Comment by tzs | Hacker News Reader

Comment by tzs | Hacker News Reader

The layman's explanation I've seen about how these mRNA vaccines work is that they get some of your cells to manufacture a protein that is characteristic of the virus, which the cells release and the immune system takes care of.

Then later if you get the virus, the immune system already recognizes that protein and takes care of the virus.

Question: why do we need to have our cells make the protein? Couldn't we synthesize and distribute the protein itself and inject that?

Question 2: what happens to the cells that take in the mRNA and make the protein? Do they just make a certain amount of it, then go back to normal?

Or do they keep making it for the lifetime of the cell, and stop doing whatever that cell is normally supposed to do?

Or do they get killed doing this, much like if they were infected by the virus (except, of course, that unlike the with the virus, what they are making is not viral, so the maximum number of cells that would be killed making the protein is equal to the number of mRNA strands in the injection)?

1. In 40 years, there have only been 20 protein drugs approved.

2. Yes the cells go back to to normal after the mRNA degrades. The mRNA does not last long, it is like data in ram vs data on a hard drive.

See this video:

https://www.youtube.com/watch?v=T4-DMKNT7xI

20 protein drugs? mAbs are proteins and hundreds of those have been approved.

mAb = monoclonal antibody

Yes, and to be clear, antibodies are a subset of proteins.

Wow, this video is really good.

Why have there only been 20 protein drugs approved?

These are good questions.

Proteins are chemical compositions - useful machines. Each one (especially outside the context of a cell) requires custom environments to be kept stable. And the processes to manufacture them require other organisms - from which you must now purify that (unstable) protein. And it’s not self-replicating so if you need weekly doses of Ng of material for X doses, you need to produce that much material. RNA solves all of these issues. RNA is a template of common composition that can encode any protein (same chemistry, but in different orders can encode for any arbitrary protein). It can be synthesized in a chemically defined system. And it can persist long enough to produce many generations of proteins. And it can even sometimes be designed to be self replicating. From a theoretical perspective it’s so much better than delivering a custom-purified shot to your blooodstream - different for each virus.

The second question is the hard part - delivery. With the advent of ‘gene therapies’ we needed easy to deliver DNA and RNA to living human cells. We’ve come a long way here and have a number of technologies (oftentimes co-opted from viruses) that range from permanent integration into the cell’s genome (lentivirus) to transient (AAV [see Oxford’s vaccine]) to chemical transfection (Pfizer and Moderna). The RNA in these vaccines is chemically more stable than normal RNA, so it will have half-lives of weeks rather than hours inside cells - but it will degrade after a time and the cells will no longer produce the protein. Proteins in a cell have half-lives of hours to days and even stabilized RNA will be less than a month. After that the material produced by this 'vaccine' will be degraded and gone. However, at that point, the immune system will have permenantly 'encoded' antibodies for the shape of the produced spike protein.

What changes are made to mRNA in these vaccines to make them last longer? Also wouldn't our immune system attack it as foreign then? It seems to me as a layperson that this must have been a key novel and clever part to make these vaccines work. I'd like to read more but don't know where to start.

It's not just proteins. The cells infected with the mRNA present those proteins on the outside of the cell to be recognized by other cells which start a chain process.

Skip to around 12:30 in here: https://www.youtube.com/watch?v=35Idb_lCU4o

He goes through the entire biochem process. Even the cells infected with the mRNA will need to be removed by the immune system using cytotoxic T-cells, so they need to get the chain process going.

The reason we have "memory" for viruses is because a ton of random stuff in our immune systems evolved to multiply exponentially when they come in contact with viruses or proteins that indicate certain infections. It's a lot of stuff and you can't just inject that memory in; you have to stimulate the immune system to create them at a very large scale.

It's not just antibodies. There are memory T-cells, parts of the complement system that get activated; a whole host of things.

My issue is that our immune systems are incredibly complex, and there are a lot of components to this "memory" that are not entirely understood. Every other vaccine is an inactivaed virus (via heat treatment) or attenuated (virus run through other hosts to make it less dangerous to humans). The first vaccine was just a close relative: cow/horse pox instead of smallpox. The former are not dangerous in humans, but seem to produce the same immune memory.

The mRNA vaccines are at attempt to say, "Let's strip out all that other stuff and find just the thing we need." But our immune systems are incredibly complicated. It will be interesting to see if these things actually work at scale.

The trials were to make sure the vaccine is safe in a short about of time. It's not really going to test effectiveness until deployed at scale.

That's not very true. Phase II trials are designed test safety, phasE III trials are designed to test efficacy. Statistics is advanced (and magic) enough that we're now reasonably sure that the vaccine has a 95% efficacy. That's not 'totally sure', we'll only be totally sure it works once everyone is vaccinated and the pandemic stops. But we _know_ it works, in the scientific-probabilistic meaning of knowledge.

>Even the cells infected with the mRNA will need to be removed by the immune system using cytotoxic T-cells

I don't think that this is accurate.

I'm going off what he says in the video.

1. One advantage of the mRNA vaccine is that each strand of mRNA is translated to protein many times before it is degraded. So less vaccine has to be manufactured and the dosage can be smaller. Another advantage is that since it lacks proteins you do not develop immunity to the vaccine itself, meaning that you can receive multiple booster doses.

2. Yes, the mRNA is ultimately degraded. But part of the process of developing the vaccine is fine tuning the precise rna sequence in order to achieve the desired half life.

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