The overall goal of this project is to develop a safe and effective vaccine that would prevent group A streptococcal infection. Previous studies have shown that M proteins, the major protective antigens of these organisms, contain both protective as well as potentially harmful tissue- crossreactive epitopes. The previous funding period focused on the identification of protective epitopes of "rheumatogenic" M proteins and their separation from the potentially harmful autoimmune epitopes. The Specific Aims for this renewal proposal are: 1) To determine the primary structures of defined regions of selected serotypes of M proteins that contain protective as opposed to tissue-crossreactive epitopes. 2) To construct recombinant, multivalent M protein vaccines and to determine protein conformations that evoke optimal protective immune responses in laboratory animals. 3) To determine indirectly the potential protective efficacy of multivalent M protein vaccines. 4) To develop strategies of mucosal delivery of multivalent M proteins that evoke local and systemic protective immune response. 5) To determine the minimal primary structures of selected M proteins that are capable of activating bactericidal T lymphocytes in vitro.