mRNA vaccine development for COVID-19

by ChristianKl1 min read21st Mar 20208 comments

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Covid-19
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Epistemological status:

A bunch of sources and a reasoning while reading the source. Go to the sources for the factual claims and reason about claims and say if you think I made a mistake. Join the conversation in the comments.

Between CureVac and BioNTech, two of the three companies that have platforms for mRNA vaccine production are German. It might be faster to develop new vaccines with such mRNA technology then to develop old protein based vaccines. The technology is the hope that we will get a vaccine sooner then we would get a vaccine that's produced the traditional way.

BigPharma giant Johnson & Johnson that uses a more traditional approach to developing vaccines expects to hit clinical trials only in November.

Moderna, the third company with such technology, that’s from the US, started their human trials on 16th of March. BioNTech, announced a $135 million partnership with Shanghai-based Fosun Pharmaceutical Group to co-develop its COVID-19 vaccine candidate in China. They are going to start clinical trials in late April because they can leverage Fosun’s Chinese “clinical trial, regulatory and commercial capabilities”.

In their conference call CureVac said that after talking with regulators they will only do their clinical trials in early summer. This gives the impression that the German regulatory bodies prevent them to go as fast as the Moderna trials in Seattle or BioNTech trials in China.

The EU just gave CureVac 80 million Euro funding to scale up their production capacity to be able to produce 1 billion vaccine doses in one campaign. It’s great that they fund production capacity but it would be worthwhile if EU and German regulators would also reduce the red tape so that CureVac can start human trials in other jurisdictions.

This situation looks to me like it would be beneficial if we can push EU/German regulators to cut red tape for CureVac in addition to giving money or another jurisdiction would allow them to run their human trials earlier.

(While researching this post I also created a Google Sheet that lists more COVID-19 vaccine efforts)

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In our previous related thread of related conversation, you mentioned:

Inovio Pharm that also develops a COVID-19 vaccine. It's technology is based on delievering DNA based.

I noticed that I feel more worried about DNA-based vaccines than mRNA based vaccines. I probably should try to articulate some of why.

After doing some preliminary skimming and examining my pre-existing knowledge around this... I'm now kind of conflicted and confused?

(Exploring this turned into a giant sprawl. It would be multiple research projects for me to fully dissolve my confusion here. I'll leave the majority of my thoughts as a comment on this, but it may be so biology-dense that it mostly serves for my own reference.)


mRNA practically degrades itself. If an mRNA enters the cytoplasm, it might get diced by DICER but it otherwise is probably only good for a limited number of protein-producing ribosome-reads before it gets degraded or digested into unreadability.

DNA is a more robust molecule, befitting the archive-storage of the cell. In eukaryotes, almost all of it is permanently locked up in the nucleus, both for access and regulation reasons and as a protection against UV and other mutagens. DNA outside of the nucleus in a eukaryotic cell usually only comes up only in the context of viruses, cancer, GMOs, or ongoing problems or oddities with that cell.

(But apparently bits of it exist naturally, but have probably been understudied? That's something that I didn't fully realize until today. Pathology and pathogen-imitating GMOs are literally the only context where I have ever heard this come up before.)

How can this possibly happen non-pathologically in humans? What really confuses me is... getting DNA outside the nucleus in the first place as a non-freak occurrence requires at least one of:

  • Generation of loose DNA partial-transcripts while trying not to generate extra confusion during cell replication
    • If it's handled as ssDNA, that actually would leave it in a form pretty distinct from the usual dsDNA storage. And even as dsDNA, there are epigentic tags you could use to see that it's handled correctly.
    • This does have the benefit of being an "out" channel from the nucleus, not a security-vulnerability "in" channel.
    • I think I've reasoned myself to thinking this is the most likely explanation? I'll have to do more research to confirm/negate this guess.
  • DNA cut-outs that permanently leave the nucleus, never to return (resulting in its absence in the next replication cycle)
    • You could come up with a clever working version made from frequently-duplicated genes with extra copies (ex: transposons), but... I've never heard of this. And it's a little evolutionarily-fragile.
    • This does have the benefit of being an "out" channel from the nucleus, not a security-vulnerability "in" channel.
  • Reverse-Transcriptase (the most insidious of all viral proteins, that thing that crafts DNA from RNA)
    • Humans do have a special RT for extending telomeres, but it's rarely expressed, and if a random cell is expressing it that's a cancer waiting to happen.
    • There are retrotransposons that copy-paste themselves around the genome. But like... that's basically a nasty virus that got lazy and whose deck is short a few cards.
  • Cytoplasmic replication
    • I am under the impression that this is not happening

In eukaryotes, I get the impression that DNA is usually not getting replicated out there in the cytoplasm, at least? DNA viruses usually have to do at least one of two things:

  • Get themselves into the nucleus somehow (via small size and/or transport proteins)
  • Carry their own replication proteins around with them in the virion, to produce those initial RNA transcripts that produce enough replication proteins for them to get by.

