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Vaccine Comparison

F. tularensis FopB Protein Vaccine F. tularensis GroEL protein vaccine F. tularensis vaccine LVS LPS F. tularensis vaccine rLm/iglC F. tularensis vaccine X4072(pTUIA-15) Francisella tularensis capB mutant vaccine Francisella tularensis clpB mutant vaccine Francisella tularensis FTL0552 mutant vaccine Francisella tularensis FTT0918 mutant vaccine Francisella tularensis galU mutant vaccine Francisella tularensis guaA mutant vaccine Francisella tularensis guaB mutant vaccine Francisella tularensis IglB mutant vaccine Francisella tularensis purF mutant vaccine Francisella tularensis purMCD mutant vaccine Francisella tularensis sodC mutant vaccine Francisella tularensis wbtA mutant vaccine Francisella tularensis wbtI mutant vaccine FSC043 J5dLPS/OMP KKF24 LVS sodB(Ft)
Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information
  • Vaccine Ontology ID: VO_0004034
  • Type: Subunit vaccine
  • Status: Research
  • Antigen: .5 μg recombinant FopB protein
  • FopB gene engineering:
    • Type: Recombinant protein preparation
    • Detailed Gene Information: Click Here.
  • Adjuvant: CpG DNA vaccine adjuvant
    • VO ID: VO_0001237
    • Description: 10 μg of CpG oligodeoxynucleotide (5′-TCCATGACGTTCCTGACGTT-3′; Operon, Huntsville, AL)
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0011446
  • Type: Subunit vaccine
  • Status: Research
  • Antigen: F. tularensis chaperonin GroEL (Hsp60)
  • groEL gene engineering:
    • Type: Recombinant protein preparation
    • Description: Hsp60 was identified by Western blotting with a monoclonal antibody to GroEL (Sigma-Aldrich, Poole, United Kingdom). Hsp60 was excised from large-format unstained gels and electroeluted into 4× Laemmli buffer (0.1 M Tris-HCl [pH 7.3], 0.768 M glycine, 0.4% [wt/vol] SDS) by using the Hoefer gel eluter (Amersham Pharmacia, Buckinghamshire, United Kingdom) at 70 V for 2 h, following the manufacturer's instructions. The eluted product was pooled and purified by dilution (more than 20×) in ammonium bicarbonate (3.95 g/liter) and SDS (1 g/liter) and centrifuged over a dialysis membrane (10,000-molecular-weight cutoff; Vivascience, Lincoln, United Kingdom). The protein was then diluted (20×) in sterile water and centrifuged further, until significant concentration was achieved (Hartley et al., 2004).
    • Detailed Gene Information: Click Here.
  • Adjuvant: IL-12 vacince adjuvant
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Vaccine Ontology ID: VO_0000308
  • Type: Subunit vaccine
  • Antigen: Francisella tularensis live vaccine strain (LVS) lipopolysaccharide (LPS) (Dreisbach et al., 2000). The chemical composition of the lipid A moiety of LVS LPS is quite different from that of enteric LPS. The LVS LPS lacks a functional lipid A. This apparently confers a survival advantage on the bacterium, since its LPS does not participate in induction of nitric oxide production that might limit its intracellular growth. Further, since other data indicate that LVS LPS is unable to block macrophage stimulation by functional LPS, the structure must be distinct enough to not permit recognition as an antagonist for traditional LPSs. The ability of LVS LPS to stimulate protection in C3H/HeJ mice, which are defective in the ability to recognize and respond to enteric LPS at least in part due to a point mutation in Toll-like receptor 4, suggests that LVS LPS is recognized through receptors other than Tlr4 (Dreisbach et al., 2000).
  • Preparation: Francisella tularensis live vaccine strain (LVS) LPS is purified from whole F. tularensis LVS bacteria. A culture of F. tularensis LVS is grown in 4-L flasks at 37°C for 48 h in Trypticase soy broth with cysteine. The cultures are centrifuged for 15 min, washed 3 times in PBS, once in methanol, and once in acetone, and then lyophilized. The LPS is then extracted. After the crude LPS is treated with DNase, RNase, and proteinase K, the pellet is harvested by centrifugation 3 times for 12 h. LPS preparations are then reconstituted in endotoxin-free PBS and stored at 4°C (Dreisbach et al., 2000).
  • Virulence: No traditional endotoxin has been associated with virulent F. tularensis. More recent reports indicated that purified LVS LPS was not endotoxic in d-galactosamine-sensitized mice and failed to activate Limulus amoebocyte lysate. LVS LPS also failed to stimulate human monocytes or peripheral blood lymphocytes to proliferate, produce TNF-α, or produce IL-1. Mouse peritoneal exudate macrophages treated with LVS LPS did not produce TNF-α or nitric oxide, and there was no increase in surface immunoglobulin expression by a mouse pre-B-cell line in response to LVS LPS. The only reported biological activity of LVS LPS is activation of complement (Dreisbach et al., 2000). LPS purified from F. tularensis LVS did not activate murine B cells for proliferation or polyclonal immunoglobulin secretion, nor did it activate murine splenocytes for secretion of interleukin-4 (IL-4), IL-6, IL-12, or IFN-gamma. However, in vivo experiments have suggested that LVS LPS contributes to the virulence of Francisella, in that LPS-defective Lpsd C3H/HeJ mice are reported to be more susceptible to LVS infection than Lpsn C3H/HeN (Dreisbach et al., 2000).
