Novel adenovirus vaccine vectors lacking thrombosis-associated interactions with platelet factor 4

The adenoviral vector-based AstraZeneca and Janssen COVID-19 vaccines have been associated with rare cases of thrombosis, believed to be triggered, among other factors, by vector binding to the blood protein platelet factor 4 (PF4). To identify vectors with lower thrombosis risk, we screened 50 natural and hexon-modified adenoviruses (Ads). Unlike the applied COVID-19 vaccines and most tested vectors, Ad34 and Ad80, as well as Ad5 vectors with deleted or chemically shielded hexon hyper-variable region 1 (HVR1), did not bind to PF4. Furthermore, interactions with PF4 substantially modified Ad5 infectivity in various immortalized and primary cells, suggesting that PF4 may influence existing vector tropism. Finally, HVR1-deleted Ad5 and Ad34 vectors expressing SARS-CoV-2 spike S1 domain were tested as vaccine candidates in mice and induced robust cellular immune responses. Therefore, the identified PF4 non-binding vectors may represent safe and efficient candidates for clinical applications.

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Publication Details

Journal
iScience
Published
2025-12-05
DOI
https://doi.org/10.1016/j.isci.2025.114329
Primary Topic
Virus-based gene therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

Novel adenovirus vaccine vectors lacking thrombosis-associated interactions with platelet factor 4

Tapani Viitala, Daniel Pembaur, Wibke Bayer, Anja Ehrhardt et al.
iScience
Virus-based gene therapy research
article

Novel adenovirus vaccine vectors lacking thrombosis-associated interactions with platelet factor 4

Tapani Viitala, Daniel Pembaur, Wibke Bayer, Anja Ehrhardt, Vincenzo Cerullo, Alexander T. Baker, Elise Chabot, Dirk Grimm, Sara Feola, Vera Kemp, Florian Kreppel, Franziska Jönsson, Sebastian Schellhorn, Firas Hamdan, Georgia Koukou, Abhishek Singharoy, Daniel D. Pinschewer, Denice Weklak, Katrin Schröer, Alan L. Parker, Erwan Sallard, Wenli Zhang, Matías Ciancaglini, Daipayan Sarkar, Elena Scurti, Nissai Beaude, Natascha Schmidt, Xiaoyan Wang, Chun Kit Chan, Malik Aydin, Lucie Manov-Bouard, Carmen Musielak
article en

Abstract

The adenoviral vector-based AstraZeneca and Janssen COVID-19 vaccines have been associated with rare cases of thrombosis, believed to be triggered, among other factors, by vector binding to the blood protein platelet factor 4 (PF4). To identify vectors with lower thrombosis risk, we screened 50 natural and hexon-modified adenoviruses (Ads). Unlike the applied COVID-19 vaccines and most tested vectors, Ad34 and Ad80, as well as Ad5 vectors with deleted or chemically shielded hexon hyper-variable region 1 (HVR1), did not bind to PF4. Furthermore, interactions with PF4 substantially modified Ad5 infectivity in various immortalized and primary cells, suggesting that PF4 may influence existing vector tropism. Finally, HVR1-deleted Ad5 and Ad34 vectors expressing SARS-CoV-2 spike S1 domain were tested as vaccine candidates in mice and induced robust cellular immune responses. Therefore, the identified PF4 non-binding vectors may represent safe and efficient candidates for clinical applications.

iScienceVol. 29(1)
University of Helsinki (FI), Witten/Herdecke University (DE), University of Basel (CH), Leiden University Medical Center (NL), University of Naples Federico II (IT)
Deutsche Forschungsgemeinschaft
Openalex Percentile: Top 60%
Virus-based gene therapy research
DOIOpen Access PDFOpenAlex
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