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The protein they're trying to manufacture is indeed quite simple - AFAIU both BioNTech and Moderna put together their sequences in a weekend. (Though there was

The protein they're trying to manufacture is indeed quite simple - AFAIU both BioNTech and Moderna put together their sequences in a weekend. (Though there was a more involved process of winnowing down the sequences for the most effective ones.) The technically challenging parts are: - delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) - manufacturing: both producing the mRNA itself at a large scale, and inserting it into the delivery mechanism, at a large scale and in low-temperature conditions - testing: the newly-developed payload and the existing platform were integrated at small scales within weeks, but testing the thing for safety and efficacy took months EDIT: As schoen pointed out, this was not actually released by Moderna, but reverse engineered by third-party researchers. Original text was: "Hence they feel safe releasing this. Their moat is not the gene sequence, their moat is everything else."

schoen 6y ago
> Hence they feel safe releasing this. Their moat is not the gene sequence, their moat is everything else. One or more of the vaccine developers may have released such details, but this particular file is a reverse engineering effort by unaffiliated scientists based on analyzing the dregs of used vaccine vials (!). Edit: See https://news.ycombinator.com/item?id=26628594 https://news.ycombinator.com/item?id=26628594 for more substantive discussion about this.
- azernik 6y ago
  Ah - thanks for pointing this out! Edited to make sure readers see it.
wespiser_2018 6y ago
from what I've gathered, the rate limiting step for production as of yet, is creating the lipid vesicles and getting the RNA inside of them. Only a few companies have a process for this, and the supply chain for the precursors is limited as well.
- _joel 6y ago
  Could be wrong but AFAIU the Pfizer one doesn't encapsulate in a lipid, hence why it needs lower temperatures.
  - Exmoor 6y ago
    They're both encased in lipids. Pfizer didn't have long term data on long-term storage at standard freezer temperatures, but has since confirmed their vaccine can be stored at similar conditions to Moderna.
  - xjlin0 6y ago
    Pfizer one does contain 4 kinds of lipids to encase the RNA. The encapsulation percentage is however unknown. https://www.technologyreview.com/2020/12/09/1013538/what-are-the-ingredients-of-pfizers-covid-19-vaccine/ https://www.technologyreview.com/2020/12/09/1013538/what-are...
  - wespiser_2018 6y ago
    RNA would get thrashed by your immune system if it isn't encapsulated by something: liposome deliver of therapeutic RNA is really next-generation tech, and the fact that the RNA does what it's supposed inside the your cells is no small feat either. From the CDC "ingredients" for the BioNTech/Pfizer vaccine, along with cholesterol (which modulates the stability of lipid membranes), they report using this molecule, which would form a phospholipid bylayer, just like our own cells use: https://www.sigmaaldrich.com/catalog/product/avanti/850365P?lang=en&region=US https://www.sigmaaldrich.com/catalog/product/avanti/850365P?...
outworlder 6y ago
> delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) Of note, the immune system is pretty good at destroying foreign mRNA so you also need to evade it. This article is pretty good: https://berthub.eu/articles/posts/reverse-engineering-source-code-of-the-biontech-pfizer-vaccine/ https://berthub.eu/articles/posts/reverse-engineering-source...
- dnautics 6y ago
  I wouldn't even say the immune system, your body has a ton of nonspecific RNA-digesting enzymes floating around to patrol for exactly this sort of thing happening, even by accident, as cells can sometimes rupture. It's a problem enough that good RNA researchers have a reputation of being clean freaks. Some RNA labs I've been in had a lingering, slightly sweet smell, that's the nonspecific RNAase inhibitor that gets sprayed on everything.
  - azernik 6y ago
    RNA is also just generally fantastically unstable and reactive. You don't want any surface to be too alkaline, for example. There's a reason that basically every life form switched to DNA. (Though RNA may have been more stable under the high-UV-exposure conditions the early Earth.)
- azernik 6y ago
  Though AFAIU once you've gotten the RNA inside the cell, you're home free.
dnautics 6y ago
sequence is actually released by Moderna in their patent: https://www.modernatx.com/sites/default/files/US10702600.pdf https://www.modernatx.com/sites/default/files/US10702600.pdf though they do present multiple sequences, so I guess you'd have to go to the FDA application to figure out exactly which one got used.
- mikehollinger 6y ago
  Reading the primary claim is fascinating: "A composition, comprising: a messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a betacoronavirus (BetaCoV) S protein or S protein subunit formulated in a lipid nanoparticle." I have a "I'm sure that means something to somebody" feeling. It's also surprising that the remaining claims seem to describe the resulting bits of the sequence, and that that primary claim can stand on its own. Of course, I'm by no means an expert.
  - bdonlan 6y ago
    Claims are read in the context of the body of the patent and generally known and/or cited knowledge in the field in question. As long as you define precisely what you mean by your terms in the body, you can be as succinct as you want in the claims.
  - ethbr0 6y ago
    It's an interesting structure, but probably partly out of patent law. To wit, SARS-nCoV-2 is non-patentable, being of natural occurance. But a specific composition that encodes its spike protein, encapsulated in a lipid nanoparticle? That's much more of a creative work.
    - The_rationalist 6y ago
      If it's just the spike protein encapsulated in a lipid nanoparticule (for isolation and transportation?), that looks like something not creative and quite established for people in the field of genetic material transport.
