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I would love it if somebody would post a more detailed explanation of the mRNA vaccine manufacturing process here on HN. The news media keeps mumbling vague te

I would love it if somebody would post a more detailed explanation of the mRNA vaccine manufacturing process here on HN. The news media keeps mumbling vague terms like "ingredients", and it's frustrating. Conventional vaccine production is a highly biological process... chicken eggs being used to make the flu vaccines and so forth. I was under the impression that the mRNA vaccines are chemically much simpler -- just strands of a particular RNA sequence (swapping Pseudouridine for Uracil), encapsulated in a very clever lipid coat. Presumably the biotech industry is really really good at manufacturing strands of RNA by now, right? I mean that seems like it's something they would've been doing every day for the last 20 years. So are the only novel manfuacturing steps the Pseudouridine substitution and the lipid coat?

baybal2 5y ago
It's still a biological molecule, with all resulting side effects: i.e., it wanting to fall apart under every imaginable influence when isolated, and concentrated outside of a living cell. I would want to know how they do it (mRNA isolation) too, but nobody will share that knowledge for free. Even most simple methods like inactivation require a cell culture tech, which means lots of expensive bioreactors, and extreme levels of sterility.
makomk 5y ago
As I understand it, the big problem isn't so much chemical as physical - they need to encapsulate the mRNA evenly within lipid particles of a reasonably uniform size, and there's some pretty advanced microfluidic technology involved in doing this. Conventional vaccine production has the advantage that biology takes care of all that pesky encapsulation business.
maxerickson 5y ago
They brew them. A DNA sequence that encodes the intended mRNA strand is embedded into a bacterial plasmid. Bacteria take in that plasmid and reproduce, making a bunch of plasmids with the mRNA encoding DNA embedded in them. The bacteria are killed and broken open and the plasmids are purified. The DNA sequence is then cut out of the plasmids and transcribed into mRNA. https://www.nytimes.com/interactive/2021/health/pfizer-coronavirus-vaccine.html https://www.nytimes.com/interactive/2021/health/pfizer-coron... I bet getting that batch of bacteria to grow and make lots of the desired plasmids is a nice trick to pull off.
- janekm 5y ago
  That's the easy part (literally possible in a home laboratory: https://youtu.be/2hf9yN-oBV4 https://youtu.be/2hf9yN-oBV4), the encapsulant and microfluidics for getting the mRNA into it seems to be the hard part.
  - maxerickson 5y ago
    literally possible in a home laboratory Getting sufficient production of the target isn't easy. The guy at your link includes 'countless failures' in his intro!
- KirillPanov 5y ago
  Wow, very surprised to hear that those mRNA come from actual living, metabolizing, (albeit single-cell) organisms. Why do they do it that way? When you order DNA plasmids from places like Addgene the stuff they ship you is chemically synthesized using enzymes rather than and entire complete living cell, right? I would've thought Pfizer would do the same thing and then transcribe that DNA into mRNA. Is it because of the massive quantities of material they need to produce?
andreareina 5y ago
Derek Lowe goes into it a little bit with some links to further resources. [1] https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my... [2] https://blogs.sciencemag.org/pipeline/archives/2021/02/22/more-on-mrna-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/22/mo...
- KirillPanov 5y ago
  > [1] https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my... Okay, this is the best article of them all, the one I was wishing for. Congratulations, you win ten thousand Internets! Best part (although the whole thing is totally worth reading): As Neubert says, “Welcome to the bottleneck!” Turning a mixture of mRNA and a set of lipids into a well-defined mix of solid nanoparticles with consistent mRNA encapsulation, well, that’s the hard part. ... Everyone is almost certainly having to use some sort of specially-built microfluidics device ... These will be special-purpose bespoke machines, and if you ask other drug companies if they have one sitting around, the answer will be “Of course not”. This is not anything close to a traditional drug manufacturing process. And this is the single biggest reason why you cannot simply call up those “dozens” of other companies and ask them to shift their existing production over to making the mRNA vaccines.
hrasyid 5y ago
Here's an article about the manufacturing process and its challenges: https://www.economist.com/science-and-technology/2021/02/06/how-vaccines-are-made-and-why-it-is-hard https://www.economist.com/science-and-technology/2021/02/06/... The Economist isn't a technical publication but it is known to do its homework and get details like this right.
- KirillPanov 5y ago
  Wow, this is a much better article than the one from the NYTimes. Thank you. Especially for this gem: Supplies of raw materials such as nucleotides are also tight. According to Dr Zarur, Thermo Fisher, an American chemical-supplies company, has spent $200m on a new facility in Lithuania to make these molecules, though the firm itself would not confirm this. I would not have expected this, but it definitely explains a whole lot of otherwise-cryptic claims being made in the WTO debate. I guess it does sort of make sense. The worldwide demand for pure bulk nucleotides probably shot up hundreds or thousands-fold as a result of COVID-19 vax manufacturing.
thehappypm 5y ago
You're in luck, the New York Times wrote an amazing piece on this exact topic: https://www.nytimes.com/interactive/2021/health/pfizer-coronavirus-vaccine.html https://www.nytimes.com/interactive/2021/health/pfizer-coron...
- KirillPanov 5y ago
  The graphics are cute, but the article left me with way more questions than answers. It spent most of its time trying to impress the reader with how much interstate shipping was involved in the process (who cares?). No details on which ingredients are the ones causing so much consternation at the WTO right now, nor any answer to the obvious question "why aren't the DNA plasmids made the same way other commercial plasmid services make them"? But hey, it's the NYTimes. They have to hold the attention of an audience that mostly has no science background.

