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

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

112 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
Article number	eabl8213
Journal	Science Advances
Volume	7
Issue number	49
DOIs	https://doi.org/10.1126/sciadv.abl8213
State	Published - Dec 2021
Externally published	Yes

Funding

Funders	Funder number
National Cancer Institute	DP2CA195764

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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

@article{4f6081ceaa0c410baf4e31862820224c,

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",

volume = "7",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "49",

}

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

TY - JOUR

T1 - ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome

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

Y1 - 2021/12

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.

UR - http://www.scopus.com/inward/record.url?scp=85120669805&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abl8213

DO - 10.1126/sciadv.abl8213

M3 - Article

C2 - 34851659

AN - SCOPUS:85120669805

SN - 2375-2548

VL - 7

JO - Science Advances

JF - Science Advances

IS - 49

M1 - eabl8213

ER -

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

Abstract

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UN SDGs

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