The team, which included scientists from Flinders University and Greifswald University, discovered 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).

Immune System Mix-Up Triggers Clotting

When this confusion occurs, the body produces antibodies that activate clotting. Although this reaction is extremely rare, identifying the exact cause is a major step forward. It means vaccine developers can now modify the adenovirus protein to prevent this issue and improve vaccine safety.

Flinders University researcher Dr. Jing Jing Wang says the findings offer a clear path forward.

“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.

From VITT Discovery to Molecular Explanation

This 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 COVID19 pandemic in 2021. It appeared after the use of adenovirus vector-based vaccines, including the Oxford-AstraZeneca vaccine widely used in Australia.

Scientists determined that VITT is caused by a harmful autoantibody that targets PF4.

Earlier work led by Dr. Wang and Professor Tom Gordon, Head of Immunology at SA Pathology in South Australia, decoded the structure of this PF4 antibody in 2022. That study also identified a genetic risk factor linked to an antibody gene called IGLV3.21*02. The discovery connected cases across different countries and helped establish a long-term collaboration with Greifswald University, led by Professor Andreas Greinacher.

Evidence From Infection and Vaccination

In 2023, Professor Ted Warkentin from McMaster University in Canada reported a nearly identical condition caused by the same PF4 antibody in patients who had natural adenovirus (common cold) infections, with some cases proving fatal.

A follow-up study in 2024 involving Flinders, Greifswald, and McMaster Universities showed that antibodies from vaccine-related and infection-related cases were indistinguishable. This pointed to the adenovirus itself, rather than a specific vaccine ingredient, as the source of the problem. However, the exact molecular mechanism was still unclear at that time.

Breakthrough Study Reveals Molecular Trigger

According to Professor Tom Gordon, the latest findings, published in the New England Journal of Medicine, mark the culmination of years of global research.

“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 explained that the team’s detailed molecular analysis finally uncovered the missing piece.

“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.”

Safer Future Vaccines Within Reach

Immunologist Professor James McCluskey from the University of Melbourne and the Peter Doherty Institute called the work a major scientific milestone.

“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 exact trigger now identified, researchers say vaccine developers can adjust the pVII protein in adenovirus-based vaccines to remove this rare risk.

These findings are expected to support the development of safer vaccines that remain effective and widely accessible, especially in regions where adenovirus-based vaccines play an important role in preventing disease.