Asthma is an allergic airway disease (AAD) characterized by eosinophilic inflammation, mucus hyper-secretion, and airway hyper responsiveness, and it is caused by dysregulated immune responses. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae, including its components as well as a live attenuated mutant, and pneumococcal infection induce Tregs and can thus potentially be harnessed therapeutically for asthma treatment. Previously, a pep27 deletion mutant (Delta pep27) demonstrated a significantly attenuated virulence in a sepsis model, and Delta pep27 immunization induced serotype-nonspecific protection against S. pneumoniae infection, as well as influenza virus, possibly via an immune tolerance mechanism. Here, the potential of Delta pep27 immunization for asthma protection was studied. Mice were immunized intranasally with Delta pep27 before or after ovalbumin sensitization and subsequent challenge. Delta pep27 immunization suppressed hallmark features of AAD, including antigen-specific type 2 helper T cell cytokine and antibody responses, peripheral and pulmonary eosinophil accumulation, and goblet cell hyperplasia. Thus, a Delta pep27 vaccine may be highly feasible as a preventive or therapeutic agent for asthma. (C) 2019 Published by Elsevier Inc.