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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 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."




sequence is actually released by Moderna in their patent:

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.


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.


> I have a "I'm sure that means something to somebody" feeling.

Break it down! It's not so bad:

> A composition

A bunch of stuff

> a messenger ribonucleic acid (mRNA)

mRNA are cellular instructions on how to make proteins that are read by ribosomes that make those proteins as they read along.

> an open reading frame

This is something that starts with a "start codon" and ends with an "ending codon" and encodes valid instructions to make a protein between.

> encoding a betacoronavirus (BetaCoV) S protein or S protein subunit

The instructions refer to the spike protein of a betacoronavirus, or a fragment thereof, because this is what we want the immune system to pay attention to (and make antibodies to bind to and neutralize).

> in a lipid nanoparticle

The immune system gets pissed off about mRNA floating around, because that's one of the things that happens with active infection. So if you want this to get into cells and tell them to make your protein, you need to encase it so that it mostly escapes immune notice itself.


Why haven’t viruses or bacteria evolved to use a lipid nano particle to evade the immune system? Seems like a big security flaw in our cells?


I remember someone coming up with a song to encourage people to wash their hands more thoroughly much earlier in this pandemic.

https://twitter.com/vesselofspirit/status/123748864242514739...

According to the song lyric, "novel coronavirus / has a lipid outer shell". So it seems like some viruses have taken advantage of this.


Yeah I think that's the reason for the 20-30 second wash since it takes time for the soap to break down the fatty layer.


That stupid ebola song came to mind. It's very catchy. https://www.youtube.com/watch?v=XGltVAJ4JCk



And it's pretty common; the flu viruses have one.


If you squint you could say that viruses are already doing that. A lipid bilayer is a key component of several kinds of membranes. All of our cells have a lipid bilayers separating the inside from the outside. The corona virus is also built from these same lipids, which is why it's vulnerable to soap.

Anyway, I think the important thing that the other commenter was saying is that mRNA needs to be carefully packaged to be medically useful. You can't inject pure RNA as a vaccine because not only is the mRNA going to be quickly degraded before it gets anywhere but if the immune system sees any RNA floating around by then it kicks itself into a frenzy because free-floating RNA is usually a sign that something nasty is afoot.


Don't give them any good ideas


They have. That spike protein is part of their envelope ("nanoparticle").

The envelopes used in an RNA vaccine are generally simpler, because they're working under different constraints than viruses. For example, their envelopes don't need to be easily manufactured in a cell.

But some RNA and DNA vaccines do use viruses as their delivery mechanisms, eg the J&J COVID vaccine.


Because some have. Phages for example.


Maybe those lipid particles are too unstable if they are not spiked with various proteins?

Moderna vaccine has to be kept in -70 C. Viruses that can survive for any extended period of time only in -70 C won't find many hosts.

Also maybe the process of creating virus shell can't naturally be done without protein scaffold.


Doesn't this describe almost ANY vaccine - I think that it's probably bad public policy to allow anyone to patent ALL COVID vaccines - I think that patenting a particular vaccine (a particular mRNA string) should be allowed, but not effective wildcards in the RNA


No. It doesn't describe the viral vector vaccines (J&J/AstraZeneca). It doesn't describe the inactivated virus vaccines. It doesn't include the viral fragment (NovaVax) vaccines. And it wouldn't describe some possible mRNA vaccines because of differences in formulation or differences in targeting.

While this particular Moderna claim would likely affect BioNTech/Pfizer's mRNA vaccine, it's not clear whether it would survive in litigation, too.

As to a "specific string"-- if you could just pad a few codons onto the end and not be violating the patent, that's not too worthwhile.


Technically you wouldn't even have to do that. Just change a few codons to alternative codons, it wouldn't even change the amino acids being produced.


This is a great animation of the life cycle of an HIV virus. It’s not exactly what happens with the pandemic virus but it gives you a good idea of the complexity of the process of viral reproduction (vaccine or immune response isn’t covered here):

https://vimeo.com/260291607

Animation of transcription from mRNA: https://youtu.be/TfYf_rPWUdY


The "SARS-CoV-2 entry" video was really interesting too, and I recommend watching them both to see how they are different.

https://vimeo.com/510310488


Nice!!! I didn’t even notice that was uploaded! The differences between HIV and SARS-CoV-2 makes me wonder what reliability there is in this process, and if some viruses are more reliably able to enter the cell than others (presumably those that are more infectious?)


