MRNA Vaccine Safety: Answer of the European Medicines Agency (EMA)

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Sagittarius A-Star
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mRNA Vaccine Safety: Understanding the answer of the European Medicines Agency (EMA)
On Feb 28th, the anti-vaccination group "Doctors for Covid Ethics" wrote a first open letter with questions to the European Medicines Agency (EMA) regarding safety concerns of mainly mRNA vaccines. They have the hypothesis, that the LNPs of an mRNA vaccine go partly from the injection site into blood vessels and go there into endothelial cells. Then they fear - to my understanding - that the endothelial cells create spike proteins, present them, and that then T killer cells destroy the endothelial cells the thereby the blood vessels.

I try to understand the first paragraph of the answer of the EMA to question #3, published on the official site of the EMA (marked in bold by me):

EMA said:
3. If such evidence is not available, it must be expected that during expression of the vaccines’ nucleic acids, peptides derived from the spike protein will be presented via the MHC I - pathway at the luminal surface of the cells. Many healthy individuals have CD8-lymphocytes that recognize such peptides, which may be due to prior COVID infection, but also to cross-reactions with other types of Coronavirus [3; 4] [5]. We must assume that these lymphocytes will mount an attack on the respective cells. We request evidence that this probability was excluded in pre-clinical animal models with all three vaccines prior to their approval for use in humans by the EMA.

It is rare for cytotoxic lymphocytes to attack cells exposing an antigen on their surface to the extent of hampering the immune response to reinfection or vaccination. Optimal cytotoxic T lymphocytes activation requires recognition of multiple virus epitopes as well as the presence of additional co-stimulatory signals.
Source:
https://www.ema.europa.eu/documents/other/reply-open-letter-concerning-vaccines-covid-19_en.pdf

via:
https://www.ema.europa.eu/en/news-e...n-letter-concerning-covid-19-vaccines-section

My questions to the EMA answer, marked in bold:
  • What does it mean attacking exposing cells to an extent hampering the immune response?
  • Does a cell, creating a spike protein from and mRNA LNP, present multiple virus epitopes?
  • Why is a co-stimulating signal required for the activation of T killer cells?
 

Answers and Replies

  • #2
atyy
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  • Does a cell, creating a spike protein from and mRNA LNP, present multiple virus epitopes?
  • Why is a co-stimulating signal required for the activation of T killer cells?

The mRNA vaccines create memory T cells that activate to multiple virus epitopes (there are many epitopes even on just the part of the spike protein that the mRNA vaccines present).
https://www.sciencedirect.com/science/article/pii/S266637912100015X
https://www.science.org/doi/10.1126/sciimmunol.abj1750

A co-stimulating signal is required for optimal activation of killer T cells. Some of this is described in the the context of cancer therapy.
https://www.thelancet.com/journals/ebiom/article/PIIS23523964(20)303078/fulltext
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511336/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336166/
 
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  • #3
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A co-stimulating signal is required for optimal activation of killer T cells.
Yes. I found also a good video on killer T cell activation. With this information I conclude, that the first paragraph of the answer of the EMA to question #3 is off-topic.

Regarding question #2:
2. If such evidence is not available, it must be expected that the vaccines will remain entrapped in the circulation and be taken up by endothelial cells. There is reason to assume that this will happen particularly at sites of slow blood flow, i.e. in small vessels and capillaries [2]. We request evidence that this probability was excluded in pre-clinical animal models with all three vaccines prior to their approval for use in humans by the EMA.

... Non-clinical studies with COVID-19 mRNA vaccines do not indicate any detectable uptake of lipid nanoparticles by endothelial cells. ...
Source:
https://www.ema.europa.eu/documents/other/reply-open-letter-concerning-vaccines-covid-19_en.pdf

Here, I miss a theoretical explanation of the EMA for what was found in non-clinical studies.

Does the following paper deliver such a theoretical explanation?

To my understanding, ionizable LNPs are positively charged in muscle tissue (acid: pH < 0) and electrically neutral in blood (alkaline: pH > 0). So there is an uptake by dendritic cells, as intended, but not by cells in the blood system, like blood cells or endothelial cells.
Ionizable lipids are protonated at low pH, which makes them positively charged, but they remain neutral at physiological pH (refs7,11,14). The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells and, thus, improve the biocompatibility of lipid nanoparticles
Source:
https://www.nature.com/articles/s41578-021-00358-0
 
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