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.
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.
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.
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.
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.
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.
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.
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.
Animation of transcription from mRNA: https://youtu.be/TfYf_rPWUdY
Transcriptase: https://youtu.be/5MfSYnItYvg DNA polymerase: https://www.youtube.com/watch?v=bee6PWUgPo8 The Ribosome: https://youtu.be/TfYf_rPWUdY
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.
But a specific composition that encodes its spike protein, encapsulated in a lipid nanoparticle? 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".
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?
Aha! That's what is surprising to me - I assumed that that would have been done previously / protected previously. That explains it.
So somewhat like how a fishing fly differs from the insect it represents.
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`
I just don't think it was every profitable enough for them to put in this enormous capital expenditure.
As in, "do not generate enough income"? Really? Now?
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.
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.
But since the demand is 14 000 000 000 doses, there should still be a little bit of money in it?
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.
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.
The true unit cost of HCV cures is unknowable but possibly half of the current price.
We don't really need the same quantities of that, though.
It can be said that hepatitis care is more necessary than covid.
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?...
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...
(Though RNA may have been more stable under the high-UV-exposure conditions the early Earth.)
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.
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.
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.
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?
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.
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
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.
https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my...
Why manufacturing of these vaccines is a hard part.
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."