Scientists Explain Rare Blood Clots Linked to COVID-19 Vaccines & Adenovirus Infection

Scientists Identify Root Cause of Rare Blood Clots Linked to COVID-19 Vaccines and Infections

A rare but serious condition involving dangerous blood clots, known as vaccine-induced immune thrombocytopenia and thrombosis (VITT), has puzzled medical researchers since it was first observed following the rollout of certain COVID-19 vaccines. Now, a study published in the New England Journal of Medicine has pinpointed a specific mechanism driving this adverse event, offering a path toward safer vaccine design.

The research, conducted by teams in Australia, Canada, and Europe, reveals that VITT arises from a complex interplay between the body’s immune response to adenovirus-based vaccines – and, less commonly, natural adenovirus infections – and a pre-existing genetic predisposition. The findings explain why the condition is so rare, why it occurs more frequently after a first vaccine dose in some populations, and how future vaccines might be engineered to avoid this complication.

Immune System Misfire Triggered by Viral Protein Mimicry

Adenovirus-based COVID-19 vaccines, such as the Oxford-AstraZeneca and Johnson & Johnson (J&J) vaccines, utilize a harmless adenovirus to deliver genetic instructions for building the SARS-CoV-2 spike protein. This triggers an immune response, preparing the body to fight off the virus. However, in a small number of individuals, this process can go awry.

Researchers discovered that a protein on the surface of the adenovirus, called protein VII (pVII), bears a striking resemblance to a region of a human blood protein, platelet factor 4 (PF4). In individuals with a specific inherited version of an antibody gene (IGLV3‑21*02 or *03), the immune system can mistakenly target both pVII and PF4. This initial immune response isn’t enough to cause VITT on its own, as the gene variant is present in up to 60% of the population.

The critical step occurs when a single, specific mutation arises in one of the antibody-producing cells. This mutation, designated K31E, alters a single amino acid within the antibody, redirecting its focus from pVII to PF4. Once the antibody binds to PF4, it activates platelets, leading to the formation of dangerous blood clots and a decrease in platelet count – the hallmarks of VITT.

A Specific Mutation Confirmed as the Culprit

Remarkably, the K31E mutation was detected in all VITT patient antibodies examined during the study. When researchers reversed this mutation in laboratory-engineered antibodies, their harmful activity disappeared, definitively proving that this specific change is essential for the development of VITT. “This study shows, with molecular precision, how a normal immune response to an adenovirus can very rarely go off-track,” explains Theodore Warkentin, professor emeritus in the Department of Pathology & Molecular Medicine at McMaster University and corresponding author of the study.

The team employed advanced techniques, including antibody sequencing, mass spectrometry, and the creation of humanized mouse models, to unravel this complex mechanism. The mouse models confirmed that the VITT antibody caused clotting, while the “back-mutated” version did not.

Implications for Vaccine Safety and Future Development

This discovery addresses several long-standing questions surrounding VITT. It explains why adenoviral-vector vaccines – and natural adenovirus infection – can trigger the condition, why PF4 is the target, and why VITT is so rare. It also sheds light on why the incidence of VITT 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 (due to boosting pre-existing immunity from low baseline antibody levels).

Perhaps most importantly, the identification of pVII and the K31E mutation provides a clear roadmap for vaccine developers. By redesigning adenoviral vaccines to minimize the similarity between pVII and PF4, it may be possible to prevent this rare but life-threatening complication while preserving the vaccines’ effectiveness. “What’s exciting is that we can now point to a specific viral component that can be redesigned. It means future adenoviral vaccines can keep all their advantages while sidestepping the rare immune misfire that causes VITT,” Warkentin adds.

The research builds upon previous work by Warkentin and colleagues, including a 2021 study that first identified VITT as a distinct syndrome, a 2023 study demonstrating that natural adenovirus infection can also trigger PF4-reactive antibodies, and a 2024 study revealing that vaccine- and virus-induced cases share an identical antibody “fingerprint.”

This latest research represents a significant step forward in understanding and mitigating the risks associated with adenovirus-based vaccines, paving the way for even safer and more effective immunization strategies in the future.