  • Vaccine Ontology ID: VO_0011447
  • Type: Recombinant vector vaccine
  • Status: Research
  • Antigen: F. tularensis intracellular growth locus, subunit C (iglC)
  • IglC1 gene engineering:
    • Type: DNA vaccine construction
    • Description: Constructed recombinant L. monocytogenes (rLm) vaccines stably expressing seven F. tularensis proteins including IglC (rLm/iglC) (Jia et al., 2009).
    • Detailed Gene Information: Click Here.
  • IglC2 gene engineering:
    • Type: Recombinant vector construction
    • Description: Constructed recombinant L. monocytogenes (rLm) vaccines stably expressing seven F. tularensis proteins including IglC (rLm/iglC) (Jia et al., 2009).
    • Detailed Gene Information: Click Here.
  • Vector: rLmΔActA
  • Immunization Route: Intradermal injection (i.d.)
  • Vaccine Ontology ID: VO_0011548
  • Type: Recombinant vector vaccine
  • Status: Research
  • Antigen: F. tularensis 17 kDa major membrane protein (TUL4) precursor
  • TUL4 gene engineering:
    • Type: Recombinant vector construction
    • Description: A 1.0-kb EcoRV-SphI DNA fragment was prepared by the technique of Birnboim and Doly (6) from the plasmid pTUL4-9 (39), a derivative of pUC18. The fragment contains the gene encoding the T-cell-reactive 17-kDa protein TUL4 but contains no other expressed open reading frames (40). The isolated 1.0-kb fragment was ligated to the Asd+ plasmid pYA248 (27) after the plasmid had been cleaved with EcoRI and SphI and after the EcoRI site had been made blunt by using the Klenow fragment. The translation initiation codon of pYA248 was followed by a short sequence of 36 putatively encoding nucleotides of the Francisella DNA. The recombinant plasmid, denoted pTULA-15, was transformed (16, 20) into S. typhimunium x3730. By using a lysate of the X3730 recombinant, transduction of phage P22 HT int into X4072 was performed according to standard methods (12, 37). The presence of TUIA in lysates from transduced strains was confirmed by Western blot analysis, and one of the strains, denoted S. typhimurium X4072(pTUL4-15), was selected for the experiments (Sjöstedt et al., 1992).
    • Detailed Gene Information: Click Here.
  • Vector: S. typhimurium X4072
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Vaccine Ontology ID: VO_0002840
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • capB gene engineering:
    • Type: Gene mutation
    • Description: This capB mutant is from Francisella tularensis (Jia et al., 2010).
    • Detailed Gene Information: Click Here.
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0002841
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • clpB gene engineering:
    • Type: Gene mutation
    • Description: This clpB mutant is from Francisella tularensis (Conlan et al., 2010).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intradermal injection (i.d.)
  • Vaccine Ontology ID: VO_0002842
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • FTL0552 gene engineering:
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0002843
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • FTT0918 gene engineering:
    • Type: Gene mutation
    • Description: This FTT0918 mutant is from Francisella tularensis (Twine et al., 2005).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intradermal injection (i.d.)
  • Vaccine Ontology ID: VO_0002844
  • Type: Live, attenuated vaccine
  • Status: Licensed
  • Host Species as Laboratory Animal Model: Mouse
  • galU gene engineering:
    • Type: Gene mutation
    • Description: This galU mutant is from Francisella tularensis (Jayakar et al., 2011).
    • Detailed Gene Information: Click Here.
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0002845
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • guaA gene engineering:
    • Type: Gene mutation
    • Description: This guaA mutant is from Francisella tularensis (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Vaccine Ontology ID: VO_0002846
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • guaB gene engineering:
    • Type: Gene mutation
    • Description: This guaB mutant is from Francisella tularensis (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Product Name: KKF235
  • Vaccine Ontology ID: VO_0002847
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • IglB gene engineering:
    • Type: Gene mutation
    • Description: This IgIB mutant is from Francisella tularensis (Yu et al., 2010).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Oral immunization
  • Vaccine Ontology ID: VO_0002850
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • purF gene engineering:
    • Type: Gene mutation
    • Description: This purF mutant is from Francisella tularensis (Quarry et al., 2007).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • PurC/PurD gene engineering:
    • Type: Gene mutation
    • Description: This purMCD mutant is from Francisella tularensis (Pechous et al., 2006).
    • Detailed Gene Information: Click Here.
  • purM gene engineering:
    • Type: Gene mutation
