Can mrna spike protein block other proteins entering cells?

Question

When vaccinated with pfizer a mrna is injected which eventually creates spike proteins. These will bind to cells. Now there is a rumour that when these spike protein binds to cells it can block other important proteins from binding to that cell. Is this true? Can someone debunk this.

Answer 1

Short answer: No.

What I am going to do here is some back-of-the-envelope style calculations and a bit of explaining, so bear with me...

The way that these vaccines work is by causing the mRNA to enter the cell, where it is translated into the encoded protein sequence. This is then translocated to the surface of the cell and in some cases into the extracellular space (ref 1; see figure 2).

This means that some of the protein produced is floating around and could bind to a cognate receptor on another cell (or even on the surface of the cell it came from, in which case it won't go any further). However, in the case of the spike protein, this receptor is the Angiotensin converting enzyme-2 (ACE2) protein, which is a receptor for Angiotensin II. In a natural infection it is thought that the levels of spike protein (ref 2) produced by the replicating virus are high enough that it prevents the normal function of ACE2 and enhances damage and further infection.

We (by that I mean I, myself) don't know what proportion of the expressed protein is released from the cell into the extracellular space, but based on my experience in the lab using similar methods for DNA transfection, it will only be a small proportion of the protein produced. It may be that this information is known or it may be proprietary, but I would be willing to bet it is less than 50%, and maybe much lower.

We do know the sequence of the mRNA in the vaccine and can make at least some order-of-magnitude estimates of the number of RNA molecules in a dose (30 micrograms for Pfizer, or about 0.5 ug/kg body weight, assuming 60 kg average body weight per person). Not all of these molecules will be fully functional - some will have manufacturing errors that terminate the protein early, some won't be packaged properly, some will be degraded during preparation, some won't make it into a cell, etc.. However, we can assume about 1-10 trillion (1-10 x 10¹²) molecules, which as it turns out, is about the 10-100 times the number of viral genome copies that your lungs produce at peak infection (ref 3; see fig 1). Now, if we assume that each produces a single protein before being degraded, we have a corresponding 1-10 trillion protein molecules.

This sounds like a lot, but rest assured that this number is tiny in terms of what we are looking at - there's about 10²¹ sugar molecules in a teaspoon of sugar (4.2 g/teaspoon, molar mass sucrose = 342.3 g/mol).

Now, back to the virions. If we assume that each one of these genomes produces a virion (whether functional and infectious or not), and that each virion contains 24 spike trimers (ref 4), or 72 individual spike proteins (24 trimers x 3 spikes per trimer), then we have roughly the same number of spike proteins produced by the virions as by the vaccine, and we know that the virus can do some damage via this route (see ref 2). So, in theory, we could produce enough protein to effect some damage to your cells.

The other major variable here is the amount of ACE2 in a cell - I don't think this can be quantified easily. It is known that some cell types have more than others, but in terms of molecules per cell, it is unlikely to be static and would be very very hard to determine. This means that maybe there are only 10 (very unlikely, it is an important molecule) or maybe there are millions of molecules per cell (also unlikely). If we take a number somewhere between the two - lets say 100,000/cell (10⁵/cell) - that means we would need 10⁷ (10 million) cells to mop it all up. There are about 4-6 million cells in a ml of blood, so we would need about 2 ml of blood to cope with that. I can also say, just to give you some sense of scale, if you clumped the cells together, 10 million cells is about the size of a large drop of water while it is hanging.

However, it's not that simple in any biological system, these sorts of things have kinetics of production, so we wouldn't produce all that protein in one big hit. Here's some known kinetics (ref 5; see fig 3) for a test of these sorts of vaccines, which shows that about (I estimate) 50% of that protein is produced within a few hours and then tails off over the next day or so. Indeed these people (ref 6) showed for their experimental spike vaccine version, that the vaccine peaked at 12 hours and was gone 48 h post injection. Spreading the production out means that the body has time to produce more ACE2, minimizing the affect of the spike production. Some (as I mentioned before) won't make it out of the cell or won't be released into the extracellular fluid. The vaccine particles are also spread via the blood, so the effect is not localized and any effects somewhat diluted because of that.

Whatever actually happens, we know that this type of vaccine has almost no short-term serious side effects, and is very unlikely to have longer term effects too. The vast majority of people experience a sore arm for a day or so and maybe some other symptoms (aches, tiredness, fever), almost all of which can be attributed directly to activation of the immune system.

So, the (very) long and short of it is - while it is plausible that this vaccine could IN THEORY produce enough protein to block the normal function of ACE2 in some cells, we don't see this happening in real life for a huge number of reasons.

References:

1. Park et al. Int J Biol Sci. 2021 17(6):1446.
2. Sriram and Insel. Br J Pharmacol. 2020 Nov;177(21):4825-4844
3. Sender et al. PNAS. 2021 Jun 22; 118(25): e2024815118
4. Ke et al., Nature. 2020 588:498–502
5. Pardi et al., J Control Release. 2015 Nov 10; 217: 345–351.
6. Zhang et al., Cell. 2020 Sep 3; 182(5): 1271–1283.e16