Supplemental Digital Content is available in the text.

Background Acute rheumatic fever triggered by pharyngeal and skin Group A Streptococcal infections (GAS) disproportionately affects indigenous Māori schoolchildren. This stepped-wedged study in Whakatāne, New Zealand compared whole-school-cluster allocated Streptococcus salivarius probiotic effectiveness on GAS pharyngeal prevalence (carriage and pharyngitis) following antibiotics, compared to antibiotics-alone for GAS positive children. Each of two clusters followed a sequence with a different Streptococcus salivarius exposure period over ten winter weeks in 2015. Method Both clusters had high Māori schoolchildren rolls (99% and 81%) at high risk of acute rheumatic fever. The parents/guardians of 60% of eligible schoolchildren consented. Schoolchildren had pharyngeal swabs and sore-throat questionnaires administered by external student-nurses, informing GAS prevalence (primary outcome) and pharyngitis (secondary outcome). GAS positive schoolchildren’s usual care was 10 days once-daily oral amoxicillin. One whole cluster then commenced S. salivarius daily for 30 days. The other initial control cluster had S. salivarius six weeks later, after both clusters were re-swabbed, and GAS positive schoolchildren treated. Student-nurses and laboratory scientists assessing outcomes were blinded to prior S. salivarius exposure. S. salivarius and control period findings were compared. Results Per-protocol efficacy, informed by study swabs, showed Odds of pharyngeal GAS prevalence reduced substantially, but not significantly 0.6 (95% CI 0.29–1.21) for added S. salivarius, (n 235) compared to antibiotics-alone (n 106). Subgroup analysis of 197 originally GAS negative schoolchildren’s swabs found significantly reduced Odds of GAS prevalence with S. salivarius 0.42 (95% CI 0.19–0.94). compared to controls (n 80). Intention to treat analysis utilizing study swabs showed S. salivarius effectively reduced GAS prevalence from 15.5–7.4%, Odds 0.52 (95% CI 0.28–0.97) (n 309) compared to antibiotics-alone (n 157). Intention to treat sub-analysis utilizing all swabs for 260 GAS negative schoolchildren, demonstrated S. salivarius effectiveness Odds 0.52 (95% CI 0.27-1.00) compared to 131 controls. GAS pharyngitis declined from 10/128 to 2/128 over three months Odds 0.19 (95%CI 0.04–0.87) following antibiotics and S. salivarius. Conclusion Whole-cluster S. salivarius probiotic, given after antibiotic treatment of schoolchildren with pharyngeal GAS, significantly reduces GAS pharyngeal prevalence, carriage, and pharyngitis, by limiting GAS negative schoolchildren acquiring Group A Streptococcus. Trial registration ACTRN12615000402549