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A study published in Nature looks at unintended immune responses in mRNA therapeutics.
Prof Stephen Griffin, Professor of Cancer Virology, University of Leeds, said:
“This is a landmark study impacting both upon our understanding of the fundamental molecular biology around how proteins are made, but also with real-world relevance because of the use of modified nucleotides – the building blocks of DNA or RNA – to make the mRNA vaccines that have played such a huge role in lessening the impact of SARS-CoV2 infection across the planet.
“Essentially, what the study shows is that use of these modified building blocks can cause the cellular machinery that reads the recipe encoded by the mRNA to make proteins – known as a ribosome – to slow down, pause, and then start reading again, but beginning from a slightly different point in the recipe. Most of the time, this results in nonsense and the process stops, but rarely this can result in a new string of amino acids being added.
“What does this mean? In addition to the main vaccine-driven immune response against the spike protein, other minor responses can also arise targeting the new protein sequences. This was shown both in mice with the same immune genetics, as well as a genetically diverse group of humans who had received mRNA, but not Adenovirus delivered vaccines; modified nucleotides are not a factor in the latter case. Importantly, however, the responses were seen in the T-cells of some, but by no means all, mRNA vaccinees.
“Does this matter and is there a problem with mRNA vaccines? It matters that we understand that these events are possible, but it by no means implies that the well-established population safety record for these vaccines, which have been administered more than 13bn times since 2021, should be questioned. Moreover, now this has been identified, there is an easy fix.
“First and foremost, mRNA vaccines would not work anywhere near as well without the use of modified nucleotides as these prevent overly aggressive short-term reactions that would limit their benefit. Despite what some bad characters may say, these are now some of the most carefully characterised and extensively used vaccines that have ever been invented, and it would be overtly obvious if this aspect of their biology was causing issues. The number of people that have been spared SARS-CoV2 driven hospitalisation, death, or even a proportion of long COVID, is countless millions; it is easy for some to take the huge benefits of COVID immunisation for granted nowadays, but this was by no means a guaranteed outcome at the outset.
“Second, whilst it may be the case that minor responses to these error-driven small proteins exist in some people, the only time they are ever likely to be exposed to the same target is for a short time (a few days) following subsequent vaccination (note, the responses and mis-read proteins may well differ between the original vaccine and variant-specific boosters, making this point moot, regardless). However, we know that second and subsequent doses of mRNA vaccines show little difference in terms of the risk of adverse events compared to the first dose, if anything the chance is lower, so again the impact of possible reactions appears limited.
“Critically, whilst no vaccines are perfect, and despite clear population-scale benefits for mRNA strategies, individuals can suffer rare side effects that are more serious because humans are so genetically diverse – there are always two sides of the coin for immunisations. Nevertheless, there is no evidence to suggest that the findings in this paper relate to such events; this will, naturally, have to be confirmed beyond any doubt going forwards.
“Lastly, this may sound like an important thing to act upon, and the good news is that it is very easy to do so. Now that these investigators have identified the parts of the mRNA recipe where this is likely to take place, it is a simple matter to ensure that ribosomes that might pause only ever encounter a nonsense message that no longer results in a protein. This is important because some of the future wider therapeutic uses for RNA technology beyond vaccines may involve higher and more frequent dosing, so any and all possible issues need to be addressed. This is all part of the due diligence required for any biomedicine, and the open and transparent processes around this continue to refute nefarious anti-vaccine conspiratorial claims of mass harm caused by these, or any other current vaccines.”
Prof Neil Mabbott, Personal Chair in Immunopathology and Head of Immunology Division, The Roslin Institute & Royal (Dick) School of Veterinary Sciences , University of Edinburgh, said:
“The messenger RNA vaccines contain short strands of genetic code that provide the instructions for the cells in our bodies to make copies of the spike protein on the surface of the coronavirus that causes COVID-19. These proteins are then used to train our immune systems to recognise and destroy the virus should we become infected with it.
“Some of the molecules within these types of vaccines have been modified to make them more durable. This is to prevent our immune systems from destroying the vaccines before they have had time to stimulate an immune response to the coronavirus. However, in this study the authors show that these modifications can sometimes cause the cell to misread the vaccine’s messenger RNA, by a process known as frameshift. When this happens, it can lead to abnormal versions of the coronavirus spike protein being made.
“Importantly, the authors show that these frameshift mistakes can be prevented by removing the regions in the vaccine’s messenger RNA genetic code that are prone to being misread.
“Vaccination continues to be a very safe and effective way to protect against serious illness or death following infection with COVID-19. Across the world billions of doses of COVID-19 messenger RNA vaccines have been administered and are considered to have saved millions of lives. The findings in this study do not suggest that these frameshift mistakes are harmful to the body, nor do they suggest they are associated with the very rare adverse reactions to the vaccines that some people have experience such as myocarditis. By showing how these frameshift mistakes can prevented this provides an excellent opportunity to increase the efficacy of the mRNA vaccines and further improve their safety profile.”
Prof Max Crispin, Professor of Glycobiology and Director of the Institute for Life Sciences at the University of Southampton, said:
“mRNA vaccines have proved remarkably safe and effective. The safety of vaccines is of paramount importance to everyone and scientists from Medical Research Council Toxicology Unit have been working to identify areas which could be improved. They have identified that the current generation of mRNA vaccines generate a small amount of by-product that can stimulate the immune system. Ideally this feature would be not present. The researchers have not only identified how these by-products occur, but have also generated effective solutions for their minimisation. This means future mRNA vaccines can be designed with the immune system being more focussed on the target of interest.”
Prof Sheena Cruickshank, Immunologist and Professor in Biomedical Sciences and Academic Lead for Public Engagement with Research, University of Manchester, said:
“When you make mRNA vaccines, as mRNA is very unstable (degrades quickly), you make mRNA that has some modifications typically to enhance stability and also to reduce innate cells reacting to it overly (innate cells are our early white blood cell responders and you don’t want them to destroy the mRNA and or cause inflammation before the adaptive cells have been triggered to make antibodies)
“Some of the modifications that are used in production of vaccines are taken from nature i.e. we see similar modifications naturally.
“This paper wanted to confirm whether by stabilising the mRNA and making subtle changes to it could impact how precisely accurately the modified mRNAs work. There is limited evidence that precision maybe affected in for example single cells prokaryotic cells.
“To assess this they used a variety of molecular, cell based and functional assays to understand precisely how the stabilisation affects the targeting of the mRNA. They did find there was potential for this it be impacted via so called ‘slippery sequences’. By identifying this potential issues they can identify ways to prevent this happening and further enhance how well the mRNA work.
“It is important to say that there is no evidence at all that there have been adverse outcomes from the mRNA vaccines that this mechanism would be involved in. Nor did the paper look at patient antibody responses following mRNA vaccination. Thus, it is unclear that this potential mechanism is having any impact in the current vaccination efficacy or safety. Nonetheless this is an important study that enhances what we know and how we use the mRNA vaccine platform.”
‘N1-methylpseudouridylation of mRNAcauses +1 ribosomal frameshifting’ by Thomas E. Mulroney et al. was published in Nature at 16:00 UK time on Wednesday 6th December.
DOI: https://doi.org/10.1038/s41586-023-06800-3
Declared interests
Prof Neil Mabbott: I have no conflicts of interest to declare.
Prof Max Crispin: No conflicts of interest to declare.
Prof Sheena Cruickshank: None