    • Description: This purMCD mutant is from Francisella tularensis (Pechous et al., 2006).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Vaccine Ontology ID: VO_0002853
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • sodC gene engineering:
    • Type: Gene mutation
    • Description: This sodC mutant is from Francisella tularensis (Melillo et al., 2009).
    • Detailed Gene Information: Click Here.
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0002854
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • wbtA gene engineering:
    • Type: Gene mutation
    • Description: This wbtA mutant is from Francisella tularensis (Sebastian et al., 2007).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intradermal injection (i.d.)
  • Vaccine Ontology ID: VO_0002855
  • Type: Live, attenuated vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Mouse
  • WbtI gene engineering:
    • Type: Gene mutation
    • Description: This wbtI mutant is from Francisella tularensis (Li et al., 2007).
    • Detailed Gene Information: Click Here.
  • Immunization Route: Intraperitoneal injection (i.p.)
  • Vaccine Ontology ID: VO_0004201
  • Type: Subunit vaccine
  • Status: Research
  • Antigen: Detoxified, O-polysaccharide side chain-deficient, lipopolysaccharide non-covalently complexed with the outer membrane protein of N. meningitidis group B (Gregory et al., 2010).
  • Adjuvant: CpG DNA vaccine adjuvant
  • Immunization Route: intranasal immunization
  • Vaccine Ontology ID: VO_0000307
  • Type: Live Attenuated
  • IglC gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • Preparation: KKF24 is a recombinant strain of Francisella novicida U112 with iglC mutation (F. novicida delta-iglC::ermC) (Lauriano et al., 2003). Strains were grown at 37°C in Trypticase soy broth supplemented with 0.1% cysteine (Pammit et al., 2006).
  • Virulence: KKF24 is highly attenuated for virulence in mice and growth within amoebae (Pammit et al., 2006).
  • Description: KKF24 has been identified as a live attenuated vaccine against subsequent intranasal (i.n.) challenge with the wild-type organism of Francisella tularensis (Pammit et al., 2006).
  • Vaccine Ontology ID: VO_0000271
  • Type: Live Attenuated
  • Preparation: F. tularensis LVS (ATCC 29684; American Type Culture Collection, Rockville, Md.) was cultured on modified Mueller-Hinton agar plates or in modified Mueller-Hinton broth, and then frozen in broth at -70C; 1-ml aliquots were periodically thawed for use. The number of CFU after thawing varied less than 5% over a 6-month period (Elkins et al., 1996).
  • Virulence: LVS is virulent for laboratory mice and causes a fulminant infection with a histopathology quite similar to that of human tularemia (Elkins et al., 1996).
  • Description: Live attenuated strain (LVS) is derived from the multiple passage of a fully virulent strain of F. tularensis subspecies holarctica and has previously been produced in the US as an investigative new drug. Numerous studies have shown the effectiveness of the LVS vaccine in humans and in animal models of the disease, and protection against aerosol challenge with F. tularensis subspecies tularensis has been demonstrated (Isherwood et al., 2005).
  • Product Name: LVS sodB mutant
  • Vaccine Ontology ID: VO_0000263
  • Type: Live Attenuated
  • SodB from F. tularensis SCHU S4 gene engineering:
    • Type: Protein
    • Detailed Gene Information: Click Here.
  • Preparation: sodBFt is made by amplifying a region of the sodB gene by PCR. The full-length sodB gene is also amplified. These amplified fragments are cloned separately into a PCR cloning vector and excised by digestion with restriction enzymes. The digested fragments are ligated simultaneously to an XbaI/SalI-digested pPV shuttle vector to yield pPV-sodB. The PstI site upstream of the start codon is used as a marker for screening of mutant colonies. pPV-sodB is then transformed in Escherichia coli S17-1 and transferred into F. tularensis LVS via conjugation. The mutants are selected on modified chocolate agar plates supplemented with Isovitalex, L-cysteine hydrochloride, 1% hemoglobin, 2 µg/ml chloramphenicol, and 100 µg/ml polymyxin B. Colonies obtained on the chloramphenicol plates following the first recombination event are analyzed by PCR, followed by the digestion of PCR products with PstI enzyme. The positive mutant colonies are selected for a second recombination event by plating on medium containing 5% sucrose. Chloramphenicol sensitivity and sucrose resistance following the second recombination event are confirmed by PCR and PstI digestion of the amplified products. The positive mutant clone is referred to as sodBFt (Bakshi et al., 2006).
  • Virulence: sodB(Ft) has increased sensitivity to paraquat and hydrogen peroxide (H2O2), the redox cycling compounds, as well as with reduced virulence in both C57BL/6 and BALB/c mice (Bakshi et al., 2006).
  • Description: sodBFt is a live vaccine strain mutant of Francisella tularensis with reduced Fe-superoxide dismutase gene expression (Bakshi et al., 2006).
Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response Host Response

