Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity

Clin Infect Dis. 2017 Oct 16;65(9):1523-1531. doi: 10.1093/cid/cix599.


Background: Group A Streptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into >220 different emm 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 single emm type. However, recent evidence has led to the hypothesis of immune cross-reactivity between emm types.

Methods: We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 major emm 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-related emm 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 with emm clusters, raising new opportunities to design multivalent vaccines with broad coverage.

Keywords: Streptococcus pyogenes; emm-cluster; immunity; skin infection; vaccine.

MeSH terms

  • Adolescent
  • Antibodies, Bacterial / blood
  • Antibodies, Bacterial / immunology
  • Antigens, Bacterial / immunology*
  • Bacterial Outer Membrane Proteins / immunology*
  • Carrier Proteins / immunology*
  • Child
  • Child, Preschool
  • Enzyme-Linked Immunosorbent Assay
  • Fiji / epidemiology
  • Humans
  • Longitudinal Studies
  • Skin Diseases, Bacterial / epidemiology*
  • Skin Diseases, Bacterial / immunology*
  • Streptococcal Infections / epidemiology*
  • Streptococcal Infections / immunology*
  • Streptococcus pyogenes / immunology*
  • Students


  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Bacterial Outer Membrane Proteins
  • Carrier Proteins
  • streptococcal M protein