Infectious diseases physicians encounter few clinical syndromes matching the toxic force of fulminant invasive group A streptococcal disease (iGAS) and many of us are haunted by at least one unforgettable case. The best reassurance we can offer the public, and ourselves, is that these cases are very rare. However, contemporaneous iGAS outbreaks in the northern and southern hemispheres now lay bare the fragility of this reassurance. Although a clear majority of iGAS cases respond to antibiotics and aggressive supportive care, the most severe iGAS conditions are prominent causes of death and disability due to sepsis. How this common mucosal pathogen invades the bloodstream or deep tissues of (sometimes) previously healthy individuals is but one unsettling enigma. To wit—how do we explain deadly polyclonal outbreaks of a penicillin-susceptible pathogen in the year 2023? And how, despite nearly a century of directed efforts, do we still not have a vaccine?

Streptococcus pyogenes, the classical Lancefield group A Streptococcus (GAS), is a highly coevolved, human-restricted pathogen, with a remarkably diverse clinical portfolio spanning superficial, locally invasive, and disseminated acute infections, to postinfectious syndromes with chronic disease consequences. Centuries before Theodor Billroth described streptococci “arranged in pairs, sometimes in chains” in 1874, the GAS clinical spectrum was well captured by Thomas Syndenham and others under the umbrella term “scarlatina” (scarlet fever). Fatal scarlet fever epidemics made GAS an early immunization target; in 1796, Erasmus Darwin (Charles’ grandfather) wrote, “No one could do an act more beneficial to society, or glorious to himself, than by teaching humanity how to inoculate this fatal disease [scarlet fever]; and thus to deprive it of its malignity”. Yet unrelentingly, humans still experience more than 750 million cases of GAS pharyngitis or impetigo each year, with at least 500 000 annual deaths from iGAS and rheumatic heart disease (RHD).