Human Response

  • Vaccination Protocol: The vaccine was administered by scarification. A single 0.6-mL drop of LVS vaccinwas placed on the volar surface of the left forearm. A bifurcated needle was used to administer 15 pricks through the drop. The skin surface was then cleaned with sterile gauze, and all excess fluid was removed. Volunteers were given no special bandage or covering for the site. There were no restrictions on showering or wetting the vaccination site. Volunteers were enrolled from 2 iterations of LVS vaccination. From the first iteration, 17 volunteers were enrolled; 10 mL of blood and inoculation site samples were obtained from each person. Baseline skin swabs from this group were performed on the volar surface of the left forearm. Post-vaccination swabs were performed directly at the site of inoculation. Four different personnel obtained skin swabs using similar techniques. In the second iteration of vaccination, swabs were obtained from 24 volunteers using the same time points, but no blood samples were obtained (Hepburn et al., 2006).
  • Persistence: LVS genomic DNA is detectable at the inoculation site up to 2 weeks after inoculation. This suggests that replicating organisms are present at the inoculation site, which poses a theoretical risk of person-to-person transmission. However, this risk of transmission is likely to be very minimal (Hepburn et al., 2006).
  • Side Effects: One volunteer recorded a temperature of 38.3°C on day 2. One volunteer developed 4×5-cm axillary lymphadenopathy 28 days after vaccination. No other volunteers had fever or lymphadenopathy. All volunteers had a take reaction. No severe erythema or deep ulcer was observed in any volunteer. During this study, there were no incidents of inadvertent inoculation of remote sites or person-to-person transmission (Hepburn et al., 2006).
  • Efficacy: LVS genomic DNA is almost universally detectable at the inoculation site for the first 2 days after LVS vaccination and is detectable in for 1–2 weeks after vaccination. Live LVS bacteria were detected in culture for the first 2 days after vaccination. While LVS DNA at the inoculation site was detected well past 2 days, this does not confirm the presence of viable bacteria past this time point (Hepburn et al., 2006).
  • Description: All but one volunteer had samples obtained at each of the 5 time points. The positive controls for the extraction of the samples taken were positive. The results of blood cultures were negative at baseline and at all time points. Additionally, PCR results of whole blood samples were negative using both tul4 and fopA assays at baseline and at all time points. Baseline skin swab samples were negative for LVS F. tularensis by real-time PCR assays. Skin swab samples were uniformly positive for LVS F. tularensis by PCR on day one, 40 of 41 samples were positive on day 2, and several samples were positive 1 and 2 weeks after vaccination. Two volunteers had negative results on day 7 or 8 but positive results on day 14 or 15. All 9 samples from day 35 were negative with both PCR assays (Hepburn et al., 2006).

Mouse Response

  • Host Strain: C57BL/6 and HLA-DR4 tg
  • Vaccination Protocol: mice were anesthetized i.n. with 3% isoflurane by use of a rodent anesthesia system and were immunized i.n. on day 0 with 7.5 μg rFopB in 25 μl of sterile PBS. This was accompanied by immunization with 10 μg of CpG oligodeoxynucleotide on days −1, 0, and +1. Mice were boosted once on day 14 with the same amount of antigen (Yu et al., 2010).
  • Challenge Protocol: Mice were challenged i.n. with approximately 3.5 × 104 CFU (∼5 50% lethal doses [LD50s]) of LVS on day 30 (Yu et al., 2010).
  • Efficacy: Intranasal vaccination of mice with rFopB conferred 50% protection (P < 0.05) against an otherwise lethal pulmonary challenge of 5 LD50s of LVS (3.5 × 104 CFU) in both C57BL/6 and HLA-DR4 tg mice compared with the protection conferred to LVS-challenged mock-vaccinated mice, all of which succumbed to the infection by day 10 (Yu et al., 2010).
  • Host Ifng (Interferon gamma) response
    • Description: Spleens were collected at 14 days postvaccination, and single cells were prepared and assayed for FopB- and LVS-induced IFN-γ production. Differences in IFN-γ stimulation between rFopB- and mock-vaccinated mice were significant (Yu et al., 2010).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Groups of BALB/c mice 6 to 8 weeks old (Charles River International, Margate, United Kingdom) were immunized i.p. on days 0 and 14 with 25 μg of Hsp60/100 μl of saline with or without 0.5 μg of murine IL-12. Control groups were immunized with either IL-12 only or 100 μl of saline containing eluted protein-free gel. IL-12 was kindly provided by Roche Pharmaceuticals. Blood samples were obtained from each mouse by tail vein bleeding immediately prior to challenge (day 28). The serum was separated by microcentrifugation and stored at −20°C until analysis. Groups of mice were either challenged or culled to provide spleen cells a further 14 days later (Hartley et al., 2004).
  • Challenge Protocol: F. tularensis LVS, F. tularensis subsp. holarctica HN63, and F. tularensis subsp. tularensis Schu S4 were used for challenges. The strains were harvested into PBS after growth on BCGA for 24 h at 37°C and diluted to a given optical density. Confirmation of the dose was achieved by plating out a serial dilution. Groups of mice were challenged on day 28 with either 103 or 104 MLD of LVS i.p. or 100 MLD of HN63 or 10 MLD of Schu4 subcutaneously as separate challenges. Mice were monitored for 14 days, and survival to a humane end point was recorded (Hartley et al., 2004).
  • Efficacy: Researchers have shown that mice that had been immunized with purified heat shock protein 60 (Hsp60, groEL) isolated from Francisella tularensis were protected against a subsequent challenge with some strains of the bacterium (Hartley et al., 2004).

