"Premature", a "hypothesis": Experts' doubts about the study that claims to have 'deciphered' the thrombus by vaccine

A new study that addresses the formation of thrombi among people vaccinated with AstraZeneca and Janssen is monopolizing the conversation among the scientific community this Thursday morning. After reading it almost with the ghosts still, many are those who question what the team led by the German Rolf Marschalek raises, which in the end, they say, is a “hypothesis”.

The ‘preprint’ -without peer review- was published this Wednesday in Research Square, and suggests that “Variants of the protein ‘Spike'” SARS-CoV-2, the virus that causes covid-19, who would stay “dissolved” outside the cells “They can initiate serious side effects when they bind to ACE2 receptors in blood vessels.”

However, this is “a hypothesis”, as the specialists in molecular biology are warning when reading the work. This is corroborated by the immunologist of the Barcelona Global Health Institute, Adelaida Sarukhan, who warns that what this team has tested “on cell lines in the lab” is that the protein ‘Spike’ or ‘S’ encoded in un adenoviruscan generate shorter RNA while generating soluble ‘S’ protein“, Explain.

The scientist points out that based on this observation, the German team suggests that this is the cause of the very rare blood clots found among people vaccinated with AstraZeneca O Janssen, which are the adenovirus-based vaccines licensed so far in the US and Europe. The Russian Sputnik vaccine also uses this viral vector “but there is less transparency and fewer people” to whom it has been administered, says Sarukhan.

Regarding these adenovirus-based vaccines, the immunologist recalls that for the DNA sequence to end up in protein ‘S’ it has to go through the intermediate step of RNA, that is, “it does not go from DNA to protein directly, but DNA it has to be transcribed into RNA and then translated into protein. ” When the DNA carrying the adenovirus enters the cell nucleus -continues-, it is transcribed to RNA, “and It is in this phase of transcription from DNA to RNA that they propose that shorter RNA can be generated., what they call ‘splices’ – splices or joints – cut “.

The new study proposes that that cut in the RNA is translated into protein ‘Spike’ but without the transmembrane region -the ‘S’ protein normally remains anchored in the cell membrane because they have a fragment called transmembrane, which is what anchors it in our membrane. German researchers have seen that “this cut RNA can produce protein ‘S’ without this transmembrane region and, by not having it, its destiny is to be secreted by cells and ends up in the extracellular space and enters the circulation more easily. And they propose that this circulating ‘S’ protein can stick to ACE2 receptors and activate the cascade that causes thrombi “, explains the immunologist.

In the same way, his colleague, the CSIC immunologist Matilde Cañelles, explains: “These vaccines direct the DNA towards the nucleus of the cells and, being in the nucleus, they would produce mutant proteins, a little cut, that, instead of sticking to the surface of the cells -which is what usually happens with the proteins that the vaccines produce-, some of them would lack the part that allows them to stick to the cells and they would remain solubilized, that is, they would leave the cells and could stick to cells in the blood vessel area, which would produce the thrombi “.

Doubts that arise

“But it is all a hypothesis”, both scientists warn. “It does not mean that it is not true, but they have to prove that it is so. It seems unlikely to me that such high amounts of protein ‘S’ are generated as to produce this. I have seen that there is the doubt, “says Sarukhan.

For her part, the CSIC expert stresses that she thinks “very premature“say that this directly proves the thrombus mechanism” because they don’t test it, they do it in cell lines and have not demonstrated the presence of these soluble proteins in patients, it would have to be put under more studies “.

If this theory were true, it would mean that “probably these same people in whom thrombi occur after vaccination, thrombi would also occur if they passed covid-19”

Cañelles adds that if this theory were true, it would mean that “probably these same people in whom thrombi occur after vaccination, thrombi would also occur if they passed the covid-19 disease“.

In fact, researchers have named this mechanism “Vaccine-Induced Covid-19 Mimic Syndrome” (VIC19M, for its acronym in English).

It is worth mentioning that this “interesting” work raises an “additional and not mutually exclusive” discussion, which is why it would complement the research carried out by the team of the also German Andreas Greinacher, what are “more advanced in terms of degree of evidence” since they have demonstrated the presence of antibodies in patients. These scientists, who have termed this reaction as ‘vaccine-induced thrombotic thrombocytopenia syndrome’ (WHITEbelieve that something in the vaccine interacts with a protein on platelets called factor plaquetario 4 (PF4), which triggers an autoimmune reaction.

How long would it take to modify vaccines?

If the theory that these pieces of RNA that remain “solubilized” are the triggers of thrombi were true, then “it could be solved” to avoid possible future cases of these very serious adverse effects of the AstraZeneca and Janssen vaccines. “Just modify a couple of codons, that is, a pair of bases in the DNA of the protein ‘S’ so that ‘splicing’ does not occur. If true, it can be fixed, which is good. But the thing is if it is true “, maintains the expert.

The “great advantage“Of the vaccines based on adenovirus and messenger RNA is that it is” relatively fast “to modify them.” It would be a question of days or weeks. Then it would have to be produced, “says the immunologist from ISGlobal in Barcelona, ​​a center promoted by the” la Caixa “Foundation.

Regarding whether it would be necessary to carry out new clinical trials of modified vaccinates, Sarukhan believes that these they would be more “agile” with phases one and two, but “probably not” phase 3 would be necessary, which is the one that defines the dose and the pattern in humans. “It is one of the great questions that has been on the table, since the vector is the same and basically the same protein,” he acknowledges.


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