Bioengineer Rohan Ingrole needed to floss a mouse’s teeth.
The intent wasn’t to help mice get a clean bill of health at the dentist. Each bit of store-bought floss was coated with dead influenza viruses, or lab-made bits and pieces of them. Ingrole, of Texas Tech University in Lubbock, wanted to vaccinate the animals, giving them protection against flu through their gums.
Vaccines that target the moist tissues that line cavities like the mouth or nose aim to build up immune defenses in the parts of the body that pathogens tend to invade, says Harvinder Gill, a bioengineer at North Carolina State University in Raleigh. Influenza virus, for instance, typically enters the body through the nose before making its way toward the lungs.
Protecting mucous membranes isn’t always a simple task. Because these mucosal tissues come into direct contact with the air around us, as well as surfaces like fingers, their cells are tightly packed to help keep pathogens out. This can also prevent vaccines targeting the places like the mouth from permeating the body and prompting an immune response.
Researchers have previously designed vaccines that target the mouth’s leakier tissues — where cells aren’t quite as close together — in the forms of cheek patches or liquid drops under the tongue. Then, while reading a paper on dental structure, Gill learned about the junctional epithelium, a leaky collection of cells at the base of a small pocket where gums attach to teeth.
That pocket is a tough target, however, because it sits below the gumline. “We needed something more precise [than a drop of liquid],” Gill says. “And then we thought ‘Oh, hey, we already have floss…. Why don’t we just use [floss] to also deposit the vaccines into this location?”
But no one had flossed a mouse before, Ingrole says, and the peculiar task posed some challenges. What was the best way to simultaneously open a mouse’s mouth and get the floss in the right spot? Was there a technique that would help protect the mouse’s gums from damage?
Initial tests flopped because floss kept slipping off the bottom incisors of the mice. As Ingrole applied gentle force to move the floss back and forth, he inadvertently tugged the animals’ jaws down and the floss slipped out. “One day, after a failed attempt, I was just going around [the lab] and I saw this key chain lying on the table,” says Ingrole. “It made me wonder, can I use the ring of this key chain to provide support to the mouse jaw? It turned out to be a game changer.”
Even with a support tool, it’s a two-person job to floss a mouse. One person gently holds the mouse — lulled into deep sleep with an inhaled anesthetic — in an upright position by the scruff of its neck. That person also pops the mouse’s head through key ring, allowing the animal’s lower jaw to hang open and rest against the ring’s edge. The second person then plays dental hygienist, swooping in with an influenza-coated piece of floss.
And with each swipe back and forth, the floss delivers a vaccine through the gum’s junctional epithelium, helping the mouse’s immune system learn to fight off the virus, Ingrole and colleagues report July 22 in Nature Biomedical Engineering. No needle prick necessary.
Ingrole, Gill and colleagues found that floss coated with four different types of influenza vaccines sparked immune defenses in mice. Vaccinated mice were more likely to survive flu infections than unvaccinated mice, even when they had access to food and water immediately after flossing.
What’s more, protection against the disease from one of the four vaccine types was similar to that from a vaccine given through the nose. But noses have a direct connection to the brain, Gill says. Safety tests of nasal vaccines need to show that there’s not high risk of neurological side effects like Bell’s palsy, a sudden weakness in facial muscles that causes one side of the face to droop. Material introduced to the gums, on the other hand, lowers that risk because the gum-targeting vaccines aren’t likely to make it to the brain.
“It’s very clever, I like the strategy,” says Stephanie Langel, a viral immunologist at Case Western Reserve University in Cleveland who was not involved in the work. But analyses of the kinds of antibodies that the mice developed suggest that while the intranasal and floss vaccines both trigger immune defenses in the blood, the intranasal vaccine may be better than the floss vaccine at protecting mucosal linings, such as those in the nose.
That could mean that although both vaccination methods are good at preventing severe disease and death in mice, intranasal vaccines might be better blocking transmission, Langel says. Adding the right vaccine-boosting compound called an adjuvant to the floss could help the body make more antibodies in places like the saliva or nose to protect against pathogen invasion.
The technology still needs some work before it makes it into people. In an early test looking at just the method, a one-handed floss pick coated in a fluorescent dye deposited roughly 60 percent of the dose into the gum pockets of 27 people, the team found. Now, Gill says, the goal is to develop new tools that aim to make it easier to floss and ensure people are getting a consistent dose.
If floss vaccines prove effective, it could provide a painless, needle-free way to vaccinate, Gill says. And if people are comfortable with flossing their teeth with a vaccine on their own, “it has the potential to be self-administrable.”
Self-administration could be huge for vaccination during a pandemic, Ingrole says. During the COVID-19 pandemic, scores of health care workers were diverted toward vaccination efforts. “Imagine if you had this vaccine that could just get delivered at your doorstep,” Ingrole says. “You no longer have to go stand in line for hours.”
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