> This is somewhat of a problem for our vaccine - it needs to sneak past our immune system. Over many years of experimentation, it was found that if the U in RNA is replaced by a slightly modified molecule, our immune system loses interest. For real.
> So in the BioNTech/Pfizer vaccine, every U has been replaced by 1-methyl-3’-pseudouridylyl, denoted by Ψ. The really clever bit is that although this replacement Ψ placates (calms) our immune system, it is accepted as a normal U by relevant parts of the cell.
In case others don't know this, the reason this is abbreviated Ψ (psi) is that Ψ is the first letter of Greek ψευδής 'false, lying', the origin of the prefix pseudo-.
It's part of an instruction to cells to make something. Viruses replicate by instructing cells to make viruses. Our cells don't know how to make Ψ, so the replicated virus would have the normal instruction.
No. For a number of reasons. First of all, the virus uses the nucleotides (A, G, C and U, for wich Ψ is used as a substitute) produced by the attached cell to create a copy of it's genome (RNA). The nucleotides are produced by the cell, the virus does not instruct the cell to produce them. It just tells the cell to produce and assemble the proteins AND the RNA.
Second, our immune system doesn't just attack and recognize free floating RNA, but the virus itself. And different parts of the virus. First and foremost it will recognize the surface proteins (like the spike protein) because those are the things that it can see while the virus is outside of the cell. Also these are the things that the infected cells present on their surface (MHC II sites, if I'm not mistaken) to the immune system. (As far as I can understand, cells have to present the proteins they produce to the immune system otherwise they get killed. If they produce alien virus proteins that get recognized by the immune system, they also get killed.)
Interesting enough, the immune system somehow also recognizes the so called nucleocapsid protein, which is the one used to wrap the viral RNA inside the virus. (But it gets produced by the cells, so I guess they get presented on the cell surface so the immune system can learn to recognize and counter them.) I didn't look into the details too much, but as far as I can understand it's not clear yet how those antibodies (the ones created against this protein) work, because antibodies are supposed to be used outside of the cells, but the nucleocapsids are only present inside the cells and then inside the virus.
To sum it up: the immune system is much more complex, has several recognition mechanisms, the viral RNA is mostly packed into the viruses (or are inside the cells) and the viruses don't have any way to produce Ψ (or any of the other nucleotides).
> I didn't look into the details too much, but as far as I can understand it's not clear yet how those antibodies (the ones created against this protein) work, because antibodies are supposed to be used outside of the cells, but the nucleocapsids are only present inside the cells and then inside the virus.
You are correct, the antibodies are made and they end up not recognizing the nucleocapsid protein while it is in the virus but when the infected cell displays internal proteins with MHC I, which helps T-Cells target the infected cell. MHC I displays self and MHC II displays proteins that have been "eaten" by the surveillance cells of the immune system.
Maybe I'm thinking too simplified here, but wouldn't this only work on the first iteration? After all the virus would replicate with Us in your cells and then the replicas wouldn't have the advantage anymore.
But that's what I mean, viruses need to replicate. They do this by injecting their RNA into your cells and hijacking your ribosomes for their replication. So the first viruses would definitely get past your immune system, but the replicated viruses would then be produced by your cells, so they wouldn't have the U->psi replacement that the first generation had. So every subsequent generation of the virus could be fought by your immune system. Effectively giving the virus a head start of one replication cycle. I'm guessing this wouldn't change much. But I'm not a biologist.
1) As someone else pointed out, this molecule substitution would not persist during replication. New viruses being produced in your cells would be made with a normal "U".
2) Your immune system does not usually attack the RNA housed inside a virus, but rather protein fixtures on its "body".
"Many people have asked, could viruses also use the Ψ technique to beat our immune systems? In short, this is extremely unlikely. Life simply does not have the machinery to build 1-methyl-3’-pseudouridylyl nucleotides. Viruses rely on the machinery of life to reproduce themselves, and this facility is simply not there. The mRNA vaccines quickly degrade in the human body, and there is no possibility of the Ψ-modified RNA replicating with the Ψ still in there. “No, Really, mRNA Vaccines Are Not Going To Affect Your DNA[2]“ is also a good read."
As far as I could tell, this would work well for getting a synthetic virus into the human body, but without the necessary mechanics within our cell, the special Ψ chemical won't be reproduced by the virus. That'd mean the replicated virus would get snatched up by the immune system as soon as it'd get released from the cell.
Theoretically, a complex enough RNA string could be used to have our cells build the necessary cellular machinery to properly reproduce the virus, but that's a kind of altering DNA that's a whole different can of worms. There's probably cheaper and easier way of defeating the immune system, for example by simply "enhancing" ebola or HIV to make them more infectious and more resistant to our current drugs.
RNA is genetic material, but it encodes instructions to make proteins, which form the physical shell of the virus crucial to its function. As a very rough analogy, the RNA is source code and the proteins are the compiled program.
It's often the protein molecules that the immune system learns to recognise and attack.
RNA vaccines work because your body automatically translates them into some recognisable part of the viral protein, and then develops an immune reaction to that.
If a virus had Ψ instead of U in its RNA, it's still going to be making the same type of proteins. I can't see why it would be more likely to evade an immune response.
We are really quite fortunate that there was a ton of work done on coronaviruses, mRNA vaccines, adenovirus vaccines, etc prior to the pandemic. It seems like a pandemic even a year or three prior would have made the vaccine rollout considerably slower.
No they have allergies to the polyethylene glycol PEG compound in the lipid nanoparticles. It is also used in skin creams, toothpastes, condom lubricants and in larger quantities as a laxative. Some people are just allergic to it.