dylan604 6y ago
> put together their sequences in a weekend meh, I could do that over a weekend never sounded so scary, or impressive at the same time. That weekend just so happened to stand on the shoulders of prior decades of research though. i guess this is big pharma's version of `apt-get install`
- o-__-o 6y ago
  Modern a has been working on mRNA since 2010 and mRNA vaccines since 2012. They have the process down pretty solid, but vaccines do not bring in the bacon.
  - azernik 6y ago
    Now that they've spent a year developing the mass-production methods and infrastructure, it might bring in the bacon! e.g. there's a steady annual market for a flu vaccine for whatever the latest strain is, and being able to get that to market faster than the competition could give them an edge. I just don't think it was every profitable enough for them to put in this enormous capital expenditure.
    - dylan604 6y ago
      When you can have Uncle Sam cover that capex, it makes it even more financially appealing.
  - hutzlibu 6y ago
    " but vaccines do not bring in the bacon." As in, "do not generate enough income"? Really? Now?
    - azernik 6y ago
      Now is a very atypical situation :-P
      - technick 6y ago
robinsord 6y ago
Okay. I’ll bite: Why do all vaccines have such heavy metal loads? Why are we OK with aluminum and other metals being loaded into these vaccines and shot into our bodies? I’m baffled as to why every tech breakdown of these vaccines sidesteps this fundamental question. Meanwhile we judiciously avoid heavy metals in our food for obvious reasons: like preventing Alzheimer’s.
The_rationalist 6y ago
- delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) Sounds like a problem you solve once and for all, for any vaccine. And also that this problem was already solved since decades (e.g viral vectors) - testing: the newly-developed payload and the existing platform were integrated at small scales within weeks, but testing the thing for safety and efficacy took months And so many people have been killed by this overly conservative testing, phase ~<2.5 was enough
- TeMPOraL 6y ago
  > Sounds like a problem you solve once and for all, for any vaccine. I strongly doubt it. It's more like a problem you solve once for a particular class of payload and particular destination. Biology doesn't do packet switching - everything is just rapidly bumping into everything else at random, so your envelope needs to be designed in a way that's ignored by everything else than molecules at your target site, and it needs to not react with the payload it's carrying. > And so many people have been killed by this overly conservative testing, phase ~<2.5 was enough Overly conservative? That's what super-accelerated testing looks like. We're lucky it went well; had they screwed up, it would scare a lot more people away from vaccinating, lengthening the pandemic and increasing death toll.
- baq 6y ago
  a bad vaccine could kill much more than that. remember that RNA vaccines are developed for 10+ years now and COVID19 is the first time they actually worked without side effects.
MuffinFlavored 6y ago
> but testing the thing for safety and efficacy took months What kind of tweaks were made from "the version they threw together in a weekend" to "the version that is in production now"? What's a typical "mRNA" feedback iteration loop like?
- shellfishgene 6y ago
  I'm not sure if there were changes in the sequence at all necessary during testing, however if you align the sequences given in that link from Biontech and Moderna, you see they encode the exact same protein (which is of course necessary). However the RNA sequence contains quite a few differences between the companies, they often use a different codons. This could be to make the translation more efficient, and can be a thing to optimize.
- deleted 6y ago
  [deleted]
amelius 6y ago
Would it be possible to use the same delivery mechanism for other mRNA sequences?
- azernik 6y ago
  Almost certainly - e.g. the J&J vaccine (a DNA vaccine, not mRNA, but same principle) is using a viral delivery platform that they'd had sitting on the shelf for years and have used for other vaccines. After the massive capex that has gone into mass-production of encapsulated mRNA delivery systems, I suspect this new technology will be very cost-competitive for the big markets like the annual flu vaccine.
Yizahi 6y ago
Additional reading (was posted here some time ago): https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my... Why manufacturing of these vaccines is a hard part.
mschuster91 6y ago
> - delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) The most amazing thing is that now that the platform is proven secure in dozens of millions of people, it should be be very easy and fast to get approval for other payloads. Biontech for example wants to go after cancers - a platform that can deliver payloads targeted to an individual's cancer is nothing short of a game changer in cancer treatment because the current standard of blasting the patient's body with a lot of highly toxic chemicals is arcane compared to letting the body's immune system do the cleanup.
- azernik 6y ago
  Even if the platform is safe, the payload itself needs to have its safety proven. Remember, the payload is just instructions, and those instructions make your cells pump out oodles of arbitrary proteins. That in itself can cause health problems. see e.g. the AstraZeneca vaccine's safety issues, which were caused IIUC by immune responses to the manufactured proteins. DNA vaccine, not mRNA, but the principle is the same. re: cancers, that is actually what this technology was originally developed for! Moderna has been spending about a decade getting this tested and proven out for the cancer role, and they're quite close. From my quick reading of the literature, there seems to be some regulatory confusion about how exactly to run approval for this kind of personalized drug design (testing the method of generating the individual drugs?), but the bar is usually much lower for cancers with high mortality rates.

