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: Manish Mahawar, Seham M Rabadi, Sukalyani Banik, Sally V Catlett, Dennis W Metzger, Meenakshi Malik, Chandra Shekhar Bakshi
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e61539 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23613871 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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