If the treatment involves entering the nucleus of fully-intact undamaged cells, or replicating itself (so really, either of these methods), the alarm bells in my head would be blaring.

But if it's just circles of extracellular DNA... I'm now kind of conflicted and confused? How virus-like do you have to be to make that a viable thing to do?

Some other lingering points of confusion/research:

Plants use ambient restriction-enzymes to make being a random cytoplasmic DNA a hazardous game (on the assumption that ambient cytoplasmic DNA is usually viruses, and the non-viruses will have co-evolved with the particular restriction enzymes to make this system work). I don't actually know that animals do, though. And you could always species-tailor it...

I also have no idea how efficient or inefficient extracellular transcriptase would be for producing mRNA transcripts. If it's inefficient, you might have to use a pretty strong primer, and I find myself a tiny bit concerned about that in a long-lived human therapeutic.

mRNA production has fewer dependencies than protein production. To me, it feels reasonably intuitive that this might be a bit faster to assemble, especially at scale and in the face of QC. However, I have a lot of uncertainty around this.

About this next thing, I am more sure. What is more challenging about mRNA, and a good part of why it hadn't been a major method before, is delivery* into cells, and maybe targeting that delivery (if needed). If they've got a great lipid coating already configured for this, at that point it's easier to treat this like a modifiable platform and not just a single product. And that could help turnaround time a lot.

Being able to treat this as more of a modifiable-platform than a tailored product is where I suspect the big gains of this method lie.

*Delivery method being a major challenge is generally true of all large-molecule drugs and therapeutics (ex: protein-based), and probably even some of the small-molecule ones. Although I've seen more and more biotech companies specializing into this kind of thing, so humanity is probably getting better at it.

There's something almost comical or ironic about immune response probably foiling most attempts to develop something whose eventual goal is to trigger an immune response, but later. But that's probably a good part of the story of why this was so hard.


P.S. I was about to recommend you make a high-level post about this. I'm glad to see that you already did! I'm probably going to continue a bit of that conversation here, as this seems like a better place for it.

There are many application where targeting the delievery seems important. With vaccines the immune system should pick up the proteins regardles of which cell produces them. There still seems to be some complexity to it as far as the CureVac press briefing indicates. They argued that this is a time where they need to have the founder of the company lead it instead of a rather newish CEO because of the complexity.

Protein origin shouldn't matter, but mRNAs are not yet proteins. So for mRNA vaccines, they still need a lipid coating for delivery that evades the immune system but will still fuse with cell membranes.

(Normal cell-to-bubble-to-cell delivery involves mostly protein-based tagging and anchoring, and viruses often imitate parts of this process (this is much of what coronavirus spike-proteins are doing, for instance). But if you are using variants of tags that appear unfamiliar to the immune system, you can easily get an immune reaction against them. I'm not precisely sure how these companies have solved this problem, whether it's by using protein-tagging some entirely-lipid-based solution, or what.)

They might not need to be targeting particular cell-types very heavily, it's true. But they still need to be targeting for delivery to cells-in-general.

To me the successful CureVac phase I trial for Rabies suggests that they do have a solution for the general targeting.

Given that Moderna is already doing their human trials this month and Biontic next month it seems they also have the problem of delievery to cells-in-general solved.

What is the correlation between types of vaccines and needed testing time, if any?

mRNA vaccines are new technology. CEPI (Coalition for Epidemic Preparedness Innovations) was in the past investing money in the technology because of a hope of it being faster. Existing mRNA vaccines did pass phase 1 trials but there's no mRNA vaccine yet that's passed a phase 3 trial.

It's not clear how it affects that actual testing time. Actual testing time will depend a lot on how the actual effects in vivo will be.