schoen 6y ago

> Hence they feel safe releasing this. Their moat is not the gene sequence, their moat is everything else. One or more of the vaccine developers may have released such details, but this particular file is a reverse engineering effort by unaffiliated scientists based on analyzing the dregs of used vaccine vials (!). Edit: See https://news.ycombinator.com/item?id=26628594 https://news.ycombinator.com/item?id=26628594 for more substantive discussion about this.

azernik 6y ago
Ah - thanks for pointing this out! Edited to make sure readers see it.

wespiser_2018 6y ago

from what I've gathered, the rate limiting step for production as of yet, is creating the lipid vesicles and getting the RNA inside of them. Only a few companies have a process for this, and the supply chain for the precursors is limited as well.

_joel 6y ago
Could be wrong but AFAIU the Pfizer one doesn't encapsulate in a lipid, hence why it needs lower temperatures.
- Exmoor 6y ago
  They're both encased in lipids. Pfizer didn't have long term data on long-term storage at standard freezer temperatures, but has since confirmed their vaccine can be stored at similar conditions to Moderna.
- xjlin0 6y ago
  Pfizer one does contain 4 kinds of lipids to encase the RNA. The encapsulation percentage is however unknown. https://www.technologyreview.com/2020/12/09/1013538/what-are-the-ingredients-of-pfizers-covid-19-vaccine/ https://www.technologyreview.com/2020/12/09/1013538/what-are...
- wespiser_2018 6y ago
  RNA would get thrashed by your immune system if it isn't encapsulated by something: liposome deliver of therapeutic RNA is really next-generation tech, and the fact that the RNA does what it's supposed inside the your cells is no small feat either. From the CDC "ingredients" for the BioNTech/Pfizer vaccine, along with cholesterol (which modulates the stability of lipid membranes), they report using this molecule, which would form a phospholipid bylayer, just like our own cells use: https://www.sigmaaldrich.com/catalog/product/avanti/850365P?lang=en&region=US https://www.sigmaaldrich.com/catalog/product/avanti/850365P?...