Mouse Response

  • Host Strain: BALB/cByJ, C57BL/6J, BALB/c.scid
  • Vaccination Protocol: Normal mouse serum (NMS) was obtained by bleeding normal BALB/cByJ mice from the lateral tail vein and pooling the resulting serum. Normal BALB/cByJ mice were then immunized with 10 µg of LPS intradermally (i.d.), and immune mouse serum (IMS) was obtained 3 or 30 days later. BALB/cByJ mice were given 0.5 ml of a 1:4 dilution of these sera i.p. 1 day before challenge with 103 LVS bacteria i.p. (Dreisbach et al., 2000).
  • Persistence: T-cell-deficient BALB/c.nu/nu mice treated with LVS LPS survived lethal challenge for 2 to 3 weeks longer than control (PBS-treated) mice; these mice eventually succumbed to challenge after ~3-4 weeks (Dreisbach et al., 2000).
  • Immune Response: LPS purified from F. tularensis LVS lacks the ability to nonspecifically activate murine B cells for proliferation or polyclonal immunoglobulin secretion. It is also unable to activate murine or human macrophages (Dreisbach et al., 2000). It does not stimulate murine splenocytes to secrete IL-12, IL-6, IL-4, or IFN-γ (Dreisbach et al., 2000). LVS LPS is unable to activate murine or human macrophages. LVS LPS does stimulate specific antibody production and in purified form is a weak immunogen that induces primarily an IgM response. When recognized by the murine immune system as a component of the bacterium, however, the resulting specific antibody response is vigorous and is characterized by the production of large amounts of IgG, particularly IgG2a. Despite the apparent absence of nonspecific immunostimulatory activity and minimal specific antibody production, however, treatment of mice with surprisingly small amounts of LVS LPS stimulates very strong B-cell-dependent protection against lethal LVS challenge within 2 to 3 days (Dreisbach et al., 2000).
  • Side Effects: None were noted (Dreisbach et al., 2000).
  • Challenge Protocol: BALB/cByJ mice were given various doses of LVS LPS i.d. on day 0 and challenged 3 days later with lethal doses of LVS, either 103 (1,000 LD50) or 104 (10,000 LD50) bacteria (Dreisbach et al., 2000).
  • Efficacy: Very strong protection against lethal LVS infection was demonstrated. Mice given doses as low as 0.1 ng of LVS LPS i.d. survived lethal LVS challenge, depending on the strength of the challenge given. Mice given 100 ng of LVS LPS i.d. survived LVS challenge doses approaching 106 bacteria (1,000,000 LD50). Further, in three experiments, 15 of 15 mice challenged with 104 LVS bacteria i.p. 3, 10, or 35 days after treatment with 100 ng of LVS LPS i.d. survived; however, in the same experiments none of 15 mice treated with 100 ng of LVS LPS i.d. and challenged 3, 10, or 35 days with 20 LD50 of L. monocytogenes survived. Early protection also could not be demonstrated using other types of LPS, in that mice given 100 ng of E. coli O55 LPS, Salmonella serovar Typhimurium LPS, or E. coli K235 LPS i.d. on day 0 and challenged with 103 LVS bacteria i.p. on day 3 did not survive.

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Six groups of 8 mice were sham-immunized or immunized with LVS or rLm vaccines at weeks 0 and 4 (Jia et al., 2009).
  • Challenge Protocol: At week 8, mice were anesthetized with Ketamine/Xylazine, challenged i.n. with 4400 CFU of LVS, and monitored for survival for up to 3 weeks after challenge. Intranasal challenge with 65× LD50 of LVS. Groups of mice were sham-immunized or immunized i.d. twice at weeks 0 and 4 with 5 × 104 CFU LVS or 1 × 106 CFU of rLmΔactA (vector), rLm/iglC, rLm/katG or rLm/iglC plus rLm/katG (Jia et al., 2009).
  • Efficacy: Mice immunized with rLm/iglC were protected against lethal challenge with F. tularensis LVS administered by the intranasal route, a route chosen to mimic airborne infection, and, most importantly, against aerosol challenge with the highly virulent Type A F. tularensis SchuS4 strain (Jia et al., 2009).

Mouse Response

  • Host Strain: C57BL/10
  • Vaccination Protocol: Mice were immunized twice, 4 weeks apart, by the intraperitoneal injection of 100 ,ll of PBS containing 5 x 103 (5 x 102 for the more susceptible mouse strain C57BL/10) organisms of S. typhimurium X4072 or S. typhimunum X4072(pTUIA-15) (Sjöstedt et al., 1992).
  • Challenge Protocol: Three months after the completion of immunization, mice were intravenously challenged with F. tularensis LVS at a dose of 160 to 230 bacteria. At various intervals thereafter, mice were sacrificed for the enumeration of bacteria in the liver and spleen. The CFU per organ were recorded (Sjöstedt et al., 1992).
  • Efficacy: A 17-kDa lipoprotein, TUL4, of the facultative intracellular bacterium Francisella tularensis is one of several membrane proteins that induce an in vitro response in T cells from F. tularensis-primed humans. When mice were immunized with S. typhimurium chi 4072(pTUL4-15), some animals showed an antibody response and a T-cell response to TUL4. The present study demonstrated that the 17-kDa lipoprotein TUL4 of F. tularensis is involved in a protective immunity to tularemia (Sjöstedt et al., 1992).

Mouse Response

  • Persistence: A capB mutant is attenuated in mice (Jia et al., 2010).
  • Efficacy: A capB mutant induces significant protection in mice from challenge with wild type F. tularensis (Jia et al., 2010).
  • Host IgG response
    • Description: Following i.n. immunization, LVS ΔcapB induced significantly higher levels of serum IgG, IgG2a, and IgM antibodies in mice than LVS by 7 days post immunization (Jia et al., 2010).
    • Detailed Gene Information: Click Here.
  • Host Ighv1-9 response
    • Description: Following i.n. immunization, LVS ΔcapB induced significantly higher levels of serum IgG, IgG2a, and IgM antibodies in mice than LVS by 7 days post immunization (Jia et al., 2010).
    • Detailed Gene Information: Click Here.
  • Host IgM response
    • Description: Following i.n. immunization, LVS ΔcapB induced significantly higher levels of serum IgG, IgG2a, and IgM antibodies in mice than LVS by 7 days post immunization (Jia et al., 2010).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Persistence: A clpB mutant is attenuated in mice (Conlan et al., 2010).
  • Efficacy: A clpB mutant induces significant protection in mice from challenge with wild type F. tularensis (Conlan et al., 2010).

