title: Protective immunity against tularemia provided by an adenovirus-vectored vaccine expressing Tul4 of Francisella tularensis.
abstract: Francisella tularensis, a category A bioterrorism agent, is a highly infectious organism that is passed on via skin contact and inhalation routes. A live attenuated vaccine strain (LVS) has been developed, but it has not been licensed for public use by the FDA due to safety concerns. Thus, there exists a need for a safer and improved vaccine. In this study, we have constructed a replication-incompetent adenovirus, Ad/opt-Tul4, carrying a codon-optimized gene for expression of a membrane protein, Tul4, of F. tularensis LVS. Its ability to protect against lethal challenge and its immunogenicity were evaluated in a murine model. An intramuscular injection of a single dose (1 × 10(7) PFU) of Ad/opt-Tul4 elicited a robust Tul4-specific antibody response. Assays suggest a Th1-driven response. A single dose elicited 20% protection against challenge with 100 × 50% lethal dose (LD(50)) F. tularensis LVS; two additional booster shots resulted in 60% protection. In comparison, three doses of 5 μg recombinant Tul4 protein did not elicit significant protection against challenge. Therefore, the Ad/opt-Tul4 vaccine was more effective than the protein vaccine, and protection was dose dependent. Compared to LVS, the protection rate is lower, but an adenovirus-vectored vaccine may be more attractive due to its enhanced safety profile and mucosal route of delivery. Furthermore, simple genetic modification of the vaccine may potentially produce antibodies protective against a fully virulent strain of F. tularensis. Our data support the development and further research of an adenovirus-vectored vaccine against Tul4 of F. tularensis LVS.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Kaur
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.forename: Maria T
authors.initials: MT
authors.lastname: Arévalo
authors.forename: Qingfu
authors.initials: Q
authors.lastname: Xu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Chen
authors.forename: Mingtao
authors.initials: M
authors.lastname: Zeng
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D014406:Tularemia / Q000276:immunology / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D004269:DNA, Bacterial; D008074:Lipoproteins; D014614:Vaccines, Synthetic; C075214:TUL4 protein, Francisella tularensis