Sub-clinical exposure to Streptococcus pyogenes drives the development of immunity

Summary Age-related decline in Streptococcus pyogenes infection rates suggests that immunity develops progressively through repeated exposure during early life. However, the intensity or duration of exposure required is unknown, as to why some individuals appear to develop immunity, despite having few or no previously detected infections. Here, drawing on samples from a human challenge model of pharyngeal S. pyogenes infection, we investigate whether symptomatic disease is required for induction of humoral and cellular immunity. Challenge with M75 S. pyogenes induced M75-specific serum IgG and IgA antibodies and memory B cell in both symptomatic and asymptomatic participants, with responses persisting for at least 6 months. Purified IgG from asymptomatic participants exhibited significantly enhanced binding to M75 S. pyogenes and were bactericidal when transferred into a murine model of pharyngeal infection. M75-specific IgG from these participants had an altered Fc glycosylation signature, indicative of enhanced effector function and ability to limit inflammation. However, S. pyogenes challenge had no impact on cellular or humoral immune responses to a conserved cryptic epitope, p*17. These findings show that asymptomatic (or sub-clinical) exposure to M75 S. pyogenes generates functional immune responses and contributes to the streptococcal immunity that emerges by adulthood.