Group A Strep vaccine: designing a toxin to be non-toxic

In mBio this week, a new study offers hope for a vaccine against group A Streptococcus (GAS). GAS is familiar to most of us as the cause of Strep throat, but it’s more than that. It’s also the cause of some

Predicted Structure of streptolysin O

serious and invasive infections, including septic arthritis, impetigo, and necrotizing fasciitis, so a vaccine for group A Strep (GAS) could not only keep Strep-throat-prone kids in school, it could potentially spare a great deal of human suffering.

The study in mBio follows up on earlier work that found the GAS protein streptolysin O was an effective antigen to use in an experimental vaccine in mice. However, streptolysin O is also a really potent toxin, so a vaccine that uses unadulterated streptolysin O could do more harm than good.

To get around this little detail, the group used protein structural predictions (see image) to design a detoxified version of streptolysin O. After identifying the components of streptolysin that might be responsible for its toxic activity – the regions that bind and form pores in human cells – they created a double mutant version of the protein that not only lacks toxicity, it is highly protective in immunizing mice against GAS. So it’s different enough to be safe, but still similar enough to the wild type streptolysin O to train the mouse immune system to attack GAS.

This particular study addressed GAS, but the results can be applied to vaccine development in any number of pathogens, the authors write. It’s also a good approach for studying virulence: researchers can use genetically constructed detoxified virulence factors to dissect the contributions of various functional and structural properties to the ability of a pathogen to establish and maintain infections.