_Streptococcus equi_ subspecies _equi_ (_S. equi_) is a clonal, equine host-adapted pathogen of global importance that causes a highly contagious suppurative lymphodendopathy of the head and neck, more commonly known as Strangles. The disease is highly prevalent, can be severe and spread easily by visibly infected animals or by carrier animals that show no clinical signs of disease. Antibiotic treatment is usually ineffective. However, the majority of horses develop immunity to re-infection, suggesting that vaccination should be a feasible way to prevent the infection. Live attenuated vaccine strains of _S. equi_ are available but adverse reactions have been reported and they suffer from a short duration of immunity. Thus, a safe and effective vaccine against _S. equi_ is highly desirable. In this report, Welsh mountain ponies vaccinated with a combination of seven recombinant _S. equi_ proteins, were significantly protected from experimental infection by _S. equi_, resembling the spontaneous disease. The protective antigens consisted of five surface localized proteins and two IgG endopeptidases. The results from a second vaccination trial indicate that the endopeptidases were important for good protection. The similarity of _S. equi_ to other pyogenic streptococci suggests that our findings have broader implications for the prevention of streptococcal infections
