For years, medical researchers have been hard at work trying to develop a vaccine that can confer protection against all strains of the influenza virus. Although there have been promising breakthroughs in animal studies, it always seems like we are still a way from the long-sought "universal vaccine" that could transform flu protection from a hit-or-miss struggle to a sure bet.

The current seasonal vaccines train the immune system to recognize flu particles by introducing fragments of the virus's surface proteins, most commonly, hemagglutinin (HA). However, as the structure of HA is continuously mutating, it makes it near impossible to cover all existing or future strains.

Instead, the scientists who create the yearly vaccines must make their best guesses about which existing strains will be the most pathogenic in the following months and artificially reproduce three to four different antigens based on their HA, therefore protecting against those strains and hopefully several closely related ones.

But now, new results from a team at the University of Pennsylvania suggest we are inching much closer to the universal vaccine goal. As described in Nature Communications, their RNA-based candidate vaccine successfully induced strong immune responses against a variety of flu strains in mice, rabbits, and ferrets by priming the immune system against a piece of the stalk of the HA protein that does not readily evolve or differ much between strains.

"When we first started testing this vaccine, we were blown away by the magnitude of the antibody response," co-senior author Scott Hensley said in a statement.

Unlike traditional vaccines, the UPenn vaccine does not contain antigens mixed with immune system stimulating agents. Instead, it delivers messenger RNA (mRNA) that encodes for the HA stalk fragment directly to the body’s cells, which will then construct the antigen protein using their own gene translation enzymes. This new approach has been shown to better mimic a true viral infection and therefore leads to the production of more defensive antibodies.

Following just one administration of what the researchers are calling mRNA-LNP, all three animals were protected against otherwise lethal doses of the same H1 influenza A strain that the stalk protein is derived from and a distantly related H1 strain. When given a second administration, the animals were also protected against an unrelated H5N1 strain.

Also setting it apart from other experimental vaccines, mRNA-LNP achieved the unprecedented combination of inducing an immune response against the HA stalk that is both intense enough to confer protection soon after immunization and durable enough that the recipient could stave off an infection following viral exposure many months later. Well, at least it did in mice, according to results from exposure tests four and 30 weeks after immunization. The authors note that past HA stalk antigens were either ineffective from the get-go or required multiple immunizations for sustained protection.

"If it works in humans even half as well as it does in mice, then the sky's the limit – it could be something that everyone uses in the future to protect themselves from the flu," Hensley said. He and his colleagues believe that the vaccine would only need to be administered a few times over a person’s lifetime, much like a tetanus vaccine and its subsequent once-a-decade boosters.

Unfortunately, the mRNA-LNP vaccine did not protect against one closely related H1 strain, meaning it will likely fall short of the "universal" title. However, the authors note that the beauty of the mRNA vaccine approach lies in the fact that it could be easily adapted to encode multiple antigens at once and can be quickly altered to keep apace with viral evolution.

The team hopes to begin human clinical trials within the next two years, pending success in primates.