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Infection and Immunity, December 2004, p. 6961-6968, Vol. 72, No. 12
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.12.6961-6968.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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,{dagger} Mehran Pazirandeh,1,{ddagger} 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 HapS. The HapS 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 HapS 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 HapS 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 HapS 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 HapS 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.

* Corresponding author. Mailing address: Wyeth Vaccines Research, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-8345. Fax: (845) 602-4350. E-mail: liudf{at}wyeth.com.

Editor: J. N. Weiser

{dagger} Present address: Vaccinex, Rochester, N.Y.

{ddagger} Present address: Agave Biosystem, Ithaca, N.Y.

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

Infection and Immunity, December 2004, p. 6961-6968, Vol. 72, No. 12
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.12.6961-6968.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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