Evaluating the Interaction of Platelet Factor 4 and Adenoviral Vector-Based SARS-CoV-2 Vaccines in the Pathogenesis of Vaccine-Induced Immune Thrombotic Thrombocytopenia

Abstract

The widespread use of adenoviral (AdV)-based SARS-CoV-2 vaccines, such as ChAdOx1-S (AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen), has been crucial in combating the COVID-19 pandemic. However, these vaccines have been linked to vaccine-induced immune thrombotic thrombocytopenia (VITT), characterized by the formation of anti-platelet factor 4 (PF4) antibodies, leading to thrombosis and thrombocytopenia. Previous research has demonstrated that PF4 bound to polyanionic heparin forms immunogenic complexes, resulting in anti-PF4 antibody development in heparin-induced thrombocytopenia. Similar mechanisms have been proposed for VITT, where polyanionic AdV bound to PF4 triggers antibody development. However, inconsistent findings regarding PF4/vaccine interactions necessitate further exploration of factors, such as inflammatory cytokines, that may support antibody development. This study verifies the interactions between PF4 and AdV-based vaccines while analyzing the VITT cytokine profiles. Our aim is to understand whether PF4 and AdV-based vaccines have the potential to form immunogenic complexes and the role of a heightened inflammatory environment, potentially associated with anti-PF4 antibody formation and disease severity. While significant interactions between PF4 and both vaccines were detected using surface plasmon resonance (SPR), these interactions could not be confirmed using biolayer interferometry. Since SPR exhibits higher sensitivity, this discrepancy suggests a weak interaction between PF4 and the vaccines. Cytokine analysis revealed that VITT patients with CVST exhibited elevated interleukin-8 levels, linking disease severity to a heightened inflammatory state. Additionally, HIT patients displayed even higher levels of inflammatory cytokines, which may be attributed to HIT antibody-related mechanisms or their pre-existing health conditions. In conclusion, there is a weak interaction between PF4 and the vaccines. Additional research is needed to determine if this complex can function as an immunogen under physiological conditions. Moreover, while an elevated inflammatory state is linked to VITT severity, the development and activity of VITT and HIT antibodies may be associated with distinct cytokine environments.