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Nontypeable Haemophilus influenzae is a significant pathogen in children, causing otitis media, sinusitis, conjunctivitis, pneumonia, and occasionally invasive infections. H. influenzae type b conjugate vaccines have no effect on infections caused by nontypeable strains because nontypeable strains are nonencapsulated. Approximately, one-third of episodes of otitis media are caused by nontypeable H. influenzae and the bacterium is the most common cause of recurrent otitis media. Recent progress in elucidating molecular mechanisms of pathogenesis, understanding the role of biofilms in otitis media and an increasing understanding of immune responses have potential for development of novel strategies to improve prevention and treatment of otitis media caused by nontypeable H. influenzae. Feasibility of vaccination for prevention of otitis media due to nontypeable H. influenzae was recently demonstrated in a clinical trial with a vaccine that included the surface virulence factor, protein D.