It blows my mind to see how life (and death) work at the molecular level--it's almost like some kind of manmade machine, but far more subtle and complex.


These might interest you then: 3d visualizations of cellular processes in real time. I was shown them in my intro to biology class, which filled me with the same interest.

Transcriptase: https://youtu.be/5MfSYnItYvg DNA polymerase: https://www.youtube.com/watch?v=bee6PWUgPo8 The Ribosome: https://youtu.be/TfYf_rPWUdY


It's been decades since I was in high school but I really hope these videos, or something similarly realistic and mind-bending, is in the modern biology curriculum. Learning about Darwin, Mendel, Watson and Crick and the experiments they did to develop an understanding of biology was informative, but it wasn't compelling to me. These and the work of Drew Berry and WEHI are just amazing:

https://www.youtube.com/user/WEHImovies/videos


I like the wehi videos because they take effort to make the molecular motions appear to be random, a result of stuff blundering about: https://youtu.be/7Hk9jct2ozY


Just remember that it's not really orchestrated. All of the molecules involve are kind of randomly blundering about and it's one-in-a-million collisions that are responsible for getting shit done (on membranes it's more like one in a thousand and on ropelike structures like dna or actin it's one in a hundred).


As a biochemist, that's one of the things that has kept me interested in the work - it's truly mind boggling what is going on at the molecular level every second of our lives.


I love reading articles around biology, micro/molecular biology in particular, and looking for references to agency in the text. 'selects', 'filters', 'checks', 'seeks', etc when the reality is that the whole thing is just a massive chemical reaction.


Yes.One must know all programming of molecules and all laws current in the universe. perfect hierarchy from atoms to the cells, from cells to plants, animals from animals to earth, from earth to stars


Coronavirus replication is pretty dramatically different from HIV replication-- coronaviruses are not retroviruses, and do not have a step where viral RNA is converted into DNA and integrated into the host cell's genome. Instead, coronavirus RNA is directly interpreted by the cell's ribosomes to make the proteins that ultimately build and comprise the replicated viruses.

The mRNA vaccines work in much the same way-- it's just that the mRNA vaccines only include the code for the spike protein and not the rest of the virus's machinery. So you get the vaccine and your body produces a bunch of spike protein by itself, which gives your immune system the opportunity to learn how to identify and react to the spike protein before it sees it on a real virus.


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.


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.


> That's much more of a creative work.

Probably worth noting that patents are not required to be creative. That's copyright terminology.

I think the terminology used for patents is something like "inventive and useful".


> It's an interesting structure...

I think that's the question. I'm very much used to reading "A machine-readable medium, comprising..." I'm curious what bits are unique to COVID-19, and what bits are generally protecting the idea of using a carrier to send a specific protein. In this case, is it the "S" protein phrasing that protects the specific embodiment of COVID19's spike?


Here what is claimed is encoding for any betacoronavirus's spike protein.


> Here what is claimed is encoding for any betacoronavirus's spike protein.

Aha! That's what is surprising to me - I assumed that that would have been done previously / protected previously. That explains it.


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.


My layperson's understanding is that the actual spike protein and/or mRNA are modified from the natural versions. Both for stabilization (if either falls apart quickly, they're of no use) and for response optimization.

So somewhat like how a fishing fly differs from the insect it represents.


Usually you can't patent facts. If it is natural (not synthetic) gene sequence they shouldn't be able to patent it...


> 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`


Not only did Moderna have a decade of experience with mRNA as 'drug', but the mechanism of coronavirus infection was well-understood from SARS research, namely the importance of the spike protein. All the parts were in place and just waiting for the specific SARS-CoV-2 sequence. They designed it as soon as they had access to the Wuhan sequence.


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.


The big money’s going to be in cancer treatments. If they can use this to target tumors, they’ll do quite well.


Bad news, it’s not looking very successful right now. Moderna is making back all the lost revenue with the emergency authorization tho


Can you share some of the bad news links? I've only seen the positive ones.


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.


When you can have Uncle Sam cover that capex, it makes it even more financially appealing.


And Biontech since 2008 and CureVac was founded in 2000 (after their initial CEO made a discovery that enabled Biontech + Moderna).

https://en.wikipedia.org/wiki/Ingmar_Hoerr


" but vaccines do not bring in the bacon."

