Researchers led by Flinders University, in collaboration with international collaborators, have revealed how a rare blood clotting condition develops after certain COVID19 adenovirus-based vaccines, or even after natural adenovirus infection.
A research team including scientists from Flinders University and the University of Greifswald has found that in a very small number of people, the immune system can mistakenly confuse a normal adenovirus protein with a human blood protein called platelet factor 4 (or PF4).
Disruption of the immune system causes clotting
When this disruption occurs, the body produces antibodies that activate clotting. Although this reaction is extremely rare, determining the exact cause is a major step forward. This means that vaccine developers can modify adenovirus proteins to prevent this problem and improve vaccine safety.
Flinders University researcher Dr Jing Jing Wang said the findings showed a clear path forward.
“By modifying or removing this particular adenoviral protein, future vaccines could avoid this extremely rare reaction while continuing to provide strong protection against disease,” said Dr. Wang.
From the discovery of VITT to the explanation of the molecule
The study is part of a broader international effort to understand vaccine-induced immune thrombocytopenia and thrombosis (known as VITT), a condition first identified during the 2021 coronavirus pandemic. The symptoms emerged after the use of adenovirus vector-based vaccines, including the Oxford-AstraZeneca vaccine widely used in Australia.
Scientists have determined that VITT is caused by harmful autoantibodies that target PF4.
Initial research led by Dr Wang and Professor Tom Gordon, head of immunology at SA Pathology in South Australia, deciphered the structure of this PF4 antibody in 2022. The study also identified a genetic risk factor associated with an antibody gene called IGLV3.21*02. This discovery helped link cases from different countries and establish a long-term collaboration with the University of Greifswald, led by Professor Andreas Greinacher.
Evidence of infection and vaccination
In 2023, Professor Ted Warkentin of McMaster University in Canada reported that the same PF4 antibody caused almost similar symptoms in patients with natural adenovirus (common cold) infection, which was fatal in some cases.
A follow-up study in 2024 involving Flinders University, Greifswald University and McMaster University showed that antibodies in vaccine-related and infection-related cases were indistinguishable. This pointed to the adenovirus itself being the cause of the problem, rather than specific vaccine components. However, at that time the exact molecular mechanism was still unknown.
Groundbreaking research reveals molecular trigger
Professor Tom Gordon said the latest findings, published in the New England Journal of Medicine, were the culmination of years of worldwide research.
“It has been an interesting journey with a talented team of international collaborators to complete the trilogy published in the New England Journal of Medicine to unravel the mysteries of this new group of blood clotting disorders and potentially translate our findings into safer vaccines,” Professor Gordon said.
Dr. Wang explained that the team’s detailed molecular analysis finally revealed the missing piece.
“A novel aspect of this paper is the use of powerful mass spectrometry sequencing to identify molecular mimicry between adenoviral vector proteins and the culprit target of PF4,” she says.
“This was the missing link explaining how a normal immune response can become harmful in very rare cases.”
Safer future vaccines within reach
Professor James McCluskey, an immunologist at the University of Melbourne and the Peter Doherty Institute, called the study a major scientific milestone.
“This is a remarkable piece of molecular discovery, the culmination of a series of studies that uncover the genetic and structural basis of how normal immune responses to viral proteins lead to pathogenic autoimmunity,” Professor McCluskey said.
Researchers say that now that the exact trigger has been identified, vaccine developers can adjust the pVII protein in adenovirus-based vaccines to eliminate this rare risk.
These findings are expected to support the development of safer vaccines that maintain efficacy and are widely available, especially in regions where adenovirus-based vaccines play an important role in disease prevention.
