A rare but serious complication following certain COVID-19 vaccines and, less commonly, natural adenovirus infections has been explained by an international team of researchers. The study, published today, , in the New England Journal of Medicine, identifies a specific mechanism driving vaccine-induced immune thrombocytopenia and thrombosis (VITT), a condition characterized by dangerous blood clots and low platelet counts.
The collaborative research, involving scientists from McMaster University (Canada), Flinders University (Australia), and Universitätsmedizin Greifswald (Germany), pinpointed an unexpected case of immune system misdirection as the root cause. The findings offer a pathway to redesigning vaccines to prevent this rare adverse effect while preserving their benefits.
How the Immune System Can Go Awry
The research centers around the body’s response to adenovirus, a common virus that often causes mild illnesses like the common cold. Most people have encountered adenoviruses throughout their lives and developed antibodies against them. These antibodies typically target specific proteins on the virus. However, the study reveals that in rare instances, a combination of factors can lead to the immune system mistakenly attacking the body’s own blood proteins.
Specifically, the researchers discovered that antibodies generated against a protein called Protein VII on the adenovirus can, through a rare genetic predisposition and a random mutation in antibody-producing cells, begin to bind to platelet factor 4 (PF4). PF4 is a protein normally involved in blood clotting. When antibodies bind to PF4, they activate platelets, leading to the formation of blood clots and a decrease in platelets – the hallmark of VITT.
“It’s as if a key changes shape and then fits into the wrong lock,” explained Dr. Linda Schönborn of Universitätsmedizin Greifswald, a co-author of the study. “This combination of a random mutation and a genetic peculiarity is extremely rare, which is why the risk of this complication is very low.”
A History of Investigation
The Greifswald research team initially gained attention during the peak of the COVID-19 pandemic in when they first identified the link between certain adenovirus-based COVID-19 vaccines and these unusual blood clots. The current study builds upon that initial discovery, providing a detailed molecular explanation of the underlying process.
Implications for Future Vaccine Development
The identification of Protein VII as the key trigger opens the door to developing safer adenovirus-based vaccines. Researchers believe that modifying this specific viral protein could prevent the immune misdirection that leads to VITT.
“Now we can specifically alter the responsible site in Protein VII of the vaccine and make vector vaccines safer for everyone,” said Professor Andreas Greinacher, the study’s lead author and a professor emeritus at McMaster University. “This represents particularly relevant in regions where life-threatening infectious diseases like Ebola are still prevalent and adenovirus-based vaccines are crucial.”
What This Means for Patients
VITT remains a very rare side effect. The study underscores the importance of continued monitoring and research into vaccine safety. The researchers emphasized the extraordinary willingness of patients from across Germany to donate blood samples, which was crucial to unraveling the complex immunological mechanisms at play.
The findings provide a deeper understanding of how the immune system can sometimes malfunction, offering insights that may extend beyond VITT to other rare antibody-driven adverse reactions to infections, medications, or environmental exposures. The identification of this novel mechanism could serve as a roadmap for investigating and preventing similar complications in the future.
Further information, including background videos and a link to the full study, is available on the Universitätsmedizin Greifswald website: https://www.unimedizin-greifswald.de/de/forschung/neues-aus-der-wissenschaft/2025/imstoffnochsicherermachen/. The study itself can be accessed at: https://www.nejm.org/doi/full/10.1056/NEJMoa2514824.
