Antibiotics remain the mainstay of treatment for infectious diseases, but the growing frequency of antibiotic resistance represents a major concern for healthcare worldwide. The use of antibiotics in recurrent infections raises other issues, such as their limitations for treating diverse microorganisms, deleterious effects on the microbiota of the patient and potential adverse effects. In recent years, progress has been made towards the development of novel polybacterial vaccines administered via the mucosal route. These drugs target both the innate and adaptive immune systems, at the actual point of entry of most pathogens. In addition to boosting immune responses, mucosal bacterial vaccines have an intriguing immunomodulatory activity that does not compromise their efficacy against infectious agents. We review here the current clinical evidence concerning the efficacy and safety of these mucosal vaccines for the prevention and treatment of recurrent infection. We also provide an overview completing the landscape of the potential clinical uses of these active biological agents.