This proposal meets the requirements of two major Challenge Areas within Clinical Research, "Prevention of otitis media" (04-DC101), and "Develop novel methods and address key questions in mucosal immunology" (04-AI-101). Otitis media caused by Streptococcus pneumoniae represents a significant medical burden in children. While the advent of the pneumococcal polyvalent conjugate vaccine Prevnar has decreased the burden of pneumococcal disease overall, the suboptimal mucosal immune response has proved problematic in eliciting effective protection. Even with vaccination, acute otitis media is the leading cause of pediatric physician visits and is responsible for a majority of the antibiotics prescribed to young children. This underscores the importance of development of new vaccination strategies and a greater understanding of host mucosal immunity. To this end, intranasal vaccination has recently gained considerable attention as an alternative strategy due to potential effectiveness at inducing a robust mucosal immune response. We propose to evaluate the immune responses and protective efficacy of two novel live, attenuated pneumococcal vaccines against otitis media using newly described, robust animal models. These data are expected to expand our knowledge of mucosal immunity to otitis media and provide pre-clinical data useful for advancing novel vaccines to the clinic. PUBLIC HEALTH RELEVANCE: Otitis media caused by Streptococcus pneumoniae represents a significant medical burden in children. While the advent of the pneumococcal polyvalent conjugate vaccine Prevnar has decreased the burden of pneumococcal disease overall, the suboptimal mucosal immune response has proved problematic in eliciting effective protection. Even with vaccination, acute otitis media is the leading cause of pediatric physician visits and is responsible for a majority of the antibiotics prescribed to young children. This underscores the importance of development of new vaccination strategies and a greater understanding of host mucosal immunity. To this end, intranasal vaccination has recently gained considerable attention as an alternative strategy due to potential effectiveness at inducing a robust mucosal immune response. We propose to evaluate the immune responses and protective efficacy of two novel live, attenuated pneumococcal vaccines against otitis media using newly described, robust animal models. These data are expected to expand our knowledge of mucosal immunity to otitis media and provide pre-clinical data useful for advancing novel vaccines to the clinic.