The story of mRNA vaccines began more than 30 years ago, and they will soon be poised to treat conditions from malaria to cancer.
When the broad range of vaccines against COVID-19 were being tested in clinical trials, only a few experts expected the unproven technology of mRNA to be the star. Within 10 months, mRNA vaccines were both the first to be approved and the most effective. Although these are the first mRNA vaccines to be approved, the story of mRNA vaccines starts more than 30 years ago, with many bumps in the road along the way.
The upsides of mRNA German biotechnology company BioNTech’s chief medical officer Özlem Türeci—physician, immunologist and entrepreneur—says that “mRNA has a couple of interesting features that make it attractive for vaccines.” Adaptability serves as this molecule’s key feature in this application and beyond. mRNA can be engineered not only to make antigens for vaccines but also to encode antibodies, cytokines and other proteins related to the immune system.
In 2005, Weissman and his then-colleague Katalin Karikó—now at BioNTech—found a way to make RNA less inflammatory. They showed that the inclusion of modified nucleosides, part of the basic structure of RNA, resulted in a dramatically lower inflammatory response. This work explored the use of nucleosides such as 5-methylcytidine, pseudouridine and other forms.
In the future, scientists hope to have far more control over the resulting protein production. In a collaboration that included synthetic biologist Ron Weiss of the Massachusetts Institute of Technology and others, Sanders described switchable mRNA. “It’s an on/off switch for mRNA,” Sander says, “and we proved that it works in mice.” With this form of mRNA, the therapy can be turned on when needed, and the level of protein production can be more precisely controlled.
With traditional methods of making a vaccine against influenza, developers must modify the virus or protein being made. That modification can require changes in manufacturing. For example, the modified virus might grow a little differently than expected, which might require changes in a vaccine’s formulation.
Consequently, a pharmaceutical company is likely to market an mRNA-based vaccine against influenza only when it surpasses existing ones in several ways. Weissman and virus expert Harvey Friedman of the University of Pennsylvania found targetable antigens for genital herpes. Using these antigens, the scientists developed a vaccine from nucleoside-modified mRNA and lipid nanoparticles. Tests in mice and guinea pigs showed that this vaccine prevented infection with the virus that causes genital herpes. “This vaccine is moving into clinical trials,” Weissman says.
At CureVac, data from a phase 1 clinical trial of the company’s mRNA-based vaccine against rabies looks promising. “A very low dose vaccination generated an immune response in all subjects,” says Thorsten Schüller, CureVac’s vice president of communications. “This demonstrated the potential of our mRNA technology for the first time.”
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