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

In summary, the EMA is asking for evidence that cytotoxic lymphocytes will not attack cells exposing an antigen on their surface to the extent of hampering the immune response to reinfection or vaccination. They are also asking for evidence that the vaccines will remain entrapped in the circulation and be taken up by endothelial cells.
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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?
 
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Sagittarius A-Star said:
  • 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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atyy said:
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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What are mRNA vaccines and how do they work?

MRNA vaccines are a type of vaccine that uses a small piece of genetic material called messenger RNA (mRNA) to teach the body's cells how to make a protein that triggers an immune response against a specific virus or disease. This protein is harmless and cannot cause the disease, but it helps the body build immunity to it.

Are mRNA vaccines safe?

Yes, mRNA vaccines have been extensively studied and have been found to be safe. The European Medicines Agency (EMA) has conducted thorough evaluations of the safety, quality, and efficacy of mRNA vaccines and has approved their use in the prevention of diseases such as COVID-19.

What are the potential side effects of mRNA vaccines?

The most common side effects of mRNA vaccines include pain, redness, and swelling at the injection site, as well as fever, fatigue, headache, and muscle pain. These side effects are usually mild and resolve within a few days. Rare but serious side effects, such as allergic reactions, have also been reported.

How does the EMA ensure the safety of mRNA vaccines?

The EMA has a rigorous evaluation process for all vaccines, including mRNA vaccines. This process involves reviewing data from clinical trials, monitoring adverse events, and conducting regular safety checks after the vaccine is approved and in use. The EMA also works closely with other regulatory agencies to share information and ensure the safety of vaccines.

What is the EMA's stance on the safety of mRNA vaccines for pregnant women and children?

Currently, there is limited data on the safety and efficacy of mRNA vaccines for pregnant women and children. However, the EMA recommends that pregnant women and children should be vaccinated if they are at high risk of developing severe COVID-19 or if they have other health conditions that put them at risk. Pregnant women should discuss the risks and benefits of vaccination with their healthcare provider.

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