Imagine a world where vaccines don’t require needles or syringes but are instead applied as a simple cream on your skin. Painless, affordable, and free from side effects like swelling or soreness, this vision eliminates long lines at clinics while maintaining effectiveness.

This futuristic idea may soon become a reality, thanks to researchers at Stanford University who have transformed a common skin-dwelling bacterium into a potential living vaccine.

“We all hate needles — everybody does,” said Michael Fischbach, PhD, the Liu (Liao) Family Professor and a professor of bioengineering. “I haven’t found a single person who doesn’t like the idea that it’s possible to replace a shot with a cream.”

The skin, however, is a notoriously inhospitable environment. “It’s incredibly dry, way too salty for most single-celled creatures and there’s not much to eat. I can’t imagine anything would want to live there,” Fischbach said.

Yet, resilient microbes thrive on human skin, including Staphylococcus epidermidis, a harmless bacterium present on nearly everyone. “These bugs reside on every hair follicle of virtually every person on the planet,” Fischbach noted.

Immunologists have largely overlooked these skin microbes, assuming they didn’t play a significant role in human health. However recent research from Fischbach’s team has revealed an unexpectedly strong immune response to S. epidermidis.

In a study published in Nature on Dec. 11, Fischbach and his colleagues focused on the immune system’s production of antibodies—proteins that bind to invaders and block them from spreading. Each antibody targets a specific biochemical feature of a pathogen.

To test if a mouse’s immune system could recognize S. epidermidis, lead author and postdoctoral scholar Djenet Bousbaine, PhD, conducted a straightforward experiment. She swabbed mice with S. epidermidis and monitored their antibody levels over six weeks.

The mice’s antibody response to S. epidermidis shocked Fischbach. “Those antibodies’ levels increased slowly, then some more — and then even more.” By six weeks, the concentration surpassed what’s typically observed in regular vaccinations.

“It’s as if the mice had been vaccinated,” he said. “The same thing appears to be occurring naturally in humans. We got blood from human donors and found that their circulating levels of antibodies directed at S. epidermidis were as high as anything we get routinely vaccinated against.”

This immune reaction seems to serve as a preemptive defense against potential breaches. Fischbach explained, “The best fence is those antibodies. They’re the immune system’s way of protecting us from the inevitable cuts, scrapes, nicks, and scratches we accumulate in our daily existence.”

Inspired by this natural immunity, Fischbach’s team engineered S. epidermidis to act as a vaccine. They identified a key protein, Aap, that triggers a robust antibody response. This protein protrudes from the bacterial surface, allowing immune cells to detect it.

In collaboration with Yasmine Belkaid, PhD, director of the Pasteur Institute, they confirmed the involvement of sentinel immune cells, called Langerhans cells, which alert the immune system to S. epidermidis’s presence.

The team then modified Aap to display fragments of harmful pathogens, such as tetanus toxin. In experiments, mice swabbed with this engineered bacterium developed strong antibodies against tetanus. When exposed to lethal doses of tetanus toxin, the treated mice remained symptom-free, while untreated mice succumbed.

A similar approach worked for diphtheria toxin, and the scientists found they could achieve life-saving antibody responses with just two or three applications. Even young mice colonized by S. epidermidis responded effectively, suggesting that widespread skin colonization in humans won’t interfere with its potential as a vaccine platform.

In another experiment, the researchers produced the tetanus-toxin fragment separately and attached it to Aap using a chemical process. Surprisingly, this method also generated a strong immune response, protecting mice from six times the lethal dose of tetanus toxin.

“We know it works in mice,” Fischbach said. “Next, we need to show it works in monkeys. That’s what we’re going to do.” If successful, clinical trials could begin within two to three years.

“We think this will work for viruses, bacteria, fungi and one-celled parasites,” he added. “Most vaccines have ingredients that stimulate an inflammatory response and make you feel a little sick. These bugs don’t do that. We expect that you wouldn’t experience any inflammation at all.”