Covid-19 mRNA/LNP Vaccine: understanding Biodistribution

[Sagittarius A-Star]

TL;DR Summary

Covid-19 mRNA/LNP Vaccine: understanding Biodistribution

When mRNA/LNP vaccine gets injected into the upper arm (30 µg for BionTech/Pfizer, 100 µg for Moderna), small amounts get distributed to other organs.

Both the Pfizer/BioNTech and Moderna vaccines are being given i.m., so if you’d like to know what parts of your body are producing the Coronavirus Spike protein antigen, the answer seems to be the muscle tissue at the site of injection, the lymphatic tissue downstream in your armpit on that side, your spleen, and (for the first day or two) your liver.

Source:
https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mrna-vaccines-what-happens

The biodistribution of lipid-mRNA particles was assessed in mice using various LNP-formulated modRNAs encoding luciferase. After IM injection, luciferase activity was monitored in vivo for 9 days. The highest signals were detected at the injection site and, 6 hours after injection, in the liver. The activation of the innate immune system was also determined in the same studies in mice with the mRNA-LNP encoding luciferase by measuring several chemokines/cytokines. The mRNA-LNP injection resulted in a transient induction of IL-6, MCP-1 and IP-10, indicating activation of macrophages. Following intramuscular administration of radiolabelled mRNA-LNP in rats, the highest concentration was found at the injection site. Outside the injection site, low levels of radioactivity were detected in most tissues, with the highest levels in the liver.

Source:
https://www.swissmedic.ch/dam/swissmedic/de/dokumente/zulassung/swisspar/68225-comirnaty-01-swisspar-20210430.pdf.download.pdf/20210430_SwissPAR Comirnaty.pdf

Do we know quantitatively, which percentage of the vaccine leaves the upper arm?

Do we know, how many Spike proteins are produced overall in the body?

 

[Astronuc]

Summary:: Covid-19 mRNA/LNP Vaccine: understanding Biodistribution

Do we know, how many Spike proteins are produced overall in the body?

The spike protein is on the virus, and it is the protein that binds with cells and helps the virus infiltrate the cells to which it binds.

The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain.

https://www.nature.com/articles/s41401-020-0485-4

Domains and Functions of Spike Protein in SARS-Cov-2 in the Context of Vaccine Design
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829931/

Regarding injection,

Appropriate vaccine administration/delivery is the key element to ensure successful vaccination. Typically, most vaccines are administered via the subcutaneous (SC) or intramuscular (IM) routes.
. . . .
At present, most vaccines are deposited into the subcutaneous fat or into the muscle beneath the skin. Relatively few vaccines are administered into the viable skin (epidermis and dermis). Each of these routes of application relies on the presence of dendritic cells (DCs) in the tissues that take up the antigen, process it and present it to T lymphocytes in the draining lymphoid organs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287301/

I would expect that injection is sized to get sufficient quantity of the vaccine substance into the body in order to confer the appropriate immune response.

 

[Sagittarius A-Star]

I would expect that injection is sized to get sufficient quantity of the vaccine substance into the body in order to confer the appropriate immune response.

Yes. The quantity of the vaccine substance (for example 30 µg for BionTech/Pfizer) contains a certain number of lipid nano-particles (LNP) containing mRNA genes. A certain fraction of the injected LNPs goes into dendritic cells or normal cells, in which modified spike proteins grow and be presented at the surface. I am curious, how many of such spike proteins are produced overall in the body and how many own cells will therefore been destroyed by T-killer cells.

 

[Astronuc]

The CDC describes the process for mRNA vaccines, which indicates "COVID-19 mRNA vaccines give instructions for our cells to make a harmless piece of what is called the “spike protein.”"
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mRNA.html

Nebraska medicine cites a peer-reviewed study regarding "Where does the vaccine go?" The article states, "Vaccines mostly remain near the site of injection (the arm muscle) and local lymph nodes." But that is based on macaques. https://www.sciencedirect.com/science/article/pii/S2211124720302928
Nebraska medicine - https://www.nebraskamed.com/COVID/where-mrna-vaccines-and-spike-proteins-go

It also addresses - How long spike proteins last in the body?