Mouse Response

  • Persistence: A FTL0552 mutant is attenuated in mice (Sammons-Jackson et al., 2008).
  • Efficacy: A FTL0552 mutant provided partial protection in mice from challenge with wild type Francisella tularensis SchuS4 (Sammons-Jackson et al., 2008).
  • Host Ccl2 response
    • Description: LVS induced a significantly higher MCP-1 (Ccl2) response in mice lung homogenates as compared to FTL0552 mice beginning day 3 after infection (Sammons-Jackson et al., 2008).
    • Detailed Gene Information: Click Here.
  • Host Ifng (Interferon gamma) response
    • Description: LVS induced a significantly higher IFN-gamma response in mice lung homogenates as compared to FTL0552 mice beginning day 5 after infection (Sammons-Jackson et al., 2008).
    • Detailed Gene Information: Click Here.
  • Host IL-6 response
    • Description: LVS induced a significantly higher IL-6 response in mice lung homogenates as compared to FTL0552 mice beginning day 5 after infection (Sammons-Jackson et al., 2008).
    • Detailed Gene Information: Click Here.
  • Host Il12b response
    • Description: An FTL0552 mutant induced significantly elevated levels of IL-12 in C57BL/6 mice lung homogenates by day 7 post infection compared to LVS (Sammons-Jackson et al., 2008).
    • Detailed Gene Information: Click Here.
  • Host TNF-alpha response
    • Description: LVS induced a significantly higher TNF-alpha response in mice lung homogenates as compared to FTL0552 mice beginning day 5 after infection (Sammons-Jackson et al., 2008).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Persistence: A FTT0918 mutant showed significantly reduced virulence in mice (Twine et al., 2005).
  • Efficacy: A FTT0918 provided protection in mice from challenge with wild type F. tularensis 2 months after immunization (Twine et al., 2005).

Mouse Response

  • Persistence: A galU mutant is attenuated in mice, inducing only transient weight loss (Jayakar et al., 2011).
  • Efficacy: A galU mutant induces protection in mice from challenge with wild type F. tularensis, inducing only transient weight loss (Jayakar et al., 2011).
  • Host IL-1b response
    • Description: Twenty four hours after infection of a mouse macrophage-like cell line (THP-1) or BMDCs with the galU mutant, the amount of IL-1β released into culture supernatants was significantly higher than was observed following infection with WT FT (Jayakar et al., 2011).
    • Detailed Gene Information: Click Here.

Mouse Response

Mouse Response

  • Persistence: A guaB mutant is attenuated in mice (Santiago et al., 2009).
  • Efficacy: A guaB mutant induces significant protection in mice from challenge with wild type F. tularensis (Santiago et al., 2009).
  • Host Ccl5 response
    • Description: RANTES (Ccl5) and iNOS were induced after 4 hours of infection of the mutant in mouse macrophages and were significantly higher than media controls. Levels were similar to or greater than levels induced by WT LVS (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Host Cxcl1 response
    • Description: LVSΔguaB caused a rapid increase in the levels of transcription of TLR2-dependent cytokines including TNF-α, IL-1β, KC (i.e., Cxcl1), and IL-12 p35 following infection of primary mouse macrophages as compared to media. Levels were similar to or greater than levels induced by WT LVS (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Host IL-1b response
    • Description: LVSΔguaB caused a rapid increase in the levels of transcription of TLR2-dependent cytokines including TNF-α, IL-1β, KC, and IL-12 p35 following infection of primary mouse macrophages as compared to media. Levels were similar to or greater than levels induced by WT LVS (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Host Il12a response
    • Description: LVSΔguaB caused a rapid increase in the levels of transcription of TLR2-dependent cytokines including TNF-α, IL-1β, KC, and IL-12 p35 following infection of primary mouse macrophages as compared to media. Levels were similar to or greater than levels induced by WT LVS (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Host Il12b response
    • Description: IL-12 p40 mRNA was induced later in mouse macrophages, but was expressed for a longer period of time than other expressed cytokines. Levels were similar to or greater than levels induced by WT LVS and were significantly greater than media controls (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Host Nos2 response
    • Description: RANTES and iNOS were induced after 4 hours of infection of the mutant in mouse macrophages and were significantly higher than media controls. Levels were similar to or greater than levels induced by WT LVS (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.
  • Host TNF-alpha response
    • Description: LVSΔguaB caused a rapid increase in the levels of transcription of TLR2-dependent cytokines including TNF-α, IL-1β, KC, and IL-12 p35 following infection of primary mouse macrophages as compared to media. Levels were similar to or greater than levels induced by WT LVS (Santiago et al., 2009).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Persistence: An IglB mutant is attenuated in mice (Yu et al., 2010).
  • Efficacy: An IglB mutant induces significant protection in mice from challenge with wild type F. tualrensis U112, LVS, and SchuS4 (Yu et al., 2010).

Mouse Response

  • Persistence: A purF mutant is attenuated in mice (Quarry et al., 2007).
  • Efficacy: A purF mutant induces significant protection from challenge with wild type F. tularensis (Quarry et al., 2007).

