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Otitis media (OM), middle ear infection, represents a significant burden on children, their families, and the healthcare system. OM is the major cause of hearing loss in children and if left untreated in children who suffer chronic and recurrent forms of OM, this disease can have serious life-long sequelae. Chronic and recurrent OM are recalcitrant to current therapies due to the formation of biofilms and intracellular biofilm pods by otopathogens on the middle ear mucosa and within the middle ear fluid. These pathogens actively hijack the children’s own immune response and persist in the neutrophil extracellular trap-derived DNA in the middle ear. Children who suffer from chronic and recurrent forms of OM have also been shown to have reduced antibody levels to important anti-biofilm protein antigens. These both represent potential targets for treatment or prevention and are under investigation.