Compositions and methods for making and using therapeutic formulations of multivalent hybrid polypeptides comprising immunogenic peptides of M proteins from various different serotypes of group A streptococci and antibodies thereto are provided. Also provided are nucleic acids encoding such hybrid polypeptides. The hybrid polypeptide formulations may be used, for example, in methods for treating or preventing a microbial infection and eliciting a protective immune response having broadly protective opsonic antibodies in the absence of tissue cross-reactive antibodies.