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Comment by jcims | Hacker News Reader

One thing I haven't been able to find yet is how many spike proteins are generated per strand of mRNA. Is it 1:1 or is the mRNA reused a few/buncha times before it degrades?

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Not all the mRNA makes it into your cells, but for the mRNA that does, it probably produces thousands of spike proteins before degrading.

Whoa. That's cool. A while back I wondered if we could just synthesize the proteins externally, but this way we only have to figure out how to synthesize, package and deliver mRNA and the process could be used to generate an arbitrary set of proteins. Presumably the proteins themselves are going to vary as much as the tissues in the human body, so the synthesis might be the same but the packaging and delivery parts would seem to vary widely based on characteristics of the protein.

To the best of my knowlede, the Novavax vaccine actually does this. Instead of delivering an mRNA nanoparticle, it delivers a spike protein nanoparticle. In fact, they just started phase 3 trials: https://www.sciencemag.org/news/2020/12/novavax-launches-piv...

It is reused many times as this super interesting article that I highly recommend [0] explains and I'll quote:

The very end of mRNA is polyadenylated. This is a fancy way of saying it ends on a lot of AAAAAAAAAAAAAAAAAAA. Even mRNA has had enough of 2020 it appears.

mRNA can be reused many times, but as this happens, it also loses some of the A’s at the end. Once the A’s run out, the mRNA is no longer functional and gets discarded. In this way, the ‘poly-A’ tail is protection from degradation.

Studies have been done to find out what the optimal number of A’s at the end is for mRNA vaccines. I read in the open literature that this peaked at 120 or so.

The BNT162b2 vaccine ends with:

UAGCAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAGCAUAU GACUAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAA

This is 30 A’s, then a “10 nucleotide linker” (GCAUAUGACU), followed by another 70 A’s.

[0]: https://news.ycombinator.com/item?id=25538820

I thought it gets broken down after one use? A related question: How does the mrna move itself back into the copy machinery?

It tends to 'degrade' from the end, which is why all of the additional 'A' nucleotides are tacked on to the end, it's basically a NOOP sled that gets shorter and shorter until the instance is disabled.

The mRNA isn't intended to be copied in the body. Once the dose is used up there should be no more spike proteins created.

Damn, I bookmarked that article to read later. I should have read it before posting...it answered basically all of my questions lol

I love the image of the mRNA yelling AAAAAAAAAAA throughout the body warning of the virus that is about to come (and then slowly losing energy and dissolving into nothing as all screams do).

I don't know, but I think that if it was just 1:1 it would be far easier to get the protein manufactured by cells living in a petri dish (that can be subjected to much more drastic changes) and inject those protein copies directly instead of mRNA wrapped in some fancy vector molecules.

The fancy vector molecules are just oils. AFAIK the reason they use mRNA is precisely because it's easy to make lots of it quickly through simple chemical processes. Proteins are much more complex, and harder to synthesize using traditional chemical processes.

My understanding is the mRNA is reused over and over-- the AAAAAAs at the end of the vaccine sequence are there to extend their tiny little lives a bit as the end breaks off after each reading.

Basically like little vaccine telomeres?

It's definitely not 1:1, but the mRNA degrades fairly quickly at body temperature (thus, 2 doses).

Here is a study of the effects - https://www.nejm.org/doi/full/10.1056/NEJMoa2024671.

It doesn't directly address your question, but it does show how the vaccine performs to control (labeled pbs) in terms of viral load and immune system activity when challenged with a dose of the virus.

The mRNA produced for the vaccines have various modifications that cause greater stability than normal mRNA.

The two shots have nothing to do with mRNA stability, they improve immunity, as in any other vaccine given in two or three shots.

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