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