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Vaccine Detail

M. tuberculosis phoP mutant SO2
Vaccine Information
  • Vaccine Name: M. tuberculosis phoP mutant SO2
  • Target Pathogen: Mycobacterium tuberculosis
  • Target Disease: Tuberculosis
  • Tradename: M. tuberculosis phoP mutant strain
  • Vaccine Ontology ID: VO_0000588
  • Type: Live attenuated vaccine
  • PhoP gene engineering:
    • Type: Gene mutation
    • Description: The mutant strain was constructed by a single gene (phoP) disruption of the parental M. tuberculosis MT103 strain. PhoP has shown involvement in the regulation of complex mycobacterial lipids implicated in the virulence of M. tuberculosis (Martin et al., 2006).
    • Detailed Gene Information: Click Here.
  • Preparation: Rabbits were treated with four doses of phoP prior to isolating polyclonal antibodies against phoP. Anti-phoP and monoclonal antibodies against ESAT-6 were obtained. Horseradish peroxidase-labelled goat anti-rabbit antibodies served as secondary antibodies (Martin et al., 2006). Mycobacterial cell-free protein extracts from M. tuberculosis were prepared, filtered, and precipitated with 45% (w/v) ammonium sulphate (Martin et al., 2006).
  • Description: The phoP transcription factor is part of the two-component regulatory signal transduction system component which recently was linked to regulation of complex mycobacterial lipids implicated in the virulence of M. tuberculosis, as well as to multidrug resistance occurrences in a clinical isolate (Martin et al., 2006; Perez et al., 2001) established the selection of phoP as a vaccine candidate by showing that the mutant SO2 strain shows impaired multiplication within cultured macrophages and in vivo infection models (Martin et al., 2006).
Host Response

Mouse Response

  • Host Strain: Balb/C mice
  • Vaccination Protocol: Groups of four Balb/C mice were vaccinated with either 2.5x103 CFUs of SO2 or 8x103 CFUs of M. bovis BCG and later sacrificed at 7, 14, 21, 28, 45, and 60 days post-vaccination (Martin et al., 2006).
  • Challenge Protocol: To asses protective efficacy of SO2 in Balc/c mice, mice were challenged by intravenous route with 2.5x105 CFU M. tuberculosis H37Rv at week 8 and sacrificed four weeks later.

  • Efficacy: Vaccination with M. tuberculosis SO2 induced a significantly higher proportion of CD4+/IFN-gamma+ producing cells after 45 days of vaccination when compared with BCG (Martin et al., 2006). The proportion of CD8+/IFN-gamma+ producing cells was consistently higher in the M. tuberculosis SO2group. SO2 strain and BCG both conferred significant levels of protection compared to saline controls, with reductions of 1.5 and 1.3 log10 reductions in cfu counts in lung and spleen (Martin et al., 2006). However,
  • Host Ifng (Interferon gamma) response
    • Description: Vaccination with M. tuberculosis SO2 induced a significantly higher proportion of CD4+/IFN-γ+ producing cells in mice 45 days after vaccination when compared with BCG (Martin et al., 2006).
    • Detailed Gene Information: Click Here.
  • Information about this animal model: Mouse Model for TB research

Guinea pig Response

  • Vaccination Protocol: Groups of six guinea pigs were used in two procedures. Guinea pigs were vaccinated subcutaneously with 250μl of 5x104 CFU BCG (Pasteur) or SO2 in both the low-dose and high-dose challenge experiments. Saline was also used in the low-dose experiments.
  • Side Effects: SO2-treated guinea pigs gained weight. No visible or clinical signs of disease after challenge.
  • Challenge Protocol: In the low dose challenge, guinea pigs were aerosol challenged at 12 weeks using a Henderson apparatus and 2x106 CFU/ml M. tuberculosis water suspension to give estimated inhaled dose of 10-50 CFU/lung. In high dose challenge, guinea pigs were aerosol challenged at 10 weeks with 5x107 CFU/ml M.tuberculosis in water suspension to give approimately 500 CFUs to the lungs. Animals were killed by peritoneal overdose of sodium pentabarbitone (Chandra et al., 2006).
  • Efficacy: A significant difference was observed between non-vaccinated and vaccinated (both BCG and SO2-recipient) groups receiving low-dose treatment, whereas no significant difference was evident between the BCG and SO2 groups. In high dose challenge, all non-vaccinated and BCG-vaccinated were euthanized according to set humane end-point, while all SO2-vaccinated groups showed significantly longer survival than BCG groups and saline-treated groups. Pulmonary disease most evident in non-vaccinated guinea pigs. Consolidation was significantly less in the SO2-vaccinated groups versus non-vaccinated and BCG-vaccinated groups. "M. tuberculosis SO2 strain was superior to BCG in conferring enhanced survival to infected guinea pigs, reduction in the severity of the disease in the lung, and dissemination of infection to the spleen" (Martin et al., 2006).

Mouse Response

  • Host Strain: CB-17/lcr lco SCID specific pathogen free (spf)
  • Vaccination Protocol: No vaccination was employed here. Purpose of experiment is to assess survival of SCID mice following infection with either SO2 or BCG (Martin et al., 2006).
  • Persistence: All SCID mice infected with SO2 strain survived for >245 days, whereas those infected with M. tuberculosis MT103 and SO2-pSO5 died within 62 days of infection(Martin et al., 2006).
  • Challenge Protocol: Ten mice per experimental group were infected with 200μl PBS containing 2x105, 2x104, or 2x103 viable BCG Pasteur, or 5.4x106, 5.4x105, or 5.4x104 viable SO2. Aerosol infection was also used to nebulize with 7 ml of M. tuberculosis suspension, providing 20 viable bacilli within the lungs. Survival times were determined using Mantel-Haenszel test (Martin et al., 2006).
  • Information about this animal model: Mouse Model for TB research
References
Chandra et al., 2006: Chandra S, Kaur M, Midha S, Bhatnagar R, Banerjee-Bhatnagar N. Evaluation of the ability of N-terminal fragment of lethal factor of Bacillus anthracis for delivery of Mycobacterium T cell antigen ESAT-6 into cytosol of antigen presenting cells to elicit effective cytotoxic T lymphocyte response. Biochemical and biophysical research communications. 2006 Dec 22; 351(3); 702-7. [PubMed: 17084814 ].
Martin et al., 2006: Martin C, Williams A, Hernandez-Pando R, Cardona PJ, Gormley E, Bordat Y, Soto CY, Clark SO, Hatch GJ, Aguilar D, Ausina V, Gicquel B. The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs. Vaccine. 2006 Apr 24; 24(17); 3408-19. [PubMed: 16564606 ].
Perez et al., 2001: Perez E, Samper S, Bordas Y, Guilhot C, Gicquel B, Martin C. An essential role for phoP in Mycobacterium tuberculosis virulence. Molecular microbiology. 2001 Jul; 41(1); 179-87. [PubMed: 11454210].