The protective immunogenicity of a hybrid peptide containing tandem copies of types 5, 6, and 24 M protein epitopes was investigated. An NH2-terminal peptide of type 24 M protein was chemically synthesized and then extended to include NH2-terminal peptides of types 6 and 5 M proteins yielding a 34-residue hybrid peptide containing a cysteine residue at its COOH-terminus. When conjugated via the cysteine residue to keyhole limpet hemocyanin (KLH), emulsified in CFA, and injected into rabbits, the synthetic hybrid evoked opsonic antibodies against types 5, 6, and 24 streptococci without stimulating tissue crossreactive immunity. The trivalent hybrid also was capable of priming T lymphocytes in vivo that responded to each of the native serotypes of M protein as well as to the synthetic hybrid peptide in vitro. The primed T cells failed to respond to the individual component peptides contained in the hybrid peptide, suggesting that the hybrid peptide confers conformations resembling the presentations of each of the subpeptides in the respective serotypes of M protein. The brisk immune responses to the type 6 peptide contained in the middle of the tandem hybrid indicates that with judicious placement between proline residues, potentially hidden peptides are readily accessible to the immune system. These results suggest that synthetic tandem peptides can be tailored in a fashion in which each of the component sets of protective epitopes can be made optimally immunoaccessible and immunogenic.