Abstract
Francisella tularensis is considered a potential bioterrorism agent due to its low infectious dose, high mortality rate, and ability to be spread via the aerosol route. We characterized the F. tularensis subspecies novicida mutant strain FTN0109 as a potential vaccine candidate against tularemia. This strain, which lacks an outer membrane lipoprotein, is attenuated in vitro and in vivo, as it exhibits reduced replication within murine J774 macrophages and has a pulmonary LD50 in BALB/c and C57BL/6 mice of >105 CFU (compared to WT parental strain U112, LD50 FTN0109 also conferred complete protection in BALB/c mice against subsequent pulmonary challenge with 10 LD50 (60,000 CFU) of the murine virulent Francisella strain LVS. We also have demonstrated partial protection (50%) against the highly human virulent subspecies tularensis strain SCHU S4 (25 LD50, 12,500 CFU) following intratracheal vaccination in the Fischer 344 rat, a second rodent model for tularemia. Overall, our results suggest that FTN0109 serves as a potential putative vaccine candidate against pulmonary tularemia.
Highlights
There is a need for a vaccine against the potential bioterrorism agent Francisella tularensis
We have previously shown that live attenuated strains of F. novicida can protect against pulmonary exposure to F. tularensis subsp. tularensis in the Fischer 344 rat model of tularemia [8]
The FTN0109 strain was attenuated both in vitro and in vivo, and maintained a limited ability to disseminate post-immunization from murine lungs to the spleen and liver; this mild dissemination to immune organs may aid in generating systemic antigen-specific immune responses like IFN-γ production and Th-1 type (IgG2a) responses, which are necessary to protect against a facultative intracellular pathogen such as F. tularensis [17] [24]-[26]
Summary
There is a need for a vaccine against the potential bioterrorism agent Francisella tularensis. This Gram-negative coccobacillus is the etiological agent of the zoonotic disease tularemia, and is classified as a CDC Category A Select Agent due to its previous weaponization by the United States, Japan, and the Soviet Union [1]. Live attenuated vaccines have been demonstrated to be effective against the pulmonary form of tularemia. The most successful example is the Live Vaccine Strain (LVS), developed in 1952 by the Soviet Union from subspecies holarctica by multiple passages in vitro. An efficacious live attenuated vaccine should induce potent cellular and humoral responses that protect humans against multiple forms of the disease, including pulmonary tularemia, while causing minimal adverse effects from vaccination
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