Group A streptococcus (GAS) species are responsible for a broad spectrum of human diseases, ranging from superficial to invasive infections, and are associated with autoimmune disorders. There is no commercial vaccine against GAS. The clinical manifestations of GAS infection may be attributable to the large repertoire of virulence factors used selectively in different types of GAS disease. Here, we selected five molecules, highly conserved among GAS serotypes, and involved in different pathogenic mechanisms, as a multicomponent vaccine, 5CP. Intranasal (i.n.) immunization with 5CP protected mice against both mucosal and systemic GAS infection across serotypes; the protection lasted at least 6 months. Immunization of mice with 5CP constrained skin lesion development and accelerated lesion recovery. Flow cytometry and enzyme-linked immunosorbent assay analyses revealed that 5CP induced Th17 and antibody responses locally and systemically; however, the Th17 response induced by 5CP resolved more quickly than that to GAS when challenge bacteria were cleared, suggesting that 5CP is less likely to cause autoimmune responses. These findings support that immunization through the i.n. route targeting multiple nonredundant virulence factors can induce immunity against different types of GAS disease and represents an alternative strategy for GAS vaccine development, with favorable efficacy, coverage, duration, and safety. IMPORTANCE GAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with autoimmunity. In this study, five conserved virulence factors that are involved in GAS pathogenesis were used as a combined vaccine. Intranasal immunization with this vaccine induced humoral and cellular immune responses across GAS serotypes and protected against mucosal, systemic, and skin infections. The significance of this work is to demonstrate that the efficacy of GAS vaccines can be achieved by including multiple nonredundant critical virulence factors and inducing local and systemic immunity. The strategy also provides valuable insights for vaccine development against other pathogens. © 2019 Bi et al.