Vaccination has improved health and lengthened life spans over the last two centuries, but it takes time to develop vaccines in response to emergent health threats. A paper published in PNAS presents a new type of nanoparticle vaccine technology using RNA to encode proteins that trigger immune responses. This new vaccine technology could allow us to respond more quickly to new threats, potentially saving many lives during future outbreaks.

Currently, four types of vaccines are commonly used. Inactivated vaccines contain bacterial cells or viruses that are killed or inactivated—they can’t replicate, but they can produce an immune response. Attenuated vaccines contain live bacteria or viruses that have low virulence, so they will evoke an immune response, but won’t cause a full-fledged infection. Virus-like particle vaccines contain the shell of a virus, but lack any genetic material. Finally, subunit vaccines contain proteins derived from the infectious agent, which can provoke an immune response without introducing the pathogen.

The new vaccine technology presented in this paper relies on what’s called “replicon mRNA,” which is based on a deactivated virus. It can make copies of itself and trigger the production of the proteins it encodes but can’t make new viruses, so it never escapes beyond the cells it first gets into. Replicon mRNA can be used to produce large quantities of specific proteins within the body, which in turn can provoke an immune response against those proteins.

Previous attempts to use replicon mRNA vaccines have been unsuccessful because naked replicon mRNA can induce an immune response itself. That hinders the material’s ability to induce production of the proteins, so you never get the desired immune response. Additionally, RNA degrades very quickly when it’s injected into the body, which also limits its ability to induce immunity.

In response to these known limitations of RNA as a vaccine, the researchers paired replicon mRNA technology with a specialized nanoparticle delivery system. Dendridimer-encapsulated nanoparticles range in size from 1.5nm to 10nm and are made of repetitively branched molecules (they end up looking a bit like a Koosh ball). The researchers showed that these nanoparticles could be an ideal delivery system for an mRNA-based vaccine and demonstrated the nanoparticles' stability when they were engineered to contain RNA.

After having figured out how to load the nanoparticles with replicon mRNA, the researchers tested them in live mice. They set up RNAs to encode proteins derived from multiple infectious agents: H1N1 flu, the Ebola virus, and Toxoplasma gondii. These were then used to vaccinate the mice. The vaccine was highly effective, as the mice were protected from what otherwise could be lethal infections.

The combination of dendridimer nanoparticle delivery and replicon mRNA appears to be a promising new vaccine technique. These nanoparticles effectively alleviate factors that limited the effectiveness of mRNA vaccines in the past—they keep mRNA from degrading, prevent it from provoking an unwanted immune response, and limit the possibility of mRNA-related toxicity.

In mice, these vaccines were extremely effective in preventing three diseases that were lethal in unvaccinated control mice, which is also promising. More research into this vaccine technique will be needed to fully explore the range of its potential benefits and side effects.

The key benefit, however, comes in comparison with existing vaccine approaches, which require the isolation of the infectious agent and/or the purification of some of its proteins. For the replicon mRNAs, scientists will only have to clone some of its genes. This could allow doctors and scientists to respond more quickly to new emergent infectious diseases and dangerous outbreaks. If these vaccines prove to be safe in humans, we may have an exciting new tool for stopping the spread of emergent diseases (like the current Zika virus) before they develop into full-fledged outbreaks.

PNAS, 2016. DOI: 10.1073/pnas.1600299113 (About DOIs).