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Vaccine Detail

Vaccine Information
  • Vaccine Name: LVS
  • Target Pathogen: Francisella tularensis
  • Target Disease: Tularemia
  • 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).
Host Response

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).

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

  • 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.
Elkins et al., 1996: Elkins KL, Rhinehart-Jones TR, Culkin SJ, Yee D, Winegar RK. Minimal requirements for murine resistance to infection with Francisella tularensis LVS. Infection and immunity. 1996 Aug; 64(8); 3288-93. [PubMed: 8757866].
Hepburn et al., 2006: Hepburn MJ, Purcell BK, Lawler JV, Coyne SR, Petitt PL, Sellers KD, Norwood DA, Ulrich MP. Live vaccine strain Francisella tularensis is detectable at the inoculation site but not in blood after vaccination against tularemia. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2006 Sep 15; 43(6); 711-6. [PubMed: 16912944].
Isherwood et al., 2005: Isherwood KE, Titball RW, Davies DH, Felgner PL, Morrow WJ. Vaccination strategies for Francisella tularensis. Advanced drug delivery reviews. 2005 Jun 17; 57(9); 1403-14. [PubMed: 15919131].
Rodriguez et al., 2011: Rodriguez AR, Yu JJ, Murthy AK, Guentzel MN, Klose KE, Forsthuber TG, Chambers JP, Berton MT, Arulanandam BP. Mast cell/IL-4 control of Francisella tularensis replication and host cell death is associated with increased ATP production and phagosomal acidification. Mucosal immunology. 2011; 4(2); 217-226. [PubMed: 20861832].