outworlder 6y ago

> delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) Of note, the immune system is pretty good at destroying foreign mRNA so you also need to evade it. This article is pretty good: https://berthub.eu/articles/posts/reverse-engineering-source-code-of-the-biontech-pfizer-vaccine/ https://berthub.eu/articles/posts/reverse-engineering-source...

dnautics 6y ago
I wouldn't even say the immune system, your body has a ton of nonspecific RNA-digesting enzymes floating around to patrol for exactly this sort of thing happening, even by accident, as cells can sometimes rupture. It's a problem enough that good RNA researchers have a reputation of being clean freaks. Some RNA labs I've been in had a lingering, slightly sweet smell, that's the nonspecific RNAase inhibitor that gets sprayed on everything.
- azernik 6y ago
  RNA is also just generally fantastically unstable and reactive. You don't want any surface to be too alkaline, for example. There's a reason that basically every life form switched to DNA. (Though RNA may have been more stable under the high-UV-exposure conditions the early Earth.)
azernik 6y ago
Though AFAIU once you've gotten the RNA inside the cell, you're home free.

dnautics 6y ago

sequence is actually released by Moderna in their patent: https://www.modernatx.com/sites/default/files/US10702600.pdf https://www.modernatx.com/sites/default/files/US10702600.pdf though they do present multiple sequences, so I guess you'd have to go to the FDA application to figure out exactly which one got used.

mikehollinger 6y ago
Reading the primary claim is fascinating: "A composition, comprising: a messenger ribonucleic acid (mRNA) comprising an open reading frame encoding a betacoronavirus (BetaCoV) S protein or S protein subunit formulated in a lipid nanoparticle." I have a "I'm sure that means something to somebody" feeling. It's also surprising that the remaining claims seem to describe the resulting bits of the sequence, and that that primary claim can stand on its own. Of course, I'm by no means an expert.
- bdonlan 6y ago
  Claims are read in the context of the body of the patent and generally known and/or cited knowledge in the field in question. As long as you define precisely what you mean by your terms in the body, you can be as succinct as you want in the claims.
- ethbr0 6y ago
  It's an interesting structure, but probably partly out of patent law. To wit, SARS-nCoV-2 is non-patentable, being of natural occurance. But a specific composition that encodes its spike protein, encapsulated in a lipid nanoparticle? That's much more of a creative work.
  - The_rationalist 6y ago
    If it's just the spike protein encapsulated in a lipid nanoparticule (for isolation and transportation?), that looks like something not creative and quite established for people in the field of genetic material transport.

dylan604 6y ago

> put together their sequences in a weekend meh, I could do that over a weekend never sounded so scary, or impressive at the same time. That weekend just so happened to stand on the shoulders of prior decades of research though. i guess this is big pharma's version of `apt-get install`

o-__-o 6y ago
Modern a has been working on mRNA since 2010 and mRNA vaccines since 2012. They have the process down pretty solid, but vaccines do not bring in the bacon.
- azernik 6y ago
  Now that they've spent a year developing the mass-production methods and infrastructure, it might bring in the bacon! e.g. there's a steady annual market for a flu vaccine for whatever the latest strain is, and being able to get that to market faster than the competition could give them an edge. I just don't think it was every profitable enough for them to put in this enormous capital expenditure.
  - dylan604 6y ago
    When you can have Uncle Sam cover that capex, it makes it even more financially appealing.
- hutzlibu 6y ago
  " but vaccines do not bring in the bacon." As in, "do not generate enough income"? Really? Now?
  - azernik 6y ago
    Now is a very atypical situation :-P
    - technick 6y ago

robinsord 6y ago

Okay. I’ll bite: Why do all vaccines have such heavy metal loads? Why are we OK with aluminum and other metals being loaded into these vaccines and shot into our bodies? I’m baffled as to why every tech breakdown of these vaccines sidesteps this fundamental question. Meanwhile we judiciously avoid heavy metals in our food for obvious reasons: like preventing Alzheimer’s.

