How llamas could help us fight the flu

Last year’s flu season was the worst in decades, leading to more than 80,000 deaths in the U.S. alone. Vaccination is the most effective way to prevent the flu, but even as vaccines are made available around the world, mortality levels don’t seem to be decreasing. The World Health Organization attributes between 290,000 and 650,000 deaths to the seasonal flu each year.

Researchers now think they’re on the path to a new kind of flu protection—one that might last longer and work against all types of influenza viruses. The source of their new defense: llamas.

These furry South American mammals produce special antibodies—molecules that mark foreign invaders in our bodies for destruction— that can identify a huge range of elusive influenza viruses. A new study used these antibodies to target multiple strains of influenza at once, a technique that could lead to more effective flu prevention. These antibodies can survive without refrigeration for longer, which could reduce the cost and complexity of flu treatment.

The new therapy was tested in mice, so there’s a long way to go before it reaches doctors’ offices. But researchers think this could be a big step toward eliminating a disease that afflicts between 5 and 25 percent of the U.S. population each year.

What the scientists did

To fight infections, vaccine designers take pieces of influenza viruses, neutralize them and then inject them as vaccines into a person, whose own body learns to fight those versions of the flu. Their immune system produces antibodies—proteins that match up, like a pair of puzzle pieces, with the exterior structure of the neutralized flu viruses. Later, when the vaccinated person encounters an active virus in the wild, their antibodies are ready to recognize and help destroy it.

But the flu isn’t caused by one virus. It’s the result of a collection of genetically diverse viruses that are constantly mutating. These viruses mutate at speeds that our antibodies can’t handle.

Though U.S. scientists design each year’s flu vaccine to target the most common flu strains for that particular upcoming season, the antibodies you get in a flu shot are ineffective by the time next year’s flu season arrives.

“[Our approach] could potentially be used as a preventive treatment from year to year and protect against both seasonal flu as well as potential pandemics, such as bird flu,” said Ian Wilson, a biochemist from Scripps Research who co-led the project.

In their study, Wilson and his colleagues bypassed the use of vaccines altogether. Rather than prompt the body to build its immunity, they used antibodies derived from llamas to combat influenza viruses directly.

The reason this works: Camelids like llamas, alpacas and camels produce small, single-domain antibodies. (They’re also found in sharks).

Influenza viruses consist of genetic material inside a protein envelope. Antibodies match, like puzzle pieces, to the proteins on the outside of a virus, but when the virus mutates the antibodies might no longer match. Image courtesy of CDC/Doug Jones, M.A.

In theory, smaller antibodies can reach parts of a flu virus that would be inaccessible to a typical human antibody. An influenza virus looks a bit like a snowball studded with golf tees. While human antibodies make contact with the fast-mutating end of the tees, the llama’s single-domain antibodies—which are 90 percent smaller—can match up with the “stem” of the tee.

The new study takes advantage of the fact that not all parts of an influenza virus are constantly mutating; these stems don’t mutate as readily as the ends, said Mehdi Arbabi-Ghahroudi, a senior researcher at the National Research Council of Canada who was not involved with the new study.

Arbabi-Ghahroudi, who was part of a team that discovered single-domain antibodies in camel blood in 1993, said if antibodies could match up to the stems of the virus’ coating proteins, “we could find antibodies that are quite conserved across different strains of influenza.”

“It’s a big breakthrough in getting to a near-universal antibody,” Arbabi-Ghahroudi added.

What the scientists found

The researchers behind Thursday’s study fused four different single-domain antibodies into one larger molecule, held together with a human protein as a scaffold. When they injected this hybrid into mice, the antibodies kept the animals safe from a wide variety of influenza type A and type B viruses—the two most common assailants in America’s annual flu epidemic. This hybrid seemed to successfully target each of the five flu strains they tested.

When the researchers injected mice with their hybrid antibody, it protected the mice from lethal doses of the flu. But the paper also explored another route of delivery: gene therapy.

The researchers used a benign virus—dubbed AAV—to embed the genetic blueprint of the llama antibodies directly into mouse cells. This procedure allowed the mice to produce the antibodies on their own.

Why it matters

Don’t expect this new antibody in your next flu shot…or even the one after that.

Gene therapy isn’t widely used in humans, and the approval process for this brand of treatment will be a rocky road, Arbabi-Ghahroudi said.

Still, the researchers wrote that nasal delivery of this gene therapy “may provide passive protection for the entire influenza season and would be of particular benefit to the elderly and other high-risk groups.”

“We are always behind,” said biologist Daniel Perez of the University of Georgia, who was not involved in the new study. “In the scientific community, we are chasing more universal approaches to control the disease. This paper is one example of that.”

Beyond the flu, the idea of using tiny antibodies to attack viruses from new angles opens up the possibility of combatting other diseases with rapid mutation rates. Single-domain antibodies have been tapped as a potential HIV treatment since at least 2010 and again in 2014.

So someday, the world may get through a flu season without the coughing and fevers (and more fatal repercussions as well) … and it might be thanks to llamas.