Virologist question, Why inject mRNA instead of the spike proteins?

[MeNeedsSomeHelp]

Why inject mRNA which will have our cells build the spike protein versus just directly inject the spike protein?

Just trying to get a deeper understanding.

[American GenX]

You should google it.  There's more info out there than you would ever want to know on the subject.  Not all COVID vaccines are mRNA.  There's more than one way to do it.  What your mentioned about injecting spike proteins sounds like how most vaccines work:

mRNA vaccines take advantage of the process that cells use to make proteins in order to trigger an immune response and build immunity to SARS-CoV-2, the virus that causes COVID-19. In contrast, most vaccines use weakened or inactivated versions or components of the disease-causing pathogen to stimulate the body’s immune response to create antibodies.

[Dollar Slice]

From what I understand - mRNA vaccines are easier and faster to make, which is why they were the first ones available. With traditional vaccines they have to use yeast (or similar organisms) to manufacture the spike protein which they use in the vaccine. So they have to bioengineer and breed special yeast that knows how to make spike protein, then manufacture it in mass quantities. With mRNA you just make lots of the mRNA in a lab and then it's the same as every other mRNA vaccine (which we have made before but not used on a large scale), so there is not much actual work that needs to be done to develop it.

The next time there's a novel virus we can just stick a new string of mRNA in the same exact vaccine package. It's incredibly efficient, which is great when you have a massive emergency that demands a vaccine ASAP. Almost all of the time waiting was testing to make sure it was safe in humans; phase one trials started in March.

The Novavax vaccine is the "inject you with the protein" type, it will probably work great, but it's coming a few months behind because the tech is just slower by nature.

[maizefolk]

As far as I know there is no reason a vaccine based on injecting the spike protein itself would work any better or worse than the mRNA approach. However, one potential issue is making enough.

Getting large amounts of a novel protein synthesized, properly folded, and purified (but not clumping into protein aggregates) is not a trivial matter and requires a lot of optimization and troubleshooting for each protein. 

Synthesizing large amounts of any mRNA molecule is basically the same process as synthesizing any other, which I suspect may be why it was possible to scale up mRNA based vaccines and get them through trials faster than the vaccine candidates based on conventional protein injections.

[MayDay]

I just learned a lot, thank you!

[Malum Prohibitum]

Takes too long to get a bunch of e choli spitting out spike proteins.  To make it simple and plain English.  In the rush for a vaccine, this gave mRNA based vaccinations a huge advantage, and Moderna was well set up to take advantage of it, since this is the whole reason Moderna exists.

[humanoid]

Why inject mRNA which will have our cells build the spike protein versus just directly inject the spike protein?

Just trying to get a deeper understanding.

I'm not a virologist, but I'm a PhD biochemist that lives within spitting distance of Moderna. Here is the short answer.

The reason you want to inject mRNA (assuming it's safe) instead of the spike protein is speed and accuracy.

Speed: because it's faster to manufacture an mRNA vaccine instead of the spike protein. Nucleotides are generally faster and cheaper to make than proteins.

Accuracy: the virus already uses our cells to make the spike protein (and other viral proteins), so the spike protein produced in our cells via the mRNA vaccine should be the most accurately folded and also contain any necessary post-translational modifications. Basically, the spike protein made in our bodies is higher quality than the one produced in a factory and then injected into us.

Bonus:
In the near future, I imagine that some mRNA vaccine manufacturers will also include several different mRNAs in the vaccine, so that our bodies produce an immune reaction to different spike protein variants (if needed). Also, mRNA vaccine manufacturers like Moderna and BioNTech will be able to respond more quickly to viral mutations.

[MeNeedsSomeHelp]

Appreciate all the replies.

So why are nucleotides generally faster and cheaper to make than proteins?



https://xkcd.com/2404/

[Abe]

Nucleotides can be put together in chemical reactions and ones of this size are straightforward to do at large scale and speed. This is because their information / function doesn’t have a significant three-dimensional component (its Linear - at least this particular type, won’t bore you with details). Proteins are generally three-dimensional in order to work (imagine folding a chain into a squishy ball in a certain order). That second step has to be done in a specific sequence of events, sometimes requires other proteins to do it right and is generally performed best by cells such as yeast or bacteria, or humans. It can’t be done accurately by machines yet.  Thus the mRNA vaccine saves manufacturing time because it cuts out the middle-man of yeast/bacteria and just has us assemble the protein in our own cells, which then stick the protein onto their outside to make the immune system see it.

[maizefolk]

Appreciate all the replies.

So why are nucleotides generally faster and cheaper to make than proteins?



https://xkcd.com/2404/

Proteins are the actual engineering equipment of life, so it isn't enough to get the right amino acids in the right order (primary structure), but also folded into the right shape (secondary/tertiary structure).

DNA and RNA is (mostly) used for information storage and retrieval. If you avoid a few simple pitfalls, mRNA shouldn't produce secondary structures, all that matters (mostly) is the order of the nucleotides within the molecule.

An analogy: which is easier to produce and deliver on short notice to a country on the far side of the world?

1) 1,000 bulldozers or 2) 1,000 copies of the blueprints for building a bulldozer (which they'll use to construct the bulldozers locally from locally sourced components).

[MeNeedsSomeHelp]

I was aware of the folds in proteins. My understanding is alpha fold 2 had a breakthrough in predicting the protein folds in simulation that more accurately matches actual folding.

Will alpha fold 2 and further developments accelerate how fast proteins can be developed?

For the mRNA, I would have thought CRISPR technology would have been needed. My understanding it CRISPR is error prone and slow.

Are all the mRNA truly identical like the blue print analogy and will all cells produce the proteins in the same way?

I really appreciated the comment about the increased accuracy by using mRNA, as the proteins would be produced by the cells in the same way as the virus.

Greatly appreciate your expertise.

[maizefolk]

Predicting how proteins will fold from their raw amino acid sequence is unfortunately a quite separate problem from actually getting them to fold properly in the real world. As Abe mentioned, often other proteins are needed to help the protein fold into the correct shape, and even things like the speed at which the ribosome translates an RNA molecule into a protein molecule can influence how the protein folds. We're a long LONG way from being able to synthesize significant amounts of properly folded proteins ourselves without using cells to do so. Some proteins can be made properly E. coli (comparatively easy to culture) or yeast (still okay). Others require chicken cells (eggs, more closely related to humans) or mammalian/human cell cultures.

CRISPR is a very separate thing from synthesizing DNA or RNA molecules. The reason people get excited about CRISPR is it lets us make targeted edits to the DNA inside of a living cell. But we've been able to synthesize DNA (and to a lesser extent RNA) outside of a cell for many decades, although it has gotten faster and cheaper to do so over time, and the size of the longest pieces of DNA/RNA we can make on our own has increased.

Another analogy: If you think of DNA/RNA synthesis as a printer for making blueprints or textbooks, CRISPR is the ability insert or remove a specific sentence or diagram from an already printed textbook.

[LennStar]

If you want to learn more about protein folding itself, in a game, you can go to http://fold.it/

Oh, I see on their website they made a video a week ago that also includes that AlphaFold2 thing (whatever it is, I didn't hear about it)

https://www.youtube.com/watch?v=Aq73E7-Lvhc&feature=emb_logo