The_rationalist 6y ago

- delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) Sounds like a problem you solve once and for all, for any vaccine. And also that this problem was already solved since decades (e.g viral vectors) - testing: the newly-developed payload and the existing platform were integrated at small scales within weeks, but testing the thing for safety and efficacy took months And so many people have been killed by this overly conservative testing, phase ~<2.5 was enough

TeMPOraL 6y ago
> Sounds like a problem you solve once and for all, for any vaccine. I strongly doubt it. It's more like a problem you solve once for a particular class of payload and particular destination. Biology doesn't do packet switching - everything is just rapidly bumping into everything else at random, so your envelope needs to be designed in a way that's ignored by everything else than molecules at your target site, and it needs to not react with the payload it's carrying. > And so many people have been killed by this overly conservative testing, phase ~<2.5 was enough Overly conservative? That's what super-accelerated testing looks like. We're lucky it went well; had they screwed up, it would scare a lot more people away from vaccinating, lengthening the pandemic and increasing death toll.
baq 6y ago
a bad vaccine could kill much more than that. remember that RNA vaccines are developed for 10+ years now and COVID19 is the first time they actually worked without side effects.

MuffinFlavored 6y ago

> but testing the thing for safety and efficacy took months What kind of tweaks were made from "the version they threw together in a weekend" to "the version that is in production now"? What's a typical "mRNA" feedback iteration loop like?

shellfishgene 6y ago
I'm not sure if there were changes in the sequence at all necessary during testing, however if you align the sequences given in that link from Biontech and Moderna, you see they encode the exact same protein (which is of course necessary). However the RNA sequence contains quite a few differences between the companies, they often use a different codons. This could be to make the translation more efficient, and can be a thing to optimize.
deleted 6y ago
[deleted]

amelius 6y ago

Would it be possible to use the same delivery mechanism for other mRNA sequences?

azernik 6y ago
Almost certainly - e.g. the J&J vaccine (a DNA vaccine, not mRNA, but same principle) is using a viral delivery platform that they'd had sitting on the shelf for years and have used for other vaccines. After the massive capex that has gone into mass-production of encapsulated mRNA delivery systems, I suspect this new technology will be very cost-competitive for the big markets like the annual flu vaccine.

Yizahi 6y ago

Additional reading (was posted here some time ago): https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my... Why manufacturing of these vaccines is a hard part.

mschuster91 6y ago

> - delivery mechanism: you need to take a very unstable molecule, protect it from the environment - both external, and when inside the patient - and insert it into a human cell. (This is called the "platform", and is usually developed independently from the specific payload.) The most amazing thing is that now that the platform is proven secure in dozens of millions of people, it should be be very easy and fast to get approval for other payloads. Biontech for example wants to go after cancers - a platform that can deliver payloads targeted to an individual's cancer is nothing short of a game changer in cancer treatment because the current standard of blasting the patient's body with a lot of highly toxic chemicals is arcane compared to letting the body's immune system do the cleanup.

azernik 6y ago
Even if the platform is safe, the payload itself needs to have its safety proven. Remember, the payload is just instructions, and those instructions make your cells pump out oodles of arbitrary proteins. That in itself can cause health problems. see e.g. the AstraZeneca vaccine's safety issues, which were caused IIUC by immune responses to the manufactured proteins. DNA vaccine, not mRNA, but the principle is the same. re: cancers, that is actually what this technology was originally developed for! Moderna has been spending about a decade getting this tested and proven out for the cancer role, and they're quite close. From my quick reading of the literature, there seems to be some regulatory confusion about how exactly to run approval for this kind of personalized drug design (testing the method of generating the individual drugs?), but the bar is usually much lower for cancers with high mortality rates.