Project Details
Projekt
Project P04: AdV interaction with PF4 and platelets
Applicants
Dr. Linda Schönborn; Professor Dr. Thomas Thiele
Subject Area
Virology
Hematology, Oncology
Hematology, Oncology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 548065690
Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare complication of AdV vector-based Covid-19 vaccines. VITT is caused by platelet activating antibodies against Platelet Factor 4 (PF4). Anti-PF4 antibodies form an immune complex with PF4 which activates platelets via their Fc-gamma-receptor, resulting in massive platelet activation, thrombocytopenia and arterial and venous thromboses. VITT occurs not only after AdV vector vaccination but also after natural AdV infection. Hence, the pathomechanisms behind VITT are deeply connected with the interplay of AdV with platelets and the human immune system. The understanding of these mechanisms will be the basis to improve patient care and to develop a new generation of safe AdV-based vaccines. The binding characteristics, molecular structure and effects of pathogenic anti-PF4 antibodies have been well characterized throughout the last years, but several key knowledge gaps remain. First, it is still unresolved which upstream molecular events initiate PF4 autoimmunity after AdV exposure - this includes the interactions between AdVs and platelets that could trigger PF4 release and provide a matrix for PF4-AdV complex formation. It is further an open question, whether different AdV types interact diversely with PF4 and therefore induce conformational changes at various levels to create the immunogenic neoepitopes that initiate anti-PF4 autoimmunity. An unexplained phenomenon is the paradoxical restriction of VITT to the first vaccine dose, which remains poorly understood. In addition, there is still an absence of a comprehensive in vivo models that recapitulates the full sequence from AdV exposure to antibody formation. The project will characterize the interactions of platelets and PF4 with different AdV types and their constituents and newly modified AdV-vector candidates provided by the members of the FOR. We will apply our established pipeline of biophysical tools including surface plasmon resonance microscopy, platelet function assays (flow cytometry and aggregometry), ELISA techniques, super resolution microscopy and a transgenic mouse model expressing human PF4 and FcγRIIa. The FOR provides a unique framework of experts for addressing the AdV-related research gaps of VITT. The combination of AdV expertise, virus reagents, advanced imaging and biophysical methods, recombinant antibodies, and in vivo models available within the FOR will put us in a leading position to better understand VITT and related pathomechanisms. The FOR will create a cutting edge and world-wide visible platform for AdV infections, vaccine development and safety as a pivotal basis to treat these infections and to fight upcoming pandemics.
DFG Programme
Research Units
