title: Identification of a live attenuated vaccine candidate for tularemia prophylaxis.
abstract: Francisella tularensis is the causative agent of a fatal human disease, tularemia. F. tularensis was used in bioweapon programs in the past and is now classified as a category A select agent owing to its possible use in bioterror attacks. Despite over a century since its discovery, an effective vaccine is yet to be developed. In this study four transposon insertion mutants of F. tularensis live vaccine strain (LVS) in Na/H antiporter (FTL_0304), aromatic amino acid transporter (FTL_0291), outer membrane protein A (OmpA)-like family protein (FTL_0325) and a conserved hypothetical membrane protein gene (FTL_0057) were evaluated for their attenuation and protective efficacy against F. tularensis SchuS4 strain. All four mutants were 100-1000 fold attenuated for virulence in mice than parental F. tularensis. Except for the FTL_0304, single intranasal immunization with the other three mutants provided 100% protection in BALB/c mice against intranasal challenge with virulent F. tularensis SchuS4. Differences in the protective ability of the FTL_0325 and FTL_0304 mutant which failed to provide protection against SchuS4 were investigated further. The results indicated that an early pro-inflammatory response and persistence in host tissues established a protective immunity against F. tularensis SchuS4 in the FTL_0325 immunized mice. No differences were observed in the levels of serum IgG antibodies amongst the two vaccinated groups. Recall response studies demonstrated that splenocytes from the FTL_0325 mutant immunized mice induced significantly higher levels of IFN-γ and IL-17 cytokines than the FTL_0304 immunized counterparts indicating development of an effective memory response. Collectively, this study demonstrates that persistence of the vaccine strain together with its ability to induce an early pro-inflammatory innate immune response and strong memory responses can discriminate between successful and failed vaccinations against tularemia. This study describes a live attenuated vaccine which may prove to be an ideal vaccine candidate for prevention of respiratory tularemia.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Manish
authors.initials: M
authors.lastname: Mahawar
authors.forename: Seham M
authors.initials: SM
authors.lastname: Rabadi
authors.forename: Sukalyani
authors.initials: S
authors.lastname: Banik
authors.forename: Sally V
authors.initials: SV
authors.lastname: Catlett
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Bakshi
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005604:Francisella tularensis / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007114:Immunization; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D009154:Mutation / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014406:Tularemia / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D014613:Vaccines, Attenuated / Q000276:immunology*; D014774:Virulence
chemical_list: D001428:Bacterial Vaccines; D016207:Cytokines; D018836:Inflammation Mediators; D014613:Vaccines, Attenuated