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.
1. Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Germany.
2. Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Germany.
3. Division of Experimental Virology, Department of Biomedicine, University of Basel, Switzerland.
4. Accession Therapeutics Limited, OX4 2JZ Oxford, UK.
5. University of Helsinki, Faculty of Pharmacy, Laboratory of Immunovirotherapy, Drug Research Program Helsinki, Helsinki, Finland.
6. Helsinki Institute of Life Science (HiLIFE), Fabianinkatu 33, University of Helsinki, Finland.
7. Translational Immunology Program (TRIMM), Faculty of Medicine Helsinki University, Helsinki, Finland.
8. Digital Precision Cancer Medicine Flagship (iCAN), University of Helsinki, Helsinki, Finland.
9. Biodesign Institute Center for Applied Structural Discovery & Biosense Network, School of Molecular Science, Arizona State University, Tempe, AZ, USA.
10. NIH P41 Biotechnology Resource Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana Champaign, Champaign, IL, USA.
11. École Normale Supérieure de Lyon, Lyon 1 Claude Bernard University, Lyon, France.
12. University of Helsinki, Faculty of Pharmacy, Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Finland.
13. AgroParisTech, Paris-Saclay University, Saclay, France.
14. MSU-DOE Plant Research Laboratory, East Lansing, MI, USA.
15. Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
16. Laboratory of Experimental Pediatric Pneumology and Allergology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Germany.
17. Department of Cell & Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
18. Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, CF14 4XN Cardiff, UK.
19. Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, University of Heidelberg, BioQuant, Germany.
20. Åbo Akademi University, Faculty of Science and Engineering, Pharmaceutical Sciences Laboratory, Finland.
21. Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, Naples, Italy.
* These authors contributed equally