Acute otitis media (OM) and OM with effusion are common childhood diseases. Nontypeable Haemophilus influenzae (NTHi) is a leading cause of OM and respiratory infections in older individuals. Currently, there is no vaccine for NTHi infection. Studies indicate that serum bactericidal antibodies are associated with protection from NTHi infection. We predict that serum antibodies with bactericidal activity to the lipooligosaccharide (LOS), a major surface antigen and virulence factor of NTHi, will confer immunity to this pathogen. LOS of NTHi is too toxic to administer to humans and detoxified LOS (dLOS) is not immunogenic, probably due to its low molecular weight. In order to improve its immunogenicity, the dLOS was convalently bound to tetanus toxoid (TT) using a clinically relevant scheme of vaccination, elicited bactericidal antibodies to LOS in an in vivo model. This investigational vaccine also showed protection against infection in a chinchilla otitis media model. We propose to evaluate the safety and immunogenicity of this dLOS-TT vaccine in adults (Phase I). Our goal is to develop a vaccine for OM and respiratory infections caused by NTHi.