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Cambridge University researchers find major flaw in mRNA vaccine technology

In December of 2023, Nature Journal published a paper by Cambridge University (UK) researchers explaining a major flaw in the mRNA technology.

This is the same technology that won a Nobel prize for its creators and was used in the Pfizer and Moderna vaccines.

In this article, I’ll try to break down the technical details of this flaw.

Paper source

How mRNA Vaccines Work

First, let’s recap how the mRNA vaccines work:

  • mRNA is created (a whole separate process), then mixed with lipid nanoparticles.
  • These are then preserved in vials, stored at a cool temperature, and transported to their destination.
  • The liquid solution is then drawn up from the vials into syringes and injected into the arms of patients (deltoid muscle), with the original intention that the nanoparticles stay in the muscle.
  • The lipid nanoparticles are then supposed get inside cells (another, whole other process), where their mRNA payload is released into the cytoplasm.
  • At this point, the ribosome would read and translate the mRNA into proteins.

It’s this last point where a flaw has been found, where the ribosome reads the mRNA.

A visual example of mRNA > proteins – source

How the Ribosome reads mRNA

Prior to discussing the issue of frameshifting, it makes sense to first provide an overview of how a cell’s ribosome would normally read mRNA.

  • The work of the ribosome is to take mRNA and translate it into proteins.
  • It reads the mRNA nucleotides: Uracil (U), Guanine (G), Cytosine (C) and Adenine (A) in groups of 3 (expressed in short-hand as codons).
  • For every triplet of nucleotides, there is a corresponding protein that it creates. 

Under normal circumstances, mRNA is transcribed from DNA within the nucleus by RNA polymerase. This mRNA sequence is then processed and exported out of the nucleus into the cytoplasm. There, the ribosome will read it and translate it into proteins.

The above image is a “codon wheel” and explains what proteins are made when you choose a pattern of three codons. For example “AGG” results in Arginine. Image source.

The Problem of Frameshifting

According to the researchers in the paper above:

“Here we demonstrate that incorporation of N1-methylpseudouridine into mRNA results in +1 ribosomal frameshifting in vitro and that cellular immunity in mice and humans to +1 frameshifted products from BNT162b2 vaccine mRNA translation occurs after vaccination.”

To put this into simpler terms…

  • The mRNA in the vaccines uses N1-methylpseudouridine (herein referred to as pseudouridine) rather than uracil, which is more commonly used.
  • Something in the characteristic of pseudouridine, which we will come back to, is causing +1 ribosomal frameshifting.
  • The proteins created as part of this process generate an off-target immune response in mice and humans. Off-target, meaning, it’s not the same immune response as it would be to the SARS-CoV-2 spike protein.

To elaborate on this and explain what frameshifting is:

  • The mRNA code in the BNT162b2 (Pfizer) vaccine has replaced the uracil bases with N1-methylpseudouridine. Apparently regular pseudouridine “yields superior nonimmunogenic vector with increased translational capacity” versus uracil. And then apparently “N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines”.
  • This N1-methylpseudouridine appears to reliably cause frameshifting due to “slippery sequences”.
  • Frame shifting relates to the reading of the mRNA codons by the ribosome. A slippery sequence is typically multiple nucleotides long. The 4 nucleotides are Uracil, Guanine, Adenine and Cytosine.
  • When the slip occurs, it means that a single nucleotide is skipped.
  • Reading is done in batches of nucleotides called codons. Each codon is 3 nucleotides long.
  • Let’s say we have a (made up) 3 codon sequence CAG AAG GAC, but we get a +1 frameshift on the C, and then the string is read as AGA AGG AC, which is completely different. CAG AAG codes for glutamine and lysine, whereas AGA AGG codes for arginine.
  • This will likely result in a protein that doesn’t fold or function correctly.
Example of protein misfolding – source

Slippery Sequences

Let’s delve slightly deeper into this “slippery sequence” idea. In the paper they give an example of these slippery sequences:

It appears that one of the slippery sequences is u*u*u* – which is 3x N1-methylpseudouridine. Plus cytosine and guanine in the above example.

The value of this is:

  • Researchers can potentially avoid or engineer around slippery sequences in the future.
  • Knowing the slippery sequences may help future researchers understand the downstream implications of this issue.

Off-Target Immune Response

Above we have looked at “how” the mRNA encoded can result in off-target proteins.

Next we’ll look at the part of the study that looks at detecting them.
This image shows a comparison of immune response against the AstraZeneca viral vector vaccine called ChAdOx1.

In a nutshell, this image shows that the BNT162b2 vaccine generates a high amount of T cell response to frame-shifted spike proteins, whereas the ChAdOx1 does not. Image source (see figure 2).

The Upshot of the Issue

So that’s an overview of what’s happening at a scientific level.

However, it’s natural to ask, what does this mean for the humans who are injected with this faulty mRNA therapeutic?

I say faulty because this wasn’t known prior to Karikó and Weissman being awarded the Nobel prize for the mRNA platform invention.

The truth is… we don’t yet know.

The paper simply states that these off-target proteins elicit an immune response. Ideally, this immune response simply destroys them. However, biology is complex, so it would be premature to jump to the conclusion that it’s as simple as that – without further research.

More research is needed.

However, I would posit that to continue saying, definitively, the vaccines are “safe and effective” is questionable.

Given that with the new information presented above, the method of action differs from what was originally proposed.

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