Why the next generation of mRNA vaccines is set to be even better

Vaccines that resemble viruses generally produce a stronger immune response, while mRNA versions are much quicker and less expensive to make. We now have the best of both worlds, in the form of mRNA vaccines encoding virus-like nanoparticles, rather than just individual proteins, as is the case with existing covid-19 mRNA vaccines.

Grace Hendricks of the University of Washington in Seattle and colleagues showed that an mRNA version of a covid-19 nanoparticle vaccine produces an immune response in mice that is up to 28 times greater than that of a standard mRNA vaccine.

Some of the unpleasant — but mild — side effects of mRNA vaccines come from the body’s immediate reaction to the injected mRNAs and the fatty particles they’re encased in, Hendricks says. With more powerful vaccines, the dose could be reduced. “So the important immune response remains the same, but the side effects would be less because you gave a lower dose,” she says.

The very first vaccines consisted of weakened “live” viruses, which were very effective but could pose risks to people with weakened immune systems. Then come inactivated vaccines containing “dead” viruses, which are safer but difficult to manufacture.

The next advance was protein subunit vaccines, which typically contain only the outer proteins of viruses. These are even safer than inactivated vaccines, but free-floating proteins tend not to produce a strong immune response.

So vaccine designers began packing viral proteins into tiny spheres to create spiky balls that look like a virus to the immune system, but are just as safe as protein subunit vaccines. One way to do this is to modify existing proteins so that they self-assemble into tiny balls, from which viral proteins, called vaccine nanoparticles, protrude.

During the pandemic, Hendricks’ colleagues created a covid-19 nanoparticle vaccine called Skycovion. It was approved in South Korea in 2022, but at that time mRNA vaccines already had a big head start and were therefore not widely used.

mRNA vaccines are much faster and easier to make than protein vaccines because they contain the recipes for making proteins, and our body’s cells do the hardest part of making those proteins. The viral proteins encoded by first-generation mRNA vaccines eventually protrude outside cells and produce a better immune response than free-floating proteins, but not as effective as nanoparticle vaccines.

Now, Hendricks and his colleagues have combined the advantages of both approaches by creating a vaccine composed of mRNA encoding Skycovion. When vaccine proteins are made inside cells, they assemble into nanoparticles, with signs of effectiveness in the mouse study.

“It was just a proof of concept of this genetic transmission,” says Hendricks. She and her colleagues are already working on launched mRNA-based nanoparticle vaccines, as they call them, against influenza, Epstein-Barr – which can cause cancer – and other viruses.

“I’m excited about the promise of mRNA-launched protein nanoparticles for vaccines,” says William Schief of the Scripps Research Institute in California, which is developing HIV vaccines. “My collaborators and I have published fantastic immunogenicity results with two mRNA-launched nanoparticles in clinical trials and several of these nanoparticles in mouse models. This new paper adds nicely to the body of work.” But despite the potential of mRNA vaccines, the United States has recently announced significant reductions in funding for their development.