title: Variability of outer membrane protein P1 and its evaluation as a vaccine candidate against experimental otitis media due to nontypeable Haemophilus influenzae: an unambiguous, multifaceted approach.
abstract: Candidate vaccine antigens for preventing otitis media caused by nontypeable Haemophilus influenzae (NTHI) should possess one or more conserved epitopes. We sought to evaluate the candidacy of P1, a surface-expressed outer membrane protein knowing that this antigen is subject to diversifying selection. Therefore, we selected NTHI strains from among >500 phylogenically variant isolates representative of the diversity found in natural populations of H. influenzae. Twenty-three variants of P1 (</=95% similarity) were identified among 42 strains. When chinchillas were immunized with recombinant P1 (rP1) obtained from one of these isolates (BCH-3), all animals developed antibodies specific for rP1. Immunized animals were protected against disease when challenged with BCH-3, but not with an ompP1 mutant of BCH-3 or a strain (BCH-2) possessing a heterologous P1 (91% identity). We conclude that (i) while P1 induces protection against NTHI-mediated otitis media, development of a polyvalent vaccine reflecting the variability of P1 would be necessary to construct an efficacious vaccine and (ii) use of a phylogenically characterized collection of representative isolates in concert with gene sequencing, cloning, gene inactivation, and animal testing offers an efficient, rational, and rigorous strategy for evaluating the potential problems associated with variability of vaccine targets and specificity of related immune responses.
authors.affiliation: The Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Bolduc
authors.forename: V
authors.initials: V
authors.lastname: Bouchet
authors.forename: R Z
authors.initials: RZ
authors.lastname: Jiang
authors.forename: J
authors.initials: J
authors.lastname: Geisselsoder
authors.forename: Q C
authors.initials: QC
authors.lastname: Truong-Bolduc
authors.forename: P A
authors.initials: PA
authors.lastname: Rice
authors.forename: S I
authors.initials: SI
authors.lastname: Pelton
authors.forename: R
authors.initials: R
authors.lastname: Goldstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000627:therapeutic use*; D002682:Chinchilla; D015195:Drug Design; D004432:Ear, Middle / Q000382:microbiology; D018073:Haemophilus Vaccines / Q000627:therapeutic use*; D006193:Haemophilus influenzae / Q000145:classification*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010033:Otitis Media / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D014169:Transformation, Bacterial; D014611:Vaccination
chemical_list: D001425:Bacterial Outer Membrane Proteins; D018073:Haemophilus Vaccines; D011994:Recombinant Proteins