The spirochaete Treponema pallidum hasn't made it easy for us to inoculate our bodies against one of history's most notorious sexually transmitted infections.
Now a team led by researchers from University of Connecticut (UConn) has used some clever detective work to identify the proteins needed for a vaccine that could potentially help us see an end to syphilis once and for all.
An estimated six million people around the globe are infected with the syphilis microbe every year. Fortunately it's treatable with a course of antibiotics, but for some treatment comes too late.
In the US, not only are infection rates climbing, a shocking number of miscarriages and still births are caused by the disease. This makes syphilis a formidable foe, and a vaccine simply can't come soon enough.
The bacteria's role in causing syphilis has been known for well over a century. But the microbe itself has proven hard to study. T. pallidum is remarkably flimsy, falling apart at the slightest provocation.
It's also temperamental, eluding most efforts to be easily grown in a laboratory setting. The best we can do is set up an infection on a rabbit's skin or testicles, which – fortunately for the host – doesn't last very long.
Meanwhile, vaccines work by showing your immune system the complex molecules on the outside of a pathogen in the hope they'll be better prepared for an invasion. If we don't know which proteins go where, there's no way to make an effective vaccine.
Treponema pallidum's genes would almost certainly provide a hint, if we can interpret them correctly. It only has about 1,000 of them in total - but where to start?
After comparing the genomes of T. pallidum strains collected from several cities across the world, UConn Health microbiologists Justin Radolf and Melissa Caimano realised they were all remarkably similar.
This isn't at all surprising. With so few genes, each one would need to be carrying its weight. When the researchers did uncover a few mutations, all of these proved to be incredibly important for the survival of the pathogen.
"They're mutating to avoid the immune system," says Radolf.
So, these newly discovered variable genes are a big blinking arrow pointing to those all-important surface proteins.
The team translated the DNA sequences into strings of amino acids using computer simulations, and produced characteristic barrel-shaped proteins that resembled classes of surface molecules found on other bacteria.
This is one of those good news/bad news moments, though.
As you might have already guessed, these proteins would also make for a terrible vaccine. Sooner or later a strain of T. pallidum would appear with a new code, and the search would begin again.
"You want the best candidate outer membrane protein for a vaccine, the one that varies the least," says Caimano.
But once they knew what to look for, it wasn't long before the researchers had a more stable target in sight.
This isn't quite the vaccine the world needs, at least not quite yet. The team plans on testing their proteins as suitable vaccine antigens next.
But it does represent the leaping of a monumental hurdle, one that might finally end the scourge of syphilis.
This research was published in mBio.