title: Protection against P. aeruginosa with an adenovirus vector containing an OprF epitope in the capsid.
abstract: Pseudomonas aeruginosa is an important opportunistic pathogen that can cause chronic and often life-threatening infections of the respiratory tract, particularly in individuals with cystic fibrosis (CF). Because infections with P. aeruginosa remain the major cause of the high morbidity and mortality of CF, a vaccine against P. aeruginosa would be very useful for preventing this disorder. The outer membrane protein F (OprF) of P. aeruginosa is a promising vaccine candidate and various B cell epitopes within OprF have been identified. Given that adenovirus (Ad) vectors have strong immunogenic potential and can function as adjuvants for genetic vaccines, the present study evaluates the immunogenic and protective properties of a novel replication-deficient Ad vector in which the Ad hexon protein was modified to include a 14-amino acid epitope of P. aeruginosa OprF (Epi8) in loop 1 of the hypervariable region 5 of the hexon (AdZ.Epi8). Immunization of C57BL/6 mice with AdZ.Epi8 resulted in detectable serum anti-P. aeruginosa and anti-OprF humoral responses. These responses were haplotype dependent, with higher serum anti-OprF titers in CBA mice than in BALB/c or C57BL/6 mice. AdZ.Epi8 induced Epi8-specific IFN-gamma-positive CD4 and CD8 T cell responses and resulted in protection against a lethal pulmonary challenge with agar-encapsulated P. aeruginosa. Importantly, repeated administration of AdZ.Epi8 resulted in boosting of the anti-OprF humoral and anti-Epi8 cellular response, whereas no boosting effect was present in the response against the transgene beta-galactosidase. These observations suggest that Ad vectors expressing pathogen epitopes in their capsid will protect against an extracellular pathogen and will allow boosting of the epitope-specific humoral response with repeated administration, a strategy that should prove useful in developing Ad vectors as vaccines where humoral immunity will be protective.
authors.affiliation: Department of Pediatrics, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
authors.forename: Anja
authors.initials: A
authors.lastname: Krause
authors.forename: Michael
authors.initials: M
authors.lastname: Rivara
authors.forename: Kyung-Kim
authors.initials: KK
authors.lastname: Hee
authors.forename: Enrico V
authors.initials: EV
authors.lastname: Vintayen
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Peter W
authors.initials: PW
authors.lastname: Roelvink
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Bruder
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wickham
authors.forename: Imre
authors.initials: I
authors.lastname: Kovesdi
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000256:Adenoviridae; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005822:Genetic Vectors; D006239:Haplotypes; D006649:Histocompatibility Antigens / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D018272:Porins / Q000235:genetics / Q000276:immunology*; D017433:Protein Structure, Secondary; D011552:Pseudomonas Infections / Q000276:immunology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000276:immunology*
chemical_list: D036022:Capsid Proteins; D000939:Epitopes; D006649:Histocompatibility Antigens; D018272:Porins