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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; Nagalo, Bolni M; Coughlan, Lynda; Umlauf, Scott; Chiu, Po-Lin; Rizkallah, Pierre J; Cohen, Taylor S; Parker, Alan L; Singharoy, Abhishek; Borad, Mitesh J.
  • Baker AT; Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA.
  • Boyd RJ; Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • Sarkar D; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • Teijeira-Crespo A; Mayo Clinic Cancer Center, Phoenix, AZ 85054, USA.
  • Chan CK; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85281, USA.
  • Bates E; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • Waraich K; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85281, USA.
  • Vant J; School of Molecular Sciences, Arizona State University, Tempe, AZ 85251, USA.
  • Wilson E; School of Molecular Sciences, Arizona State University, Tempe, AZ 85251, USA.
  • Truong CD; MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824.
  • Lipka-Lloyd M; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824.
  • Fromme P; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • Vermaas J; Computational Structural Biology and Molecular Biophysics, Beckman institute, University of Illinois, IL 61801, USA.
  • Williams D; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • Machiesky L; Institute of Infection Immunity and Inflammation, MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK.
  • Heurich M; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85281, USA.
  • Nagalo BM; School of Molecular Sciences, Arizona State University, Tempe, AZ 85251, USA.
  • Coughlan L; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85281, USA.
  • Umlauf S; School of Molecular Sciences, Arizona State University, Tempe, AZ 85251, USA.
  • Chiu PL; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85281, USA.
  • Rizkallah PJ; School of Molecular Sciences, Arizona State University, Tempe, AZ 85251, USA.
  • Cohen TS; Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff CF10 3AT, UK.
  • Parker AL; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85281, USA.
  • Singharoy A; School of Molecular Sciences, Arizona State University, Tempe, AZ 85251, USA.
  • Borad MJ; MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824.
Sci Adv ; 7(49): eabl8213, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1553714
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.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Topics: Vaccines Language: English Journal: Sci Adv Year: 2021 Document Type: Article Affiliation country: Sciadv.abl8213

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Topics: Vaccines Language: English Journal: Sci Adv Year: 2021 Document Type: Article Affiliation country: Sciadv.abl8213