As in, "do not generate enough income"? Really? Now?


Yes, really. Typical vaccines are like $5 to $200 or so. And worst of all, usually just one or two doses.

For all the horror HIV has wrought, global spending on vaccine development for HIV has been around $1 billion a year for the last few years. In contrast, the USA federal government spends $3 billion a year for HIV antiviral drugs for low-income Americans. $20,000 per patient per year for life. Unsurprisingly, new antivirals are where most of the research is.

It can sound almost like a conspiracy if I put it like that, but it's just the economics incentives. Especially since the developed countries where most of the market for charging a decent markup is, have the smallest market for most new vaccines, while having the largest markets for therapeutics for chronic conditions.

Now HIV is genuinely devillish to develop a vaccine for despite our attempts. But vaccines for hepatitis C, gonorrhea, HSV, among others appear to be possible. We almost certainly could develop effective vaccines for these with existing techniques, if someone coughed up the funding. Maybe all the buzz about mRNA vaccines will spur some progress here.


> It can sound almost like a conspiracy if I put it like that, but it's just the economics incentives

Talk about market failures! It's completely obvious that this economical system is not placing the good of the whole human species as its first priority.


"es, really. Typical vaccines are like $5 to $200 or so"

But since the demand is 14 000 000 000 doses, there should still be a little bit of money in it?


Yes, clearly. With COVID-19, there is pretty much guaranteed market for about ten billion doses. Along with direct investment by governments in wealthier countries. Most people, including politicians, want a COVID-19 vaccine real bad.

The parent poster was describing the situation with vaccine development in general, to which COVID-19 is quite the exception. A potential hepatitis C vaccine for example has very different economics, as it would not be deployed anywhere nearly as widely or quickly. Consider that, 40 years after hepatitis B immunization became available, the majority of Americans haven't been jabbed with it.


Yes, but a pandemic only comes around every hundred years or so. Moderna happened to be in the right place at the right time for this one, but delivering vaccines for a pandemic is not much of a solid business plan.


Current pricing for mRNA vaccines is something in the $4-7 dollars (that's $7.00 dollars, not $7,000.00 dollars) range. Compare that to one of the Hepatitis C treatments, which costs north of $350,000 by several accounts. Even remdesivir is something like $3000 for a course.


There are roughly 75 million HCV infections in the world.

That translates to a total cure cost of:

75M * $350k = $26.25T

There are other ARV treatments available which cost now roughly $50-100k and cure in 3 months.

Whereas immunizing everyone against coronaviruses currently costs:

8B * $7 = $56B

Clearly, the costs of the HCV cure are predatory and unreasonable because it doesn't lead to eradication and it's inaccessible to the poor and the third-world.


It's also worth noting that if it's $7 for the payer, there's a lot less than $7 of profit.


The true unit cost is probably $6 per dose. The COVID vaccines may break-even short-term. Long-term, it's probably worth keeping an extra 120M potential customers alive for what will probably result in a small profit.

The true unit cost of HCV cures is unknowable but possibly half of the current price.


"Hepatitis C treatments"

We don't really need the same quantities of that, though.


https://www.hhs.gov/hepatitis/learn-about-viral-hepatitis/da...

It can be said that hepatitis care is more necessary than covid.


The world is not in lockdown becuse of hepatitis, though.


Hepatitis isn't airborne, though, so it doesn't have an exponent threatening to blow up in everyone's face.


Now is a very atypical situation :-P


You've never been to Florida have you?


Does Florida typically throw billions of dollars at vaccine development?


Vaccines can be very lucrative. Pfizer has billions in sales for Pentacel.


There was already good work previously on SARS-1 and MERS spike protiens for use in vaccines. This is what enabled the "in a weekend" speed. https://pubmed.ncbi.nlm.nih.gov/28807998/


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.


Could be wrong but AFAIU the Pfizer one doesn't encapsulate in a lipid, hence why it needs lower temperatures.


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?...


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...


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.


> 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...


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.


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.)


Though AFAIU once you've gotten the RNA inside the cell, you're home free.


> - 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.


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.


> 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 for more substantive discussion about this.


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


> 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?


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.


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


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.


- 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


> 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.


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.


Additional reading (was posted here some time ago):

https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my...

Why manufacturing of these vaccines is a hard part.




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