Elusive universal flu vaccine sees success in animals with mRNA tech

Producing a successful seasonal flu vaccine requires a bit of fortune-telling. Each vaccine can target only up to four different flu viruses, of which there are many. If scientists’ predictions about the season’s predominant strains turn out to be wrong, a lot of time and money is wasted—not to mention that the public may be left unprotected from the flu, which can be dangerous even to the young and healthy.

But thanks to mRNA technologies, scientists may be one step closer to developing a long-sought universal flu vaccine. In the results of a study published Nov. 24 in Science, a team led by researchers from Perelman School of Medicine at the University of Pennsylvania reported that they had developed an mRNA-based vaccine capable of targeting all 20 known subtypes of the A and B flu virus. Rodents that were immunized with the vaccine produced antibodies to all 20 lineages and were protected from death when exposed to flu strains from each of the different subtypes.

“The idea here is to have a vaccine that will give people a baseline of immune memory to diverse flu strains, so that there will be far less disease and death when the next flu pandemic occurs,” Scott Hensley, Ph.D., senior author, said in a press release.

To understand what makes creating a universal flu vaccine so difficult, it helps to know a bit about how flu vaccines are developed. Every year, scientists predict which four flu viruses are going to wreck the most havoc during the upcoming flu season. They then produce a “split virion protein vaccine” based on those strains; they grow the viruses in chicken eggs, then split them into pieces to inactivate them. Those inactivated pieces are injected into the body so the immune system can produce antibodies against those four strains.

The problem with this system is that it requires scientists to produce new vaccines every year, some of which ultimately wind up being ineffective against the season’s main flu strains if the predictions turn out to be wrong. The split virion protein vaccine can only handle four strains max, limiting its ability to induce broad protection.

Scientists have tried to develop universal vaccines that target parts of the flu virus that are common among different strains, such as proteins on its surface and its internal nucleoprotein. But so far, none of them have worked, as scientists Alyson Kelvin, Ph.D., and Darryl Falzarano, Ph.D., wrote in a perspective article that ran in Science along with the study.

“Although more highly conserved, these proteins or protein domains are often difficult to produce, are poorly immunogenic and elicit immune responses without blocking infection,” Kelvin and Falzarano explained.

Instead of looking for a novel target, the scientists in the Penn study used mRNA to generate an antibody response to old ones: Hemaglutinin, or HA, proteins, spike-shaped viral proteins that jut out from the surface of the virus and help it infect host cells. Each of the 20 lineages of the A and B flu viruses, the most common types to infect humans, has its own HA protein.

Split virion protein vaccines generate antibodies against HA proteins too, and some of the most promising work on a universal flu vaccine has involved targeting a specific region of the HA protein known as the stalk, which is found in all flu viruses. In this case, the researchers targeted all 20 different HA proteins at once.

The vaccine has the same mechanism of action as the Pfizer and Moderna vaccines against COVID-19. The mRNA serves as blueprints that tell the body’s cells how to produce the HA proteins. When the vaccine is administered, the cells take up the mRNA and begin churning the proteins out. The immune system produces antibodies in response, training it to recognize and attack foreign invaders that contain those same proteins.

To see if the vaccine held up, the researchers gave it to mice and ferrets, then exposed them to flu viruses from all 20 lineages 28 days later. They found that while all of the animals weren’t completely protected from infection, they were protected from severe disease and death. Their levels of antibodies remained high four months after the vaccine was given. And it worked in rodents that had been infected with the flu before vaccination—an important distinction, as previous exposure to a disease can affect whether future vaccination against it is effective.

The scientists are now in the process of designing human clinical trials. They hope to include young children too, as they think the vaccine may be able to generate long-term immune memory to all 20 flu lineages.

They’ll have some hurdles to jump, as Kelvin and Falzarano pointed out in their article. For one, it’s not clear how a regulatory pathway toward approving a vaccine against viruses that aren’t currently circulating might work. It’s also unknown if the vaccine can be updated if completely new strains of the flu emerge. Plus, some critics might argue that immunizing against so many vaccine targets at once will drive the virus to mutate—however unlikely that may be, they noted, as the scientists saw that the vaccine did protect against infection and replication in the rodent models.

“Addressing both the limits of mRNA components and clarifying a pathway to approval are essential to the optimization and use of truly universal vaccines,” Kelvin and Falzarano wrote.