The latest research, led by biochemist Professor Anne Willis and immunologist Dr James Thaventhiran from the MRC Toxicology Group at the University of Cambridge, builds on previous research progress and aims to ensure that any safety issues with future mRNA-based therapies are prevented. Their report was published today (December 6) in the journal Nature.
Researchers have discovered that a chemically modified base called N1-methylpseudouracil contained in current mRNA therapies is responsible for the "slippage" of the mRNA sequence.
The MRC Toxicology Group, working with researchers from the Universities of Kent, Oxford and Liverpool, examined evidence of the production of "off-target" proteins in people who received Pfizer's COVID-19 mRNA vaccine. They found that one-third of the 21 vaccinated patients in the study experienced unexpected immune responses but no adverse effects, which is consistent with the wealth of safety data on COVID-19 vaccines.
The team then redesigned the mRNA sequence to avoid these "off-target" effects by correcting error-prone gene sequences in synthetic mRNA. This produces the expected protein. This design modification could easily be applied to future mRNA vaccines to produce the desired effect while preventing dangerous and unexpected immune responses.
"Research shows beyond doubt that mRNA vaccination against COVID-19 is safe. Billions of doses of the Moderna and Pfizer mRNA vaccines have been administered safely, saving lives around the world," said report co-senior author Dr. James Thaventhiran of the UK Medical Research Toxicology Group.
He added: "We need to ensure that future mRNA vaccines are equally reliable. Our demonstration of 'non-slip' mRNA is an important contribution to the future safety of this drug platform."
"These new therapies offer hope for treating a wide range of diseases. As billions of pounds of funding flow into the next group of mRNA therapies, it is important to ensure that these therapies are designed not to cause unintended side effects," said Professor Anne Willis, Director of the MRC Toxicology Group and co-senior author of the report.
Thaventhiran, who is also a practicing clinician at Addenbrooke's Hospital, said: "We can remove the error-prone code from the vaccine's mRNA so that the body can make the protein we want to generate an immune response without inadvertently making other proteins. The safety issue for future mRNA drugs is that misdirected immunity has huge potential harm, so off-target immune responses should always be avoided."
Willis added: "Our work raises both concerns and solutions to this new class of medicine and is the result of an important collaboration between researchers from different disciplines and backgrounds. These findings can be quickly put into action to prevent any future safety issues and ensure that new mRNA therapies are as safe and effective as COVID-19 vaccines."
Using synthetic mRNA for therapeutic purposes is attractive because it is cheap to produce and could therefore address severe health inequalities around the world by making these medicines available to more people. In addition, synthetic mRNA can also be changed quickly—for example, to create vaccines for new COVID-19 variants.
In Moderna and Pfizer's COVID-19 vaccines, synthetic mRNA is used to cause the body to make the spike protein from SARS-CoV-2. The body will recognize the viral proteins produced by the mRNA vaccine as foreign proteins and develop protective immunity. This immunity persists so that if the body is later exposed to the virus, immune cells can neutralize it before it causes severe illness.
The cell's decoding machinery is called a ribosome. It "reads" the genetic code of natural and synthetic mRNA to produce proteins. The precise positioning of ribosomes on the mRNA is critical for making the correct protein, because the ribosome "reads" the mRNA sequence three bases at a time. These three bases determine which amino acid is added next to the protein chain. So even a tiny movement of ribosomes along the mRNA can severely distort the code and the resulting protein.
When the ribosome encounters a string of modified bases called N1-methylpseudouridine in the mRNA, it shifts about 10 percent of the time, causing the mRNA to be misread and producing an unexpected protein—enough to trigger an immune response. Removing these N1-methylpseudouridines from the mRNA prevents the production of "off-target" proteins.
Reference: "N1-methylpseudouridylylation of mRNA leads to +1 ribosome frame transfer", December 6, 2023, "Nature".
DOI:10.1038/s41586-023-06800-3
Compiled source: ScitechDaily