Subclinical exposure to Streptococcus pyogenes drives the development of long-lived homologous immunity

Immunity to Streptococcus pyogenes infection appears to develop 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 model of pharyngeal S. pyogenes infection, we investigate whether symptomatic disease is required for induction of protective immune responses. We show that challenge with M75 S. pyogenes elicits M75-specific serum antibodies and memory B cells in both symptomatic and asymptomatic participants, with responses persisting for at least 6 months. M75-specific IgG from asymptomatic participants exhibit altered Fc glycosylation traits post-challenge, associated with enhanced binding to M75 S. pyogenes and protection when transferred into a murine model of respiratory tract infection. These findings demonstrate that asymptomatic exposure to M75 S. pyogenes contributes to the development of streptococcal immunity that emerges by adulthood.