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Extended safety and efficacy studies of a live attenuated double leucine and pantothenate auxotroph of Mycobacterium tuberculosis as a vaccine candidate.

ABSTRACT: We have previously described the development of a live, fully attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate strain with two independent attenuating auxotrophic mutations in leucine and pantothenate biosynthesis. In the present work, those studies have been extended to include testing for protective efficacy in a long-term guinea pig survival model and safety testing in the highly tuberculosis susceptible Rhesus macaque. To model the safety of the ?leuD ?panCD strain in HIV-infected human populations, a Simian immunodeficiency virus (SIV)-infected Rhesus macaque group was included. Immunization with the non-replicating ?leuD ?panCD conferred long-term protection against challenge with virulent M. tuberculosis equivalent to that afforded by BCG as measured by guinea pig survival. In safety studies, clinical, hematological and bacteriological monitoring of both SIV-positive and SIV-negative Rhesus macaques immunized with ?leuD ?panCD, revealed no vaccine-associated adverse effects. The results support the further development of the ?leuD ?panCD strain as a viable tuberculosis (TB) vaccine candidate.

SUBMITTER: Sampson SL

PROVIDER: S-EPMC3146342 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Extended safety and efficacy studies of a live attenuated double leucine and pantothenate auxotroph of Mycobacterium tuberculosis as a vaccine candidate.

Sampson Samantha L SL Mansfield Keith G KG Carville Angela A Magee D Mitchell DM Quitugua Teresa T Howerth Elizabeth W EW Bloom Barry R BR Hondalus Mary K MK

Vaccine 20110505 29-30

We have previously described the development of a live, fully attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate strain with two independent attenuating auxotrophic mutations in leucine and pantothenate biosynthesis. In the present work, those studies have been extended to include testing for protective efficacy in a long-term guinea pig survival model and safety testing in the highly tuberculosis susceptible Rhesus macaque. To model the safety of the ΔleuD ΔpanCD strain in HIV-infect ...[more]

PMID: 21549795

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Project description:Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death due to bacterial infections in mankind, and BCG, an attenuated strain of Mycobacterium bovis, is an approved vaccine. BCG sequesters in immature phagosomes of antigen presenting cells (APCs), which do not fuse with lysosomes, leading to decreased antigen processing and reduced Th1 responses. However, an Mtb derived ΔfbpA attenuated mutant underwent limited phagosome maturation, enhanced immunogenicity and was as effective as BCG in protecting mice against TB. To facilitate phagosome maturation of ΔfbpA, we disrupted an additional gene sapM, which encodes for an acid phosphatase. Compared to the wild type Mtb, the ΔfbpAΔsapM (double knock out; DKO) strain was attenuated for growth in mouse macrophages and PMA activated human THP1 macrophages. Attenuation correlated with increased oxidants in macrophages in response to DKO infection and enhanced labeling of lysosomal markers (CD63 and rab7) on DKO phagosomes. An in vitro Antigen 85B peptide presentation assay was used to determine antigen presentation to T cells by APCs infected with DKO or other mycobacterial strains. This revealed that DKO infected APCs showed the strongest ability to present Ag85B to T cells (>2500 pgs/mL in 4 hrs) as compared to APCs infected with wild type Mtb or ΔfbpA or ΔsapM strain (<1000 pgs/mL in 4 hrs), indicating that DKO strain has enhanced immunogenicity than other strains. The ability of DKO to undergo lysosomal fusion and vacuolar acidification correlated with antigen presentation since bafilomycin, that inhibits acidification in APCs, reduced antigen presentation. Finally, the DKO vaccine elicited a better Th1 response in mice after subcutaneous vaccination than either ΔfbpA or ΔsapM. Since ΔfbpA has been used in mice as a candidate vaccine and the DKO (ΔfbpAΔsapM) mutant is more immunogenic than ΔfbpA, we propose the DKO is a potential anti-tuberculosis vaccine.

Dataset Information

Extended safety and efficacy studies of a live attenuated double leucine and pantothenate auxotroph of Mycobacterium tuberculosis as a vaccine candidate.

Publications

Extended safety and efficacy studies of a live attenuated double leucine and pantothenate auxotroph of Mycobacterium tuberculosis as a vaccine candidate.

Similar Datasets

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