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The C-Terminal Fragment of the Internal 110-Kilodalton Passenger Domain of the Hap Protein of Nontypeable Haemophilus influenzae Is a Potential Vaccine Candidate

Dai-Fang Liu,^1* Kathryn W. Mason,¹ Maria Mastri,^1, Mehran Pazirandeh,^1, David Cutter,^2, Doran L. Fink,² Joseph W. St. Geme III,² Duzhang Zhu,¹ and Bruce A. Green¹

Wyeth Vaccines Research, Pearl River, New York 10965,¹ Edward Mallinckrodt Department of Pediatrics and Department of Molecular Microbiology, Washington University School of Medicine, and Division of Infectious Diseases, St. Louis Children's Hospital, St. Louis, Missouri²

Received 27 July 2004/ Returned for modification 24 August 2004/ Accepted 2 September 2004

Nontypeable Haemophilus influenzae is a major causative agent of bacterial otitis media in children. H. influenzae Hap autotransporter protein is an adhesin composed of an outer membrane Hapß region and a moiety of an extracellular internal 110-kDa passenger domain called Hap_S. The Hap_S moiety promotes adherence to human epithelial cells and extracellular matrix proteins, and it also mediates bacterial aggregation and microcolony formation. A recent work (D. L. Fink, A. Z. Buscher, B. A. Green, P. Fernsten, and J. W. St. Geme, Cell. Microbiol. 5:175-186, 2003) demonstrated that Hap_S adhesive activity resides within the C-terminal 311 amino acids (the cell binding domain) of the protein. In this study, we immunized mice subcutaneously with recombinant proteins corresponding to the C-terminal region of Hap_S from H. influenzae strains N187, P860295, and TN106 and examined the resulting immune response. Antisera against the recombinant proteins from all three strains not only recognized native Hap_S purified from strain P860295 but also inhibited H. influenzae Hap-mediated adherence to Chang epithelial cells. Furthermore, when mice immunized intranasally with recombinant protein plus mutant cholera toxin CT-E29H were challenged with strain TN106, they were protected against nasopharyngeal colonization. These observations demonstrate that the C-terminal region of Hap_S is capable of eliciting cross-reacting antibodies that reduce nasopharyngeal colonization, suggesting utility as a vaccine antigen for the prevention of nontypeable H. influenzae diseases.

Editor: J. N. Weiser

Present address: Vaccinex, Rochester, N.Y.

Present address: Agave Biosystem, Ithaca, N.Y.

Present address: Sigma Chemicals, St. Louis, Mo.

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