Background
Pharyngitis due to group A Streptococcus (GAS) represents a major cause of outpatient visits and antibiotic use in the United States. A leading vaccine candidate targets 30 of the >200 emm types of GAS. We aimed to assess natural protection conferred by GAS against respiratory symptoms.

Methods
In a 5-year study among school-aged children in Pittsburgh, Pennsylvania, pharyngeal cultures were obtained from children at 2-week intervals, and active surveillance was conducted for respiratory illnesses. We assessed protection via the relative odds of previous detection of homologous strains (defined by field-inversion gel electrophoresis banding pattern), emm types, and emm clusters at visits where GAS was detected with symptoms, versus visits where GAS was detected without symptoms. We used a cluster bootstrap of children to adjust estimates for repeated sampling.

Results
At visits where previously-detected GAS emm types were identified, we estimated 81.8% (95%CI: 67.1-91.7%) protection against typical pharyngitis symptoms among children re-acquiring the same strain, and 94.5% (83.5-98.6%) protection among children acquiring a distinct strain. We estimated 77.1% (33.7-96.3%) protection against typical symptoms among children acquiring partially-heterologous emm types belonging to a previously-detected emm cluster. Protection was evident after both symptomatic and asymptomatic detections of GAS. We did not identify strong evidence of protection against atypical respiratory symptoms.

Conclusions
Within a 5-year longitudinal study, previous detection of GAS emm types was associated with protection against typical symptoms when homologous strains were subsequently detected. Naturally-acquired protection against partially-heterologous types suggests emm type-based vaccines may have broader strain coverage than what has been previously assumed.