Identification of a Live Attenuated Vaccine Candidate for Tularemia Prophylaxis

PLoS One. 2013 Apr 17;8(4):e61539. doi: 10.1371/journal.pone.0061539. Print 2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / immunology
  • Bacterial Vaccines / immunology*
  • Cytokines / metabolism
  • Francisella tularensis / growth & development
  • Francisella tularensis / immunology
  • Francisella tularensis / pathogenicity
  • Humans
  • Immunity, Humoral / immunology
  • Immunization
  • Immunologic Memory
  • Inflammation Mediators / metabolism
  • Lung / immunology
  • Lung / microbiology
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microbial Viability
  • Mutation / genetics
  • Spleen / immunology
  • Spleen / microbiology
  • Spleen / pathology
  • Tularemia / immunology*
  • Tularemia / microbiology
  • Tularemia / prevention & control*
  • Vaccines, Attenuated / immunology*
  • Virulence

Substances

  • Bacterial Vaccines
  • Cytokines
  • Inflammation Mediators
  • Vaccines, Attenuated