Scientists Identify Immune Mutation Behind Rare Blood Clots From Adenovirus COVID Vaccines

An international team of researchers from McMaster University (Canada), Flinders University (Australia), and Universitätsmedizin Greifswald (Germany) has identified why a very small number of people developed serious blood clots after receiving certain COVID-19 vaccines or after a natural adenovirus infection. Their findings, published in the New England Journal of Medicine, point to an unexpected mistake by the immune system, which in rare cases targets the wrong molecule.

The study explains how the body can sometimes produce harmful antibodies that attack its own blood proteins, leading to vaccine-induced immune thrombocytopenia and thrombosis (VITT). The researchers pinpointed the exact viral component capable of triggering this response under unusual conditions.

VITT occurred in roughly one of 200,000 people after receipt of the Oxford-AstraZeneca COVID-19 vaccine in Europe and Australia or the Johnson & Johnson vaccine in the United States. After VITT was linked to adenovirus-based vaccines, many European countries either limited the use of the AstraZeneca vaccine or dropped it completely, and the United States abandoned the J&J vaccine. mRNA-based COVID-19 vaccines such as those from Moderna or Pfizer/BioNTech were much more commonly used in the United States and under different brand names in many other countries.

VITT is characterized by thrombosis, or the formation of dangerous blood clots in the veins or arteries, often in the brain or abdomen. It is accompanied by immune thrombocytopenia, an autoimmune disorder that depletes platelets in the blood, leading to uncontrolled bleeding. Symptoms can include severe headache, changes in vision, abdominal and back pain, vomiting, shortness of breath, easy bruising or bleeding, and leg pain or swelling.

The researchers determined that VITT can develop after repeated exposure to adenovirus, whether through vaccination or natural infection, but only in individuals who carry a particular inherited version of an antibody gene (IGLV3-21*02 or *03). Since this gene variant is present in up to 60 percent of the population, it cannot alone explain why the complication remains extremely rare.

The process begins with the immune system responding to an adenovirus protein known as protein VII (pVII). This viral protein closely resembles part of a human blood protein called platelet factor 4 (PF4). In exceptionally rare instances, while the immune system is producing antibodies against pVII, a single mutation can occur in one antibody-producing cell.

This mutation (called K31E) replaces one positively charged amino acid with a negatively charged one. Although the change involves just a single building block, it is enough to redirect the antibody's focus from pVII to PF4. When the altered antibody binds to PF4, it activates platelets, leading to the abnormal clotting and reduced platelet counts characteristic of VITT.

Importantly, the scientists found the same K31E mutation in every VITT patient antibody they analyzed. When they reversed this mutation in laboratory-engineered antibodies, the harmful clotting activity disappeared. This confirmed that the mutation is essential for the condition to develop.

To uncover this mechanism, the team used advanced laboratory techniques. They sequenced antibodies from patients with VITT, analyzed their structures using mass spectrometry, and created engineered versions to observe how the antibodies changed and behaved. The findings were further validated in a humanized mouse model. In these experiments, antibodies carrying the VITT-associated mutation caused clotting, while the "back-mutated" antibodies did not.

They also described a previously unknown biological pathway showing how a normal immune defense can shift into a harmful reaction. This insight may help scientists better understand other rare, antibody-driven side effects linked to infections, medications, or environmental exposures.

The discovery answers five long-standing questions about VITT: why adenoviral-vector vaccines and natural adenovirus infection can trigger it; why PF4 is the target (mimicry between pVII and PF4); why VITT is extraordinarily rare (it requires a specific, chance mutation in a predisposed person); why the incidence differs between populations (the involved antibody gene is more common in people of European ancestry); and why many cases occurred after a first vaccine dose (it stems from boosting pre-existing anti-pVII immunity from low baseline antibody levels).

Just as importantly, the discovery provides a practical roadmap for vaccine developers to design even safer vaccines without losing the global advantages of adenoviral vaccine technology. The discovery means future adenoviral vaccines can keep all their advantages while sidestepping the rare immune misfire that causes VITT by redesigning the specific viral component.