Scientists transform ubiquitous skin bacterium into a topical vaccine

Good news! Amazing stuff! 

"Imagine a world in which a vaccine is a cream you rub onto your skin instead of a needle a health care worker pushes into one of your muscles. Even better, it’s entirely pain-free and not followed by fever, swelling, redness, or a sore arm. No standing in a long line to get it. Plus, it’s cheap. ...

The skin is a terrible place to live ... “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.”

But a few hardy microbes call it home. Among them is Staphylococcus epidermidis, a generally harmless skin-colonizing bacterial species. ...

The initial experiments ... were simple: Dip a cotton swab into a vial containing S. epidermidis. Rub the swab gently on the head of a normal mouse – no need to shave, rinse, or wash its fur – and put the mouse back in its cage. Draw blood at defined time points over the next six weeks, asking: Has this mouse’s immune system produced any antibodies that bind to S. epidermidis?

The mice’s antibody response to S. epidermidis was “a shocker,” ... “Those antibodies’ levels increased slowly, then some more – and then even more.” At six weeks, they’d reached a higher concentration than one would expect from a regular vaccination – and they stayed at those levels. ...

Step by step, ... team turned S. epidermidis into a living, plug-and-play vaccine that can be applied topically. They learned that the part of S. epidermidis most responsible for tripping off a powerful immune response is a protein called Aap. This great, treelike structure, five times the size of an average protein, protrudes from the bacterial cell wall. They think it might expose some of its outermost chunks to sentinel cells of the immune system that periodically crawl through the skin, sample hair follicles, snatch snippets of whatever is flapping in Aap’s “foliage,” and spirit them back inside to show to other immune cells responsible for cooking up an appropriate antibody response aiming at that item.  ...

Aap induces a jump in not only blood-borne antibodies known to immunologists as IgG, but also other antibodies, called IgA, that home in on the mucosal linings of our nostrils and lungs. ...

... clever engineering ... substituted the gene encoding a piece of tetanus toxin for the gene fragment encoding a component that normally gets displayed in this giant treelike protein’s foliage. Now it’s this fragment – a harmless chunk of a highly toxic bacterial protein ...

The investigators repeated the dip-then-swab experiment, this time using either unaltered S. epidermidis or bioengineered S. epidermidis encoding the tetanus toxin fragment. They administered several applications over six weeks. The mice swabbed with bioengineered S. epidermidis, but not the others, developed extremely high levels of antibodies targeting tetanus toxin. When the researchers then injected the mice with lethal doses of tetanus toxin, mice given natural S. epidermidis all succumbed; the mice that received the modified version remained symptom-free ..."

From the abstract:

"The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8+ T cell response pre-emptively, in the absence of an infection. However, the scope and purpose of this anti-commensal immune program are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable, and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labeled commensal elicits high antibody titers under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a novel form of topical vaccination."

Skin bacterium becomes a topical vaccine | Stanford Report "Findings in mice could translate into a radical, needle-free vaccination approach that would also eliminate reactions including fever, swelling and pain."

Discovery and engineering of the antibody response to a prominent skin commensal (no public access)