Flu season has come early this year in parts of the northern hemisphere, and many people are scrambling to get their annual vaccination. That ritual may someday be history.
In a first for any infectious disease, a vaccine against flu has been made out of messenger RNA (mRNA) – the genetic material that controls the production of proteins. Unlike its predecessors, the new vaccine may work for life, and it may be possible to manufacture it quickly enough to stop a pandemic.
We become immune to a flu strain when our immune system learns to recognise key proteins, called HA and NA, on the surface of the flu virus. This can happen either because we have caught and fought off that strain of flu, or because we received one of the standard vaccines, most of which contain killed flu virus.
Flu constantly evolves, however, so those proteins change and your immunity to one year's strain does not extend to following year's. For this reason, a new vaccine has to be produced each year. Most flu vaccines are grown in chicken eggs or cell culture, a process that takes at least six months.
This time lag means that the World Health Organization has to predict months in advance which viruses are most likely to be circulating the following winter. Drug companies then make a new vaccine based on their recommendations. Of course, these recommendations can be wrong, or worse, when a completely new flu virus causes a pandemic, its first waves can be over before any vaccine is ready.
Freeze-dried vaccine
Now there could be a solution. The mRNA that controls the production of HA and NA in a flu virus can be mass-produced in a few weeks, says Lothar Stitz of the Friedrich-Loeffler Institute in Riems Island, Germany. This mRNA can be turned into a freeze-dried powder that does not need refrigeration, unlike most vaccines, which have to be kept cool.
An injection of mRNA is picked up by immune cells, which translate it into protein. These proteins are then recognised by the body as foreign, generating an immune response. The immune system will then recognise the proteins if it encounters the virus subsequently, allowing it to fight off that strain of flu.
Similar vaccines have been made of DNA that codes for flu proteins. But DNA vaccines seem unlikely ever to be approved, because of worries that they might be incorporated into human DNA, disrupting gene regulation.
Safety advantage
That is not a risk with mRNA, which cannot become part of the genome. For this reason, "RNA probably has advantages over DNA as concerns safety," says Bjarne Bogen of the University of Oslo, Norway, who is working on a DNA vaccine for flu.
Trial RNA vaccines have failed, however, after being destroyed rapidly in the blood. But CureVac, a company in Tübingen, Germany, has found that a protein called protamine, binds to mRNA and protects it. It has an mRNA vaccine against prostate and lung cancer tumours in human trials.
"Amazingly, mRNA vaccines have never been really tested against infectious diseases," says Stitz. His team used CureVac's process to make durable mRNA vaccines for common human flu strains, as well as H5N1 bird flu. In mice, ferrets and pigs, the vaccines rapidly elicited protective levels of antibodies.
Two-pronged immunity
They also induced cell-mediated immunity, which is an immune response that does not involve antibodies but activates blood cells such as killer T-cells to destroy specific pathogens. Vaccines made only of the proteins do not elicit this type of response. Having both types of immunity clears infection faster, and can also protect against flu for longer, as cell-mediated reactions still recognise flu viruses after they have evolved enough to evade antibodies.
A true universal vaccine for flu
, however, would induce immunity to proteins that are the same in all flu viruses, but which flu normally hides from the immune system. Stitz's team made an mRNA vaccine to one such protein from an ordinary seasonal flu. The vaccine not only protected animals from that flu strain, but also from H5N1 bird flu.
Vaccines that work against all flu strains could eventually be given once in childhood, like vaccines for other diseases. Meanwhile, Stitz is also working on an mRNA vaccine for rabies. "We think that mRNA would provide an excellent platform against viral, bacterial and fungal diseases," he says.
Journal reference: Nature Biotechnology, DOI: 10.1038/nbt.2436
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