A ΔclpB mutant of Francisella tularensis subspecies holarctica strain, FSC200, is a more effective live vaccine than F. tularensis LVS in a mouse respiratory challenge model of tularemia

PLoS One. 2013 Nov 13;8(11):e78671. doi: 10.1371/journal.pone.0078671. eCollection 2013.

Abstract

Francisella tularensis subsp. tularensis is a highly virulent pathogen for humans especially if inhaled. Consequently, it is considered to be a potential biothreat agent. An experimental vaccine, F. tularensis live vaccine strain, derived from the less virulent subsp. holarctica, was developed more than 50 years ago, but remains unlicensed. Previously, we developed a novel live vaccine strain, by deleting the chaperonin clpB gene from F. tularensis subsp. tularensis strain, SCHU S4. SCHU S4ΔclpB was less virulent for mice than LVS and a more effective vaccine against respiratory challenge with wild type SCHU S4. In the current study, we were interested to determine whether a similar mutant on the less virulent subsp. holarctica background would also outperform LVS in terms of safety and efficacy. To this end, clpB was deleted from clinical holarctica strain, FSC200. FSC200ΔclpB had a significantly higher intranasal LD50 than LVS for BALB/c mice, but replicated to higher numbers at foci of infection after dermal inoculation. Moreover, FSC200ΔclpB killed SCID mice more rapidly than LVS. However, dermal vaccination of BALB/c mice with the former versus the latter induced greater protection against respiratory challenge with SCHU S4. This increased efficacy was associated with enhanced production of pulmonary IL-17 after SCHU S4 challenge.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Vaccines / genetics*
  • Bacterial Vaccines / immunology
  • Cytokines / metabolism
  • Francisella tularensis / genetics*
  • Francisella tularensis / immunology
  • Gene Deletion
  • Heat-Shock Proteins / genetics
  • Humans
  • Kinetics
  • Lung / metabolism
  • Lung / microbiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Respiratory Tract Infections / immunology
  • Respiratory Tract Infections / microbiology
  • Respiratory Tract Infections / prevention & control*
  • Tularemia / immunology
  • Tularemia / microbiology
  • Tularemia / prevention & control*
  • Vaccination*
  • Vaccine Potency
  • Vaccines, Attenuated / genetics
  • Vaccines, Attenuated / immunology

Substances

  • Bacterial Proteins
  • Bacterial Vaccines
  • Cytokines
  • Heat-Shock Proteins
  • Vaccines, Attenuated

Grants and funding

This study was funded by the National Research Council Canada (http://www.nrc-cnrc.gc.ca/eng/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.