The hemagglutinin protein is bound to the nanoparticle prior to “beheading.”
Between the nanoparticle and specific mutations, the “headless” hemagglutinin construct is stabilized.
A depiction of the nanoparticle vaccine components with (left) and without (right) the variable head region.
The H1N1 stem antibody, shown in light blue, exhibits ability to bind to the H5N1 viral strain.
The H1N1 stem antibody, shown in teal, exhibits ability to bind to the H5N1 viral strain, shown in light blue.

Is a universal flu vaccine on the horizon?

Every fall, millions of people roll up their sleeves for a flu vaccine, hoping to give their immune system a leg up on influenza. But the flu virus has thousands of strains that mutate and evolve across seasons, and the vaccine can’t guard against all of them. Now, two groups of researchers have independently created vaccines that lay the groundwork for a long-sought shot that could protect against every type of flu.

“This is really cutting-edge technology,” says Antonio Lanzavecchia, an immunologist at the Swiss Federal Institute of Technology in Zurich, who is unaffiliated with both studies. “There is still work to do, but this is a clear step forward and it’s headed in the right direction.”

Scientists develop flu vaccines by predicting the strains most likely to infect a population. They use year-round flu surveillance along with field reports from countries in the Southern Hemisphere to guess which strains are most likely to hit North America at the height of the flu season—December through March. But viral guesswork is a tricky business, and it’s impossible to be 100% right. This uncertainty makes for patchy protection, and as flu strains mutate over the course of the season, vaccines become less and less effective.

Flu vaccines stimulate the production of antibodies against pieces of dead virus. Should the virus return, the antibodies can recognize, attack, and neutralize the threat. But because these vaccines are based on parts of the virus that evolve over the course of a flu season, protection is not guaranteed.

To solve this problem, two teams of researchers independently focused on a protein called hemagglutinin, found on the surface of the flu virus H1N1. It has two major components: the head—the portion of the virus that mutates and changes from strain to strain—and the stem, which is similar across most flu strains. The teams tried to remove the variable head region and keep the stem as the base of their vaccines. But hemagglutinin turns out to be rather feeble. Once beheaded, the stem falls apart, and antibodies can no longer bind to it.

To anchor the headless stem, the teams took different approaches. Researchers writing today in Nature Medicine used a two-step method: They introduced a combination of mutations to stabilize the core of the hemagglutinin stem. Then, they bound a bacteria-derived nanoparticle to the stem, which pulled the subunits of the protein together to hold it in the right position. The other team, writing today in Science, applied a combination of mutations that realigned the subunits of the stem at the top. This was enough to sustain a functional structure for the vaccine.

When the teams vaccinated mice, both groups saw full protection against H5N1, a lethal influenza strain distantly related to H1N1. In both studies, mice that did not receive the stem-derived vaccine died, but vaccinated mice all survived. In further experiments, the nanoparticle-anchoring vaccine showed partial protection in ferrets, whereas the other vaccine showed partial protection in monkeys. Two of the six vaccinated ferrets fell ill and died, compared with a 100% mortality rate for the unvaccinated ferrets. None of the monkeys died, but those that were vaccinated had significantly lower fevers than their nonvaccinated companions.

“The [experimental] designs were different, but the end results were very similar and highly complementary,” says Ian Wilson, co-author on the Science paper and a structural and computational biologist at the Scripps Research Institute in San Diego, California. “It’s a promising first step, and it’s very exciting to see this research come to fruition.” Authors of both studies say the next step is expanding protection to other strains of influenza, namely H3 and H7.