Immune Cross-Opsonization Withinemm Clusters Following Group AStreptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity

Abstract

Abstract Background Group AStreptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into >220 differentemm types, is immunogenic and elicits protective antibodies. A major obstacle for vaccine development has been the traditional understanding that immunity following infection is restricted to a singleemm type. However, recent evidence has led to the hypothesis of immune cross-reactivity betweenemm types. Methods We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 majoremm clusters (E4, E6, and D4). Pre- and postinfection sera were assayed by enzyme-linked immunosorbent assay with N-terminal M peptides and bactericidal assays using the infecting-type strain,emm cluster–related strains, and nonrelated strains. Results Twenty of the 53 paired sera demonstrated a ≥4-fold increase in antibody titer against the infecting type. When tested against all cluster-related M peptides, we found that 9 of 17 (53%) paired sera had a ≥4-fold increase in antibody titer to cluster-related strains as well. When grouped by cluster, the mean change to cluster-relatedemm types in E4 and E6 was >4-fold (5.9-fold and 19.5-fold, respectively) but for D4 was 3.8-fold. The 17 paired sera were tested in bactericidal assays against selected cluster-related and nonrelated strains. While the responses were highly variable, numerous instances of cross-reactive killing were observed. Conclusions These data demonstrate that M type–specific and cross-reactive immune responses occur following skin infection. The cross-reactive immune responses frequently align withemm clusters, raising new opportunities to design multivalent vaccines with broad coverage.