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A rare but serious clotting disorder associated with certain COVID-19 vaccines and natural adenovirus infections has intrigued the scientific community for several years. According to a new study, the cause is an unexpected error in the immune system, which attacks the wrong molecule.
An international team of researchers has identified why a very small number of people develop serious blood clots after receiving certain COVID-19 vaccines or after a natural adenovirus infection.
The conclusions of the team from McMaster University (Canada), Flinders University (Australia) and Universitätsmedizin Greifswald (Germany) point to a unexpected error of the immune system which, in rare cases, attacks the wrong molecule.
O , published on Wednesday in the magazine New England Journal of Medicineexplains how the organism can, at times, produce harmful antibodies that attack their own blood proteins, causing thrombocytopenia and vaccine-induced immune thrombosis (VITT).
Researchers accurately identified the viral component capable of triggering this response under unusual conditions, and also described a hitherto unknown biological pathway which shows how a normal immune defense can turn into a harmful reaction.
According to , this discovery could help scientists better understand other rare side effects, caused by antibodies and associated with infections, medications or environmental exposures.
“This study shows, with molecular precision, how a normal immune response to an adenovirus can very rarely derail“, says the professor Theodore Warkentinresearcher at McMaster University and lead author of the study.
“By identifying the exact viral protein involved and the specific antibody change that causes this shift, we now understand not only what happens in VITT, but also why“, he adds.
“It’s exciting that we can now indicate a specific viral component which can be redesigned. This means that future adenoviral vaccines can maintain all their advantages, simultaneously avoiding the rare failure immune system that causes VITT”, he adds.
The discovery
The researchers concluded that VITT can develop after repeated exposure to the adenovirus, either through vaccination or natural infection, but only in individuals carriers of a hereditary version specific to an antibody gene (IGLV3-21*02 or *03).
Since this genetic variant is present in up to 60% of the populationit cannot, alone, explain why the complication remains extremely rare.
The process begins with the immune system response to a protein of the adenovirus known as protein VII (pVII).
This viral protein closely resembles a part of a human blood protein called platelet factor 4 (PF4). In exceptionally rare cases, while the immune system is producing antibodies against pVII, a single mutation may occur in an antibody-producing cell.
This mutation, called K31E, replaces an amino acid with a positive charge and another with a negative charge. Although the change involves only a single constituent element, it is sufficient to redirect the antibody focus from pVII to PF4. When the altered antibody binds to PF4, it activates platelets, causing the abnormal clotting and reduced platelet count characteristic of VITT.
It is important to note that scientists found the same K31E mutation in all the antibodies from patients with VITT that they analyzed. When they reversed this mutation in laboratory-created antibodies, the harmful clotting activity disappeared, confirming that the mutation is essential for the development of the condition.
“Many people know that mutations in DNA explain situations such as congenital anomalies or cancer,” says Warkentin. “But the fact that an immune cell that is producing its normal antibodies, triggered by a virus, suddenly changes its reactivity against a protein of its own due to a specific mutation is a unprecedented spectacular discovery in scientific literature”.
According to the study authors, the discovery responds to five questions long ago about VITT:
- Why adenoviral vector vaccines, and natural adenovirus infection, can trigger it;
- Why is PF4 the target (mimicry between pVII and PF4);
- Why VITT is extraordinarily rare (it requires a specific, chance mutation in a predisposed person);
- Why does the incidence differ between populations (the antibody gene involved is more common in people of European descent); and
- Why many cases occurred after the first dose of the vaccine (results from the reinforcement of pre-existing anti-pVII immunity from low baseline antibody levels).
Equally important, the discovery provides a practical itinerary for vaccine developers to design even safer vaccines without losing the global advantages of adenoviral vaccine technology.
