If the virus that causes flu were an ice cream cone, then the yearly vaccine teaches the immune system to recognize just the scoop—chocolate one year, strawberry the next. As the virus changes each year, the vaccine needs to change, too.

The new method teaches the body to recognize the “cone” portion of the virus—the part that stays the same year-to-year. Researchers working on the technique say it works in lab animals, but warn they still need to make the vaccine more specific and show it works in much larger studies before testing it in people.

Image: PNAS

“We think it could be very generalizable,” says Peter Kim, professor of biochemistry at Stanford University and the lead investigator of the infectious disease initiative at the Chan Zuckerberg Biohub. “It could be important for coming up with a universal flu vaccine that would protect against pandemic flu, as well as for HIV.”

Flu vaccine primer

The idea behind a vaccine is to inject a person with either a killed virus or just a single protein normally found on the virus surface. The immune system learns to recognize bits of that artificial invader, and mounts a defense that it can activate months or even years later if it sees that protein again.

The challenge is that some portions of a protein are, for whatever reason, a lot easier for the immune system to detect. In the case of flu, that easily detected portion is the ice cream end—the annual vaccine against the flavor of the year. Try though they might, scientists haven’t been able to effectively direct the immune system’s attention to the cone.

The idea for the new approach came about when chemistry graduate student Payton Weidenbacher heard a talk about a protein that can bind very specifically to exactly the spot on the flu virus protein they want the immune system to recognize. Scientists call the protein, a monoclonal antibody—“mono” because it binds to just one spot and “clonal” because they can make a lot of identical copies of it.

"You should be able to do this on anything - that's the dream."

During the talk, scientists wondered if they could use the monoclonal antibody as a guide and create a way for the immune system to bind to the same spot.

Listening in, Weidenbacher remembered a chemical trick that he thought might offer a different approach. Instead of just learning from the monoclonal antibody, why not make use of it? His idea was to latch this highly specific monoclonal antibody onto the flu virus protein in the lab and use it as a stencil.

He could paint the rest of the protein with molecules that act as a chemical cloak, rendering it invisible to the immune system. Removing the stencil would leave only a tiny portion of the protein visible for the immune system to learn to recognize and eventually attack.

Using that mostly cloaked protein as a vaccine may push the immune system to mount an attack against the cone—the portion of the virus shared across flu strains, including pandemic flu.

Simple idea, difficult process

Weidenbacher mentioned his idea to Kim after the talk, but both assumed someone else would have thought of such a simple idea. Then, Weidenbacher got a late-night email from Kim. “Peter was like, ‘nobody’s done it, start now,'” says Weidenbacher.

“Payton is a chemist,” Kim says. “What he did is come up with a way of using the monoclonal antibody not as something you look at but as a reagent.”

Although the idea was simple, carrying it out was not. Weidenbacher encountered some hurdles getting the system to work, but the team’s early tests, which appear in the Proceedings of the National Academy of Sciences, look promising.

Lab animals that receive this cleverly cloaked flu protein also show an immune response to other strains of the flu—something that would only happen if they’d learned to recognize the consistent bits in the cone. Animals that received a normal vaccine didn’t respond well to other flu strains.

The researchers “skewed” the immune response, but they have work to do to get it to be more specific. If they succeed, they say it could become an approach that works for many different infectious agents.

“You should be able to do this on anything—that’s the dream,” Weidenbacher says. “With the right chemistry, you could take any monoclonal antibody off the shelf and do this.”

The Virginia and D. K. Ludwig Fund for Cancer Research and the Chan Zuckerberg Biohub funded the work.