baybal2 5y ago

It's still a biological molecule, with all resulting side effects: i.e., it wanting to fall apart under every imaginable influence when isolated, and concentrated outside of a living cell. I would want to know how they do it (mRNA isolation) too, but nobody will share that knowledge for free. Even most simple methods like inactivation require a cell culture tech, which means lots of expensive bioreactors, and extreme levels of sterility.

makomk 5y ago

As I understand it, the big problem isn't so much chemical as physical - they need to encapsulate the mRNA evenly within lipid particles of a reasonably uniform size, and there's some pretty advanced microfluidic technology involved in doing this. Conventional vaccine production has the advantage that biology takes care of all that pesky encapsulation business.

maxerickson 5y ago

They brew them. A DNA sequence that encodes the intended mRNA strand is embedded into a bacterial plasmid. Bacteria take in that plasmid and reproduce, making a bunch of plasmids with the mRNA encoding DNA embedded in them. The bacteria are killed and broken open and the plasmids are purified. The DNA sequence is then cut out of the plasmids and transcribed into mRNA. https://www.nytimes.com/interactive/2021/health/pfizer-coronavirus-vaccine.html https://www.nytimes.com/interactive/2021/health/pfizer-coron... I bet getting that batch of bacteria to grow and make lots of the desired plasmids is a nice trick to pull off.

janekm 5y ago
That's the easy part (literally possible in a home laboratory: https://youtu.be/2hf9yN-oBV4 https://youtu.be/2hf9yN-oBV4), the encapsulant and microfluidics for getting the mRNA into it seems to be the hard part.
- maxerickson 5y ago
  literally possible in a home laboratory Getting sufficient production of the target isn't easy. The guy at your link includes 'countless failures' in his intro!
KirillPanov 5y ago
Wow, very surprised to hear that those mRNA come from actual living, metabolizing, (albeit single-cell) organisms. Why do they do it that way? When you order DNA plasmids from places like Addgene the stuff they ship you is chemically synthesized using enzymes rather than and entire complete living cell, right? I would've thought Pfizer would do the same thing and then transcribe that DNA into mRNA. Is it because of the massive quantities of material they need to produce?

andreareina 5y ago

Derek Lowe goes into it a little bit with some links to further resources. [1] https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my... [2] https://blogs.sciencemag.org/pipeline/archives/2021/02/22/more-on-mrna-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/22/mo...

KirillPanov 5y ago
> [1] https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my... Okay, this is the best article of them all, the one I was wishing for. Congratulations, you win ten thousand Internets! Best part (although the whole thing is totally worth reading): As Neubert says, “Welcome to the bottleneck!” Turning a mixture of mRNA and a set of lipids into a well-defined mix of solid nanoparticles with consistent mRNA encapsulation, well, that’s the hard part. ... Everyone is almost certainly having to use some sort of specially-built microfluidics device ... These will be special-purpose bespoke machines, and if you ask other drug companies if they have one sitting around, the answer will be “Of course not”. This is not anything close to a traditional drug manufacturing process. And this is the single biggest reason why you cannot simply call up those “dozens” of other companies and ask them to shift their existing production over to making the mRNA vaccines.

hrasyid 5y ago

Here's an article about the manufacturing process and its challenges: https://www.economist.com/science-and-technology/2021/02/06/how-vaccines-are-made-and-why-it-is-hard https://www.economist.com/science-and-technology/2021/02/06/... The Economist isn't a technical publication but it is known to do its homework and get details like this right.

KirillPanov 5y ago
Wow, this is a much better article than the one from the NYTimes. Thank you. Especially for this gem: Supplies of raw materials such as nucleotides are also tight. According to Dr Zarur, Thermo Fisher, an American chemical-supplies company, has spent $200m on a new facility in Lithuania to make these molecules, though the firm itself would not confirm this. I would not have expected this, but it definitely explains a whole lot of otherwise-cryptic claims being made in the WTO debate. I guess it does sort of make sense. The worldwide demand for pure bulk nucleotides probably shot up hundreds or thousands-fold as a result of COVID-19 vax manufacturing.

thehappypm 5y ago

You're in luck, the New York Times wrote an amazing piece on this exact topic: https://www.nytimes.com/interactive/2021/health/pfizer-coronavirus-vaccine.html https://www.nytimes.com/interactive/2021/health/pfizer-coron...

KirillPanov 5y ago
The graphics are cute, but the article left me with way more questions than answers. It spent most of its time trying to impress the reader with how much interstate shipping was involved in the process (who cares?). No details on which ingredients are the ones causing so much consternation at the WTO right now, nor any answer to the obvious question "why aren't the DNA plasmids made the same way other commercial plasmid services make them"? But hey, it's the NYTimes. They have to hold the attention of an audience that mostly has no science background.