New research led by Flinders University and international experts has finally uncovered how a rare blood clotting condition can occur after some COVID19 adenovirus-based vaccines or after a natural adenovirus infection.
The international research team, including experts from Flinders University and Greifswald University, found that in a small number of people, the immune system can accidentally confuse a normal adenovirus protein with a human blood protein termed platelet factor 4 (or PF4).
When this happens, the body produces an antibody that triggers clotting. This mistake only occurs in extremely rare cases, but understanding the exact cause means vaccine developers can now adjust the adenovirus protein to prevent the problem entirely, helping make future vaccines even safer.
Flinders University researcher, Dr Jing Jing Wang says that the discovery provides a clear blueprint for vaccine developers.
"By modifying or removing this specific adenovirus protein, future vaccines can avoid this extremely rare reaction while continuing to provide strong protection against disease," says Dr Wang.
The new paper is part of an international collaboration charting a pathway from the first recognition of VITT to the identification of the exact molecular trigger.
At the height of the COVID-19 pandemic in 2021, vaccine-induced immune thrombocytopenia and thrombosis (known as VITT) emerged as a new disease following adenovirus vector-based vaccines - notably the Oxford-AstraZeneca vaccine, used in Australia.
VITT was found to be caused by an unusually dangerous blood autoantibody directed against PF4.
Flinders' Dr Jing Jing Wang and Professor Tom Gordon, Head of Immunology at SA Pathology in South Australia, led a previous study in 2022 which cracked the molecular code of the PF4 antibody and identified a genetic risk factor related to an antibody gene termed IGLV3.21*02. This finding linked VITT cases across countries and helped form a long‑term collaboration with Greifswald University, led by Professor Andreas Greinacher.
In separate research in 2023, Professor Ted Warkentin from McMaster University in Canada described a virtually identical disorder with the same PF4 antibody that was fatal in some cases after natural adenovirus (common cold) infection.
In 2024, another paper led by Flinders, Greifswald and McMaster Universities confirmed that the antibodies from vaccine‑related cases and infection‑related cases were indistinguishable. This established that the adenovirus itself, not a specific vaccine component, was the likely source of the trigger. But the precise molecular mechanism remained unknown.
Professor Tom Gordon says that the new research published in the eminent New England Journal of Medicine represents the culmination of years of international scientific detective work.
"It has been a fascinating journey with an outstanding international team of collaborators to complete a trilogy of publications in the New England Journal of Medicine to solve the mystery of this new group of blood clotting disorders, and potentially translate our discoveries into safer vaccines," says Professor Gordon.
Dr Wang said the team's molecular analysis provided the breakthrough needed to understand the mechanism.
"A novel aspect of the paper was our use of powerful mass spectrometry sequencing to identify molecular mimicry between the adenovirus vector protein and the PF4 culprit target," she says.
"This was the missing link that explains how a normal immune response can, in very rare cases, become harmful."
Immunologist Professor James McCluskey from the University of Melbourne and the Peter Doherty Institute described the research as a major scientific achievement.
"It is a brilliant piece of molecular sleuthing, the culmination of a body of work that unravels the genetic and structural basis for how a normal immune response to a virus protein leads to pathogenic autoimmunity," says Professor McCluskey.
With the precise trigger now identified, vaccine developers can modify the pVII protein in adenovirus‑based vaccines to eliminate this rare risk.
Researchers say the findings will help ensure future vaccines built on this technology remain effective, accessible and even safer, particularly in regions where adenovirus‑vector vaccines are critical tools for disease prevention.
Acknowledgements: Supported by grants (374031971-TRR240, GR 2232/9-1, SCHO 2052/1-1, TH 2320/3-1) from Deutsche Forschungsgemeinschaft (DFG), by the DFG Research Infrastructure Next Generation Sequencing (NGS) Competence Center (project 407495230) as part of the NGS Competence Network (project 423957469), by grants (INV-090519 and INV-084533) from the Gates Foundation, and by the European Medicines Agency (service contract EMA/2021/17/TDA). Jing Jing Wang was supported by an Ideas Grant (2037700) from the National Health and Medical Research Council and by a Flinders Foundation Health Seed Grant. Linda Schönborn was supported by the Else Kröner-Fresenius Stiftung ("Wiedereinstiegsförderung für forschende Ärztinnen und Ärzte"), an American Society of Hematology Global Research Award, and by Universitätsmedizin Greifswald within the Gerhard Domagk Research Program. Luisa Müller was supported by Universitätsmedizin Greifswald within the Gerhard Domagk Research Program. Sequencing was performed at the Competence Center for Genomic Analysis (Kiel).
The study, 'Adenoviral Inciting Antigen and Somatic Hypermutation in VITT' by Jing Jing Wang, Linda Schönborn, Theodore E. Warkentin, Luisa Müller, Thomas Thiele, Lena Ulm, Uwe Völker, Sabine Ameling, Sören Franzenburg, Lars Kaderali, Ana Tzvetkova, Alex Colella, Tim Chataway, Chee Wee Tan, Bridie Armour, Alexander Troelnikov, Lucy Rutten, James McCluskey, Roland Zahn, Tom P. Gordon and Andreas Greinacher in The New England Journal of Medicine. DOI: 10.1056/NEJMoa2514824
See also, 'Antibody Fingerprints Linking Adenoviral Anti-PF4 Disorders' (2024), by Jing Jing Wang (Flinders University), Linda Schönborn (Greifswald University Hospital, Germany), Theodore E Warkentin (McMaster University, Canada), Tim Chataway (Flinders University), Leonie Grosse (Ludwig Maximilians University, Germany), Paolo Simioni (Padova University Hospital, Italy), Stephan Moll (University of North Carolina School of Medicine, US), Andreas Greinacher (Greifswald University Hospital) and Tom P Gordon (SA Pathology, South Australia) will be published in the New England Journal of Medicine. DOI: 10.1056/NEJMc2402592
'VITT-like Monoclonal Gammopathy of Thrombotic Significance' (2025) by Jing Jing Wang, Theodore E. Warkentin, Linda Schönborn, Matthew B. Wheeler, M.D., William H. Geerts, Nathalie Costedoat-Chalumeau, Nicolas Gendron, Gabriela Ene, Miquel Lozano, Florian Langer, Edelgard Lindhoff-Last, Kathrin Budde,Tim Chataway, Alexander Troelnikov, Jo-Ann I. Sheppard, Donald M. Arnold, Tom P. Gordon, Thomas Thiele and Andreas Greinacher, has been published in The New England Journal of Medicine journal. DOI: 10.1101/2022.03.28.22272975.
'Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody' (2022) by Jing Jing Wang, Bridie Armour, Tim Chataway, Alexander Troelnikov, Alex Colella, Olivia Yacoub, Simon Hockley, Chee Wee Tan and Tom Paul Gordon. DOI: 10.1101/2022.03.28.22272975.
