The idea for the new approach came about when Payton Weidenbacher, a graduate student in chemistry, attended a lab presentation where scientists discussed a protein that can bind to exactly the spot on the flu virus protein they want the immune system to recognize. (The protein is called a monoclonal antibody: “mono” because it binds to just one spot, and “clonal” because scientists can make a lot of identical copies of it.) The scientists wondered if they could use the monoclonal antibody as a model and create a way for the immune system to bind to the same spot.

Listening to the discussion, Weidenbacher remembered a chemical trick that he thought might be 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.

Start now

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,’” said Weidenbacher, who joined Kim’s lab through a ChEM-H graduate program that trains students to apply chemistry know-how to problems in biology and medicine.

“Payton is a chemist,” Kim said. “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 they describe in a paper published April 26 in the Proceedings of the National Academy of Sciences, look promising.

Lab animals that received this cleverly cloaked flu protein also showed an immune response to other strains of the flu — something that would only happen if their immune systems had learned to recognize the cone. Animals that received a normal vaccine didn’t respond well to other flu strains.

Kim and Weidenbacher said they’ve “skewed” the immune response, but they have work to do to get it to be more specific. If they succeed, they said 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 said. “With the right chemistry, you could take any monoclonal antibody off the shelf and do this.”

Kim is a member of Stanford ChEM-H, Stanford Bio-X, the Stanford Maternal & Child Health Research Institute and the Wu Tsai Neurosciences Institute at Stanford.

This work was supported by the Virginia and D. K. Ludwig Fund for Cancer Research and the Chan Zuckerberg Biohub.

Stanford’s departments of Biochemistry and of Chemistry also supported the work.