpanzee adenovirus Y25 fiber knob protein

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

Abstract

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Datasets

The Capsid Structure of the ChAdOx1 viral vector/chimpanzee adenovirus Y25

Chadox1/ Chimpanzee adenovirus Y25 fiber knob protein

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