Researchers at Stanford University may be on the cusp of overcoming the fear of needles with a topical vaccine applied directly to the skin, after recent successful tests.
Eliminating not just fear but also the sharp pain and lasting soreness associated with injections is a huge milestone in the vaccine research field. According to the team behind the research, the new method would also significantly reduce the cost of vaccine production.
What’s on the Skin?
“We all hate needles — everybody does,” said lead author Michael Fischbach. “I haven’t found a single person who doesn’t like the idea that it’s possible to replace a shot with a cream.”
Fischbach points out that human skin is too dry, salty, and barren for most single-celled organisms to thrive. Yet some, such as Staphylococcus epidermidis, still manage to make a go of it. “These bugs reside on every hair follicle of virtually every person on the planet,” Fischbach said. Due to their lack of harmful effects, immunologists have long ignored skin-colonizing bacteria. However, Fischbach’s team discovered that the immune system was more aggressive against S. epidermidis than previously thought.
Fishbach’s team looked at antibody production, the centerpiece of an immune response. Antibodies are proteins designed to latch onto microbes, impeding their ability to attach to cells or travel through the bloodstream. To be effective, the antibodies must be heavily targeted and compatible with only a specific species or strain of invader.
Existing vaccines introduce inactive virus samples into the bloodstream to generate this immune response, building resistance without harming the subject. The team wondered if they could develop a similar response through an immune reaction to a foreign entity on the skin instead of in the bloodstream.
Of Mice and Germs
The team’s experiment examined if an animal that did not usually come into contact with S. epidermidis would experience an antibody response. Fischbach’s team swabbed a normal mouse subject with a solution containing S. epidermidis. Over the next six weeks, they drew blood to look for any sign of antibodies. The researchers were amazed to find the mice didn’t just make some antibodies but continually produced them in greater and greater quantities over the six weeks. The antibody response was even more potent than a typical injected vaccination. The response was strong and specific.
“The same thing appears to be occurring naturally in humans,” Fischbach said. “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. Our ferocious immune response to these commensal bacteria loitering on the far side of that all-important anti-microbial barrier we call our skin seems to have no purpose.”
The skin needs support from the immune system to be effective. Fishbach calls antibodies “the best fence” against invaders. Topical S. epidermidis differs from pathogens in the bloodstream in that it generates a preemptive response. This response is to prepare for any tear in the skin that would let in S. epidermidis or any other contagion.
Devising a Topical Vaccine
Fischbach and his team moved on to transforming S. epidermidis into a topical vaccine. The researchers identified Aap, a protein in the S. epidermidis, as responsible for setting off the immune response. Aap is a large, treelike structure jutting from the bacteria’s cell wall. The protrusion exposes itself to sentinel cells patrolling the body, allowing those sentinels to bring a sample back to other immune cells for devising a new antibody. These antibodies include blood-borne IgG antibodies and IgA antibodies that reside in the mucus.
“We’re eliciting IgA in mice’s nostrils,” Fischbach said. “Respiratory pathogens responsible for the common cold, flu, and COVID-19 tend to get inside our bodies through our nostrils. Normal vaccines can’t prevent this. They go to work only once the pathogen gets into the blood. It would be much better to stop it from getting in the first place.”
After identifying Aap as their focus point, the team manipulated it through genetic engineering. They introduced the genetic code for the treelike Aap appendage from highly toxic tetanus into an S. epidermidis sample, resulting in a harmless protein modeled after a hazardous substance. Would this enable the mice to develop an efficient immune response to real tetanus?
Successful Vaccine Testing
Fischbach’s team repeated their earlier experiment using the unaltered S. epidermidis but added a second group swabbed with the bioengineered tetanus-coded S. epidermidis applied, samples of which were applied over six weeks. The mice swabbed with the engineered tetanus toxin developed high antibody levels for that targeted bacteria. At the end of the experiment, the team injected mice from both groups with lethal amounts of tetanus. Only the tetanus-vaccinated mice survived.
Fischbach’s team then launched another round focused on diphtheria instead of tetanus, again resulting in successfully generating the targeted antibodies. With as little as two or three applications of the topical vaccine, the mice developed a life-saving antibody response.
Further changes in the team’s vaccine production methodology proved to increase effectiveness. The team created a fragment of tetanus in a bioreactor and chemically attached it to Aap so that it dotted the S. epidermidis surface. The team initially thought this would be a less effective method as the bacteria divided and the toxin diluted, yet the reverse was true. This alternate construction proved strong enough to cause mice to develop a defense against six times the lethal tetanus limit.
“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.” Should the next round of trials prove successful, Fischbach aims to begin clinical trials in the next two or three years.
“We think this will work for viruses, bacteria, fungi, and one-celled parasites,” Fischbach said. “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.”
The paper “Discovery and Engineering of the Antibody Response to a Prominent Skin Commensal” appeared on December 11, 2024 in the Nature.
Ryan Whalen covers science and technology for The Debrief. He holds a BA in History and a Master of Library and Information Science with a certificate in Data Science. He can be contacted at ryan@thedebrief.org, and follow him on Twitter @mdntwvlf.