Scientists find new way to overcome cell’s natural defenses against self-amplifying mRNA vaccines

The innovation could enable protection at lower doses, meaning vaccines could be rolled out further and faster than was previously imaginable, and opens new possibilities in gene therapy, cancer immunotherapy, and protein replacement therapies.

Scientists at Queen Mary University of London have found a way to overcome cell’s natural defenses against self-amplifying mRNA vaccines, thereby allowing them to produce significantly more of their target protein. The findings are published in Nature Communications.

mRNA-based vaccines were central to getting us out of the Covid-19 pandemic. Unlike conventional vaccines, which use a low dose of the virus to build immunity, RNA vaccines tell your cells to produce a protein which teaches your body how to fight the virus.

Since then, scientists have been working on self-amplifying mRNA vaccines (saRNA) which replicate within host cells. These next-generation vaccines could provide longer-lasting protection at lower doses, meaning vaccines could be rolled out further and faster than was previously imaginable.

The benefits go beyond pandemic protection. saRNA vaccines hold great promise as a novel strategy in gene therapy, cancer immunotherapy, and protein replacement therapies.

The barrier to saRNA vaccines lies within the technology itself.

In the process of self-replicating, saRNA generates double-stranded RNA (dsRNA) which triggers cells’ anti-virus defences. This makes the saRNA less stable, less able to replicate, and less able to instruct cells to produce the protein that trains the immune system. It’s a major flaw limiting how effective an saRNA vaccine can be.

Dr Pierre Maillard and Dr Raul Yusef Sanchez David, scientists at Queen Mary University of London’s Blizard Institute, found that adding NoV B2 (a protein known to suppress RNA interference, one of the cell’s natural defences against this double-stranded RNA ) helps overcome this problem by reducing the extent to which the cells restrict the saRNA, allowing it to produce far more of the intended protein in both stem cells and regular cells. Crucially, it does so without undermining saRNA’s ability to stimulate the immune system.

Our findings identify a strategy to overcome a fundamental barrier limiting self-amplifying vaccines. If this translates successfully in vivo, it could open new possibilities for vaccine design as well for gene therapies and cancer treatment.”

Dr Pierre Maillard, Senior Lecturer in antiviral immunity, Queen Mary University of London

A new generation of vaccines.

The research is published in Nature Communications, and the team are now working with Queen Mary Innovation, the university’s technology transfer company, to find a commercial partner to help develop the technique for clinical use.

By boosting how much protein saRNA can produce in the lab, the innovation opens new possibilities in gene therapy, cancer immunotherapy, and protein replacement therapies. If translated successfully, this technology could make gene therapy safer and more affordable; make cancer vaccines more potent; and turn protein-replacement therapy from a process of repeated infusions to one in which the patient’s body generates its own medicine.

The advance comes at a time of growing debate around funding for mRNA-based research following the United States announcement of $500m in cuts to mRNA vaccine research, a decision that sparked widespread concern in the global scientific and public health communities. Dr Maillard and Dr Sanchez David’s discoveries at Queen Mary demonstrate the continued strength of the United Kingdom as a place to invest in impactful research and innovation.