A major obstacle to the development of broadly protective M protein-based group A streptococcal (GAS) vaccines is the variability within the N-terminal epitopes that evoke potent bactericidal antibodies. The concept of M type-specific protective immune responses has recently been challenged based on the observation that multivalent M protein vaccines elicited cross-reactive bactericidal antibodies against a number of non-vaccine M types of GAS. Additionally， a new "cluster-based" typing system of 175M proteins identified a limited number of clusters containing closely related M proteins. In the current study， we used the emm cluster typing system， in combination with computational structure-based peptide modeling， as a novel approach to the design of potentially broadly protective M protein-based vaccines.