Mouse Response

  • Persistence: A purMCD mutant is attenuated in mice (Pechous et al., 2006).
  • Efficacy: A purMCD mutant induces significant protection in mice from challenge with wild type F. tularensis (Pechous et al., 2006).

Mouse Response

Mouse Response

  • Persistence: A wbtA mutant is attenuated in mice (Sebastian et al., 2007).
  • Efficacy: A wbtA mutant induces significant protection in mice from challenge with wild type F. tularensis (Sebastian et al., 2007).
  • Host Ighv1-9 response
    • Description: The titer of immunoglobulin G (IgG) antibodies directed toward the surface-exposed protein antigens in anti-LVS wbtA antisera was determined to be 8,000 + 1,849, fourfold higher than the titer for LVS-immunized mice. The IgG2a subclass predominated among the IgG subtypes analyzed (Sebastian et al., 2007).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Persistence: .A wbtI mutant is attenuated in mice (Li et al., 2007)
  • Efficacy: A wbtI mutant induces protection in mice, especially in higher doses, from challenge with wild type F. tularensis (Li et al., 2007).

Mouse Response

  • Host Strain: BALB/c
  • Persistence: To examine the relative virulence of LVS and FSC043, BALB/c mice were challenged i.d. with CFU of one or other strain and then killed on day 4 of infection, and bacterial burdens in the skin, liver, and spleen were determined. By this time, LVS was present at 100-fold-higher levels than FSC043 in the skin and liver and 20-fold-higher levels in the spleen. The BALB/c mice that were intradermally inoculated LVS showed overt signs of infection before recovering, whereas the mice inoculated with FSC043 remained healthy. When inoculated intravenously, FSC043 grew less well than virulent type A or B strains or LVS in the livers, spleens, and lungs of mice (Twine et al., 2005).
  • Side Effects: Destruction of skin and inflammation was observed at the site of inoculation of FSC043 (Twine et al., 2005).
  • Challenge Protocol: FSC033 was used as the challenge strain to assess the efficacy of the various live vaccines employed. For aerosol exposure, thawed bacteria were diluted in Mueller-Hinton broth; for intradermal inoculations, stocks of the strains were diluted in sterile saline. Intradermal inocula were injected into a fold of skin in the shaved mid-belly, and the blister that formed was circumscribed with indelible marker (Twine et al., 2005).
  • Efficacy: All immunized mice survived and were challenged 77 days later intradermally or by aerosol with type A strain FSC033. Immunization of BALB/c mice with LVS leads to excellent protection against intradermal challenge but only weak protection against low-dose aerosol challenge. The FSC043 immunization afforded a similar degree of protection to LVS against intradermal challenge and somewhat better protection against aerosol challenge (Twine et al., 2005).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Ten, 6- to 8-week-old mice were inoculated i.n. with 1 μg J5dLPS/OMP vaccine at 0, 2, and 4 weeks. Unmethylated cytidine-phosphate-guanosine (CpG) containing oligodinucleotide (ODN 10104; Coley Pharmaceutical Group, Wellesley, MA) was administered i.n. (25 μg/mouse) one hour prior to each vaccination. Control groups received CpG ODN only (Gregory et al., 2010).
  • Challenge Protocol: Vaccinated mice were challenged i.t. with F. tularensis SchuS4 on days 35 - 42 post-vaccination (Gregory et al., 2010).
  • Efficacy: Mice vaccinated with J5dLPS/OMP and CpG ODN resisted infection by type A F. tularensis. Sixty-five percent of vaccinated animals survived challenge i.t. with 10 LD50 F. tularensis SchuS4 (Gregory et al., 2010).

