Why are harmless bacteria that colonise the skin not eliminated by the immune system? The human hair follicle colonist Staphylococcus epidermidis applied to mouse skin as a cream induced a strong sustained and specific antibody response in the skin resembling vaccination. The evidence suggests mice have an autonomous immune system in the skin which prevents bacterial colonists from infiltrating deeper into the body. Swabbing the skin with engineered S. epidermidis expressing tetanus or diphtheria toxin fragments protected the mice from lethal doses of these toxins. The finding that engineered S. epidermidis applied as a cream to the skin surface can immunise mice paves the way for needle-free vaccinations.
S. epidermidis applied to mouse skin induces high levels of specific antibodies
In the absence of overt infection, the normally harmless bacterium S. epidermidis colonises the hair follicles of virtually every person in the world. This and other ‘friendly’ microbes inhabit our bodies, but the immune reactions that allow S. epidermidis to exist in hair follicles without a full-blown infection are poorly understood. It is already established that immune responses occur in the skin during infection by dangerous pathogens. But do ‘friendly’ bacteria also induce immune responses? It is known S. epidermidis induces a T cell response in the absence of infection, but the significance of this adaptive immune programme is not well defined.
Unlike humans, mice are not colonised by S. epidermidis. Pathogen-free mice swabbed on the skin with a cream containing S. epidermidis triggered the activation of B cells in the skin. The antibodies to S. epidermidis, that were generated in response to B cell activation bound to S. epidermidis, were just as strong and specific as if the animal was reacting to a pathogen. Moreover, the antibodies persisted for many months. The presence of antibodies to S. epidermidis in the skin raises the question of whether they are produced to inhibit S. epidermidis from infiltrating deeper into the body, thereby preventing a full-blown infection.
Importantly, the antibodies were produced in swabbed mice that had not had any prior exposure to other microbes, and when their lymph nodes – the internal immune hubs crucial for coordinating immune reactions – had been disabled. The presence of S. epidermidis boosted the formation of specialized structures in the skin that attract B and T immune cells, which cooperate and amplify the production of S. epidermidis antibodies. These extraordinary findings are evidence that the skin has its own autonomous immune system.
‘Vaccination’ of mice and protection from lethal bacterial toxins
The immune responses and strong antibody production observed with S. epidermidis applied to mouse skin resembles a conventional vaccine. To test the idea that vaccination against known pathogens can be achieved by swabbing the skin, researchers genetically modified S. epidermidis such that part of its immune-stimulating segment was replaced with fragments of the tetanus or diphtheria toxins known to induce potent immune responses. After applying the genetically modified S. epidermidis to the skin, strong specific immune responses to the toxins were observed comparable to the responses seen when reacting to pathogens. The mice swabbed with the genetically modified S. epidermidis were protected from subsequent lethal doses of both these toxins.
High levels of antibodies to the immunising bacterial toxin fragments were found in the skin suggesting that antibodies are ready and waiting to kill the tetanus or diphtheria toxins attempting to invade the skin and penetrate deeper into the body. Together these exciting results strongly suggest that skin has its own autonomous immune system involving T and B cell activation in response to S. epidermidis. It is anticipated that the approach where the immunogen is applied as a cream to the skin surface can be adapted to develop a novel class of vaccines without the requirement for needles.
Implications and future directions
Why pathogens but not ‘friendly’ skin colonising bacteria cause full-blown infections is a challenging question that remains to be answered. But the finding that skin has its own immune system, that can act autonomously, is new and unexpected and has important implications for the design and development of needle-free vaccine creams. It will be important to optimise the genetically modified S. epidermidis and investigate whether strains of bacteria other than S. epidermidis might also be efficient vectors. Vaccination in non-human primates and humans must be demonstrated. Will significant inflammatory reactions and side effects occur in humans? Inflammation was not reported in any of the experiments in mice.
Adhesive transdermal patches placed on the skin is a well-established and efficient method for delivering precise and consistent doses of medicines directly into the circulation, thereby bypassing the gastrointestinal tract where the drug risks being degraded or diluted. Can transdermal patches be adapted for delivering vaccine creams? It remains to be seen which the best way is to deliver vaccine creams.
The vaccine experiments have so far only been done with a modified S. epidermidis expressing immunogenic fragments of bacterial toxins, but there is no reason why the approach cannot be used for some viruses such as Covid-19, as well as fungi and one-celled parasites.
One advantage of topical application of vaccines is health care professionals may not be required to administer the creams. A substantial proportion of the population has a real fear of needles and refuse to be vaccinated, risking outbreaks of serious diseases. Parents of babies and young children dread taking their children to be vaccinated with needles. With the use of vaccine creams, it is anticipated there will be a significant increase in vaccine uptake, and consequently a boost to public health. Vaccination that does not require needles could be ready for clinical trials in 2-3 years.
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