@P_X
This thread in the darklands ...
Specifically, the question from VulchR (I wish they would join us here), the AG response, etc., your $0.02 ?
The answers (without doing a deep dive):
1. mRNA is pushed intramuscularly. Muscle cells are literally the largest cells so a significant portion of the shot probably gets in muscle cells, and some into the interstitium (space between muscle cells). It probably doesn't even hit your circulation.
2. The vehicle (liposome) will allow the mRNA to pass into the cells [muscle here], which is a great kind of tissue full of ribosomes, that are like sewing machines using mRNA going in and synthesizing the spike protein.
Things get a little less clear to me, because the rest of the virus' machinery complement the spike protein, whereas this isn't the case here but then the spike protein could produce an immunogenic signal in multiple ways
3a. Cells have major histocompatibility complex (MHC-1) molecules that they use as virtual flag poles to display flags indicating what's getting expressed int he cell itself. Spike protein could be recognized through MHC-1 and trigger cellular immune response.
3b. Spike protein is directly immunogenic and is a transmembrane protein on its own, so it could stick out the cell membrane directly and trigger an immune response
3c. Extracellular leakage or transport of the spike protein can be picked up by professional antigen presenting cells (APCs), integrating it into their MHC-2 (imagine like police sharing "Wanted" posters") and triggering cellular and humoral immune response.
The acute side-effects could therefore be due to the mRNA or due to an exacerbated immune response, which would primarily target the muscle. It doesn't seem to be the case, I suspect it's due to the short half life of mRNA (which is like a USB stick in genetic informatics), so by the time cytotoxic immune response would be triggered (cell killing), the mRNA is gone.
Same thing applies to the blood brain barrier. It's a super barrier that's hard to cross, even for mRNA, which would have to make it to the systemic circulation from the interstitial space in an interval that is shorter than the mRNA half life. Even less likely.
How is this better than the adenovirus? The concern is that if you already have some level of immune response to the adenovirus vector (which is expected to be rare, but feasible), you'll clear the vector without mounting an immune response against its payload.
Why is it safe to use the mRNA vaccines?
A) Because they have fantastic signal-to-noise ratio. This is also the reason how these were developed so insanely quickly (Fauci's institute identified the target epitope in like 10 days after they got the sequence of SARS-CoV-2!!!). Why don't design an artificial virus to do the same? See the attenuated adenovirus' problem: if people mount a response against the vaccine vector, then your vaccine is worthless.
B) Because they went through rigorous phase III testing. Safety was established in phase I, effective dosing in phase II and large scale efficacy in phase III, and at all levels safety data was very closely monitored.
TL;DR: money's on the short half life of the mRNA. Long enough to trigger an immune response, too short to produce major local or distal inflammation. The vaccine was adequately tested too and it would have to be the worst vaccine I've ever heard of to be on par with the complications of COVID.
What's the catch?! We have evidence of high efficacy in the first 2-4 months. Nobody knows how those numbers will drop over time...
(probably have some inaccuracies here but that's my best response without reading up)