It seems imperfect because it does not answer directly the questions one has posed.

 

[Laroxe]

Yes, Astronuc makes some important points. The vaccine contains mRNA which can inter into our, usually local, tissue cells. It carries the instructions for the cell to produce a protein complex that contains antigens identical to ones found on the virus spike proteins. These cells present these proteins on their surface where they are identified as foreign by various immune cells, these initiate a chemical alarm which attract other immune cells and alter the local environment, inflammation in other words. Dendric cells (and others) ingest samples of this protein literally chew up these proteins into smaller antigenic parts and purposefully move to the local lymphatic centres and initiate the adaptive immune responses. While the cells producing these proteins only do so as long as the mRNA's last, and would return to their normal functioning quite quickly. Non replicating mRNA usually only works for a few days, there are techniques to extend this to a duration of several weeks but for the Covid vaccines they are all non replicating, so production is short term. However, our immune system can be very unforgiving, many of these cells would be labelled as defective and destroyed, often along with a number of innocent bystanders who are just in the same area. I don't think it's possible to precisely quantify how many cells will take up the mRNA or that will be destroyed, the researchers are only really interested in establishing a dose that stimulates a protective level of immunity and avoids immune overreactions.
This means that we don't really get the full spike protein and most of the heavy lifting in the immune response occurs, at least initially, close to the vaccination site. This also means that most of the adverse events we see in the first few days, following vaccination, are due to the chemical alarm signals generated, which are fairly non specific and occur in all vaccinations, though at different levels.

 

[Sagittarius A-Star]

I found a good video-review of two mRNA biodistribution papers. LPP (lipopolyplex) seems to be better than LNP:

The reviewed papers are:
https://www.nature.com/articles/s41392-021-00634-z
and (see PDF page 125)
https://www.tga.gov.au/sites/default/files/foi-2389-03-1.pdf

 

[atyy]

https://www.forbes.com/sites/nathan...h-made-the-vaccines-possible/?sh=28c48e5b354f
Covid’s Forgotten Hero: The Untold Story Of The Scientist Whose Breakthrough Made The Vaccines Possible
"Without Ian MacLachlan’s innovative delivery system, Moderna and Pfizer couldn’t safely get their mRNA vaccines into your cells. So why does hardly anyone acknowledge the Canadian biochemist’s seminal contributions—or pay a dime in royalties?"

Katalin Kariko: The LNP is as important as the mRNA in the vaccine. Covid’s Forgotten Hero: The Untold Story Of The Scientist Whose Breakthrough Made The Vaccines Possible via
@forbes

 

[Ygggdrasil]

https://www.forbes.com/sites/nathan...h-made-the-vaccines-possible/?sh=28c48e5b354f
Covid’s Forgotten Hero: The Untold Story Of The Scientist Whose Breakthrough Made The Vaccines Possible
"Without Ian MacLachlan’s innovative delivery system, Moderna and Pfizer couldn’t safely get their mRNA vaccines into your cells. So why does hardly anyone acknowledge the Canadian biochemist’s seminal contributions—or pay a dime in royalties?"

Katalin Kariko: The LNP is as important as the mRNA in the vaccine. Covid’s Forgotten Hero: The Untold Story Of The Scientist Whose Breakthrough Made The Vaccines Possible via
@forbes

Here's another, perhaps more balanced view of the development of LNPs that doesn't try to pin down multiple decades of work across a number of different companies on a single individual (written by science reporters for a publication focused on the pharmaceutical industry rather than written by a guy who covers hedge funds): https://cen.acs.org/pharmaceuticals/drug-delivery/Without-lipid-shells-mRNA-vaccines/99/i8

Also, here's a nice review article published in a scientific journal that discusses the development of LNPs for mRNA delivery (though some of the authors of affiliated with Moderna): https://www.nature.com/articles/s41578-021-00358-0

The LNP space, however, is somewhat of a mess with regard to intellectual property as there are multiple patent disputes surrounding the LNP technology (as the Forbes article discusses).