Mouse Response

  • Host Strain: BALB/c
  • Vaccination Protocol: Mice were first anesthetized with 3% isoflurane using a rodent anesthesia system and then inoculated i.n. with 106 CFU of KKF24 in 25 μl of PBS. Mock-vaccinated animals were treated with PBS alone (Pammit et al., 2006).
  • Persistence: (Pammit et al., 2006)
  • Side Effects: None were noted (Pammit et al., 2006).
  • Challenge Protocol: Vaccinated mice exhibited no signs of morbidity and were challenged 30 days later i.n. with escalating inocula of the wild-type F. novicida U112 strain. Animals were monitored daily for morbidity and mortality (Pammit et al., 2006).
  • Efficacy: Intranasal vaccination with the F. novicida iglC mutant is highly efficacious against i.n. challenge with the wild-type strain (Pammit et al., 2006). Specifically, vaccinated animals challenged with 100 LD50 of U112 had an 82% survival rate, with minimal losses of body weight . When the challenge inoculum was increased to 1000 LD50 of U112, the survival rate decreased to 50%. Increasing the challenge inoculum further to 10,000 LD50 of U112 resulted in 20% survival. There was no survival of any unvaccinated animals at the challenge doses tested, indicating that all three inocula of U112 were lethal doses, as expected (Pammit et al., 2006).
  • Host Ifng (Interferon gamma) response
    • Description: It was found that all of the IFN-γ−/− vaccinated mice quickly succumbed within 4 to 5 days to the pulmonary challenge with the wild-type strain, whereas 100% of the IFN-γ+/+ mice were completely protected against both challenge doses. Both groups were able to survive vaccination with KKF24 (Pammit et al., 2006).
    • Detailed Gene Information: Click Here.
  • Host Ighg1 response
    • Description: Intranasal immunization with 106 CFU KKF24 induced a robust primary antibody response that included the induction of F. novicida-specific total, IgG1, and IgG2a antibodies. No binding was observed with unrelated antigens, levels in immune sera were significantly greater than normal mouse sera, and levels increased post-challenge (Pammit et al., 2006).
    • Detailed Gene Information: Click Here.
  • Host Ighv1-9 response
    • Description: Intranasal immunization with 106 CFU KKF24 induced a robust primary antibody response that included the induction of F. novicida-specific total, IgG1, and IgG2a antibodies. No binding was observed with unrelated antigens, levels in immune sera were significantly greater than normal mouse sera, and levels increased post-challenge (Pammit et al., 2006).
    • Detailed Gene Information: Click Here.
  • Host Il12a response
    • Description: There was potent IL-12 secretion from the stimulated cells upon i.n. vaccination with KKF24 as compared to mice inoculated with PBS. Cervical lymph node and spleen cells were stimulated by UV-inactivated KKF24 10 days after vaccination and then tested for cytokines (Pammit et al., 2006).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Host Strain: nu/nu, scid
  • Vaccination Protocol: Mice were given 0.5ml i.p. or 0.1 ml i.d. of the indicated dilution of LVS. To deplete mice of circulating cytokines, mice were treated i.p. with 500 mg of anti-IFN-g, anti-TNF-a, or control hamster immunoglobulin G (IgG) 1 h before infection with LVS. To deplete mice of neutrophils, mice were treated i.p. with 250 mg of RB6-8C5 at 3 d and again at 4 h before infection with LVS for depletion of Gr-11 cells (Elkins et al., 1996).
  • Persistence: T lymphocytes must be available for clearance of bacteria and long-term survival. Populations enriched for either CD4+ or CD8+ T cells can reconstitute long-term survival and clearance of i.d. LVS infection in scid mice, but over time, reconstituted recipients contain all subpopulations (Elkins et al., 1996).
  • Efficacy: Scid mice survive i.d. infection with doses of LVS ranging from 100 to 106 for about 20 days. All surviving recipients that cleared bacteria contained both CD4+ and CD8+ T cells in their spleens, including those that originally received highly enriched CD4+ or CD8+ T cells (Elkins et al., 1996). IFN-gamma and TNF-alpha are critical cytokines for the initial survival of infection. Mice treated with anti-TNF-a antibodies or knockout mice lacking functional TNF-a receptors are extremely susceptible to Listeria infection. Similarly, GKO mice infected i.v. or by aerosol with Mycobacterium tuberculosis succumb to infection, as do IFN-gamma receptor knockout mice infected with Listeria spp. The experiments using knockout mice unequivocally demonstrate that there is no compensatory activity available during bacterial infection for IFN-gamma and TNF-a, despite the remarkable functional redundancy generally observed in the cytokine network (Elkins et al., 1996).

Mouse Response

  • Immune Response: Reference is here (Rodriguez et al., 2011).
  • Host Il4 (interleukin 4) response
    • Description: Mast cells and secreted interleukin-4 (IL-4) effectively control intramacrophage replication of Francisella tularensis Live Vaccine Strain (LVS), and that mice deficient in mast cells or IL-4 receptor (IL-4R(-/-) exhibit greater susceptibility to pulmonary challenge (Rodriguez et al., 2011).
    • Detailed Gene Information: Click Here.

Mouse Response

  • Host Strain: C57BL/6, BALB/c
  • Vaccination Protocol: Mice were immunized i.n. with 5 × 103 CFU of LVS or sodBFt in a volume of 20 μl PBS (10 μl/nare). Unvaccinated mice, which served as a control, received an equal volume of PBS (Bakshi et al., 2008).
  • Persistence: (Bakshi et al., 2006)
  • Side Effects: None were noted (Bakshi et al., 2006).
  • Challenge Protocol: Mice immunized with 5 × 103 CFU of either LVS or sodBFt were challenged i.n. with 1 × 101 CFU (10LD100) of SchuS4 on day 21 post-immunization (Bakshi et al., 2008).
  • Efficacy: sodBFt vaccinated C57BL/6 mice not only had a significantly extended MTD (median time to death) as compared to LVS vaccinated or unvaccinated mice, but, 40% (4/10) of the sodBFt vaccinated mice survived the challenge. All naïve C57BL/6 mice challenged with a similar dose of SchuS4 strain succumbed to infection within 6–8 days post-challenge (Bakshi et al., 2008).
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Bakshi et al., 2006: Bakshi CS, Malik M, Regan K, Melendez JA, Metzger DW, Pavlov VM, Sellati TJ. Superoxide dismutase B gene (sodB)-deficient mutants of Francisella tularensis demonstrate hypersensitivity to oxidative stress and attenuated virulence. Journal of bacteriology. 2006 Sep; 188(17); 6443-8. [PubMed: 16923916].
Bakshi et al., 2008: Bakshi CS, Malik M, Mahawar M, Kirimanjeswara GS, Hazlett KR, Palmer LE, Furie MB, Singh R, Melendez JA, Sellati TJ, Metzger DW. An improved vaccine for prevention of respiratory tularemia caused by Francisella tularensis SchuS4 strain. Vaccine. 2008; 26(41); 5276-5288. [PubMed: 18692537].