Laut einer neuen Studie hatte die Blutgerinnung im Zusammenhang mit den COVID-Impfstoffen von Johnson & Johnson und AstraZeneca eine genetische Ursache | Adenovirales initiierendes Antigen und somatische Hypermutation bei VITT

Highlights from the magazine article:

>The team that initially gave this condition a name—vaccine-induced immune thrombotic thrombocytopenia, or VITT—included Andreas Greinacher, a blood expert at the University of Greifswald, in Germany. Back in 2021, as the cases of VITT emerged, he and others were unsure of what precipitated them. One theory was that they were caused by the body’s accidental reaction to the type of virus used in both the AstraZeneca and Johnson & Johnson vaccines: adenoviruses, which had been engineered to prompt the body to recognize the pandemic coronavirus but were unable to replicate and considered harmless to people. Scientists had noticed that patients with VITT had telltale markers in their blood—antibodies that bind to a chemical signal released by platelets. Maybe a reaction to the adenovirus was causing immune cells to mistakenly go after a blood component and precipitate clotting. An alternative theory was that the body was reacting to a portion of the coronavirus called “spike protein,” which showed up as part of the immunization.
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>In a study published today in The New England Journal of Medicine, Greinacher and his colleagues show that the first theory was correct: VITT was a response to the adenovirus gone awry. And they discovered a further twist: This immune overreaction happened in people who were genetically prone to it.
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>In the study, Greinacher and his colleagues looked at the antibodies in stored blood from 21 patients with VITT. Among those antibodies, they found a subset that could glom on to a portion of the adenovirus and to one of the body’s own molecules, PF4, that can influence blood clotting. A person who received one of the adenovirus vaccines but did not have a reaction also had antibodies against that same part of the adenovirus. But, crucially, that person’s antibodies did not cross-react with PF4.
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>Those antibody molecules also offered clues about the immune cells that made them. And the scientists were able to link the immune cells responsible for VITT to patients who had two specific DNA variants. A wider survey of 100 VITT patients found that all of them had immune cells with one of these genetic types—which are far from universal. This signaled to the researchers that having these particular variants is a strong risk factor for blood clotting following an adenovirus vaccine.
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>But the study also showed that this genetic background on its own was not enough to cause VITT. The immune cells that made the dangerous antibodies had experienced an additional small genetic change, and that extra mutation had prompted them to produce those cross-reactive molecules.
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>In the past, scientists have suggested that genetic predispositions might explain some adverse events that happen after vaccination. For example, some data have indicated that certain people were genetically prone to developing narcolepsy following a version of swine-flu vaccine that was briefly used in Europe. But the new study from Greinacher and his team is the first to provide concrete evidence of how people with a particular DNA variant can develop self-sabotaging antibodies following a vaccination. Arnold Lining Ju, a biomedical engineer at the University of Sydney who has studied blood clotting, told me that the paper was a landmark finding in part because of how elegantly it explains the way a specific genetic trait, combined with a particular chance mutation in certain cells, creates VITT. And because the study shows that multiple genetic changes are involved, it finally explains why this immune reaction is so rare, he said.
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>…
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>These results also mean that adenovirus-based vaccines could be made safer if they can be designed without the protein region that triggered the dangerous antibodies in VITT. “Instead of abandoning an entire vaccine platform because of a rare problem, we can engineer around the specific issue, and that’s the power of this kind of science,” Joann Arce of the Precision Vaccines Program at Boston Children’s Hospital told me. The hope is that understanding the biology of a rare event like VITT, and then addressing it, helps bolster public trust in vaccines too. Greinacher told me that adenovirus-based vaccines remain vital, including for the development of vaccines for diseases that affect mostly low- and middle-income countries. The shots could also be useful in a future pandemic, because they can be scaled up in production relatively quickly.

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Journal link:

[Adenoviral Inciting Antigen and Somatic Hypermutation in VITT](https://www.nejm.org/doi/full/10.1056/NEJMoa2514824)

Abstract:

>**Background**
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>Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare prothrombotic complication that occurs after adenoviral vector–based vaccination against coronavirus disease 2019; in rare cases, it can also occur after natural adenovirus infection. VITT is mediated by platelet-activating antibodies against the highly cationic protein platelet factor 4 (PF4). The underlying inciting antigen trigger and immunopathogenesis remain unknown.
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>**Methods**
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>We used antibody proteomics to determine the amino acid sequences of anti-PF4 antibodies from 21 patients with VITT and sequenced the genes encoding the immunoglobulin light-chain hypervariable region from 100 patients with VITT. To identify an adenoviral trigger, we used the antigen-binding fingerprints of anti-PF4 and anti–adenovirus protein antibodies to identify a shared serum clonotype and subsequently used adenovirus protein peptides and recombinant anti-PF4 VITT antibodies to map the mimicking linear epitope.
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>**Results**
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>Genomic and proteomic profiling of VITT antibodies revealed a shared immunoglobulin light-chain allele, IGLV3-21*02 or *03, harboring a critical somatic hypermutation, K31E. Only antibodies purified against adenoviral core protein VII (pVII) contained anti-PF4 species matching the VITT fingerprint; antibodies against intact virions or other adenoviral proteins did not. Cross-reactive IgGs were mapped to a basic linear epitope on pVII. A pathogenic anti-PF4 VITT antibody, back-mutated to germline (K31), lost its prothrombotic activity in vitro and in vivo and preferentially bound pVII, a finding that directly supported the role of the hypermutation in the antigenic shift from adenovirus pVII to PF4.
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>**Conclusions**
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>The results of our study indicate that VITT occurs when, in persons with immunoglobulin light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation develops that affects antibodies that recognize a specific epitope on the adenoviral core protein pVII, which results in misdirection of antibody targeting toward PF4.

19 million doses and 60 are the base for „sometimes genetic?“

Ok. no revelation here.