Abstract
Buruli ulcer, an emerging tropical disease caused by Mycobacterium ulcerans (MU), is characterized by disfiguring skin necrosis and high morbidity. Relatively little is understood about the mode of transmission, pathogenesis, or host immune responses to MU infection. Due to significant reduction in quality of life for patients with extensive tissue scarring, and that a disproportionately high percentage of those affected are disadvantaged children, a Buruli ulcer vaccine would be greatly beneficial to the worldwide community. Previous studies have shown that mice inoculated with either M. bovis bacille Calmette–Guérin (BCG) or a DNA vaccine encoding the M. ulcerans mycolyl transferase, Ag85A (MU-Ag85A), are transiently protected against pathology caused by intradermal challenge with MU. Building upon this principle, we have generated quality-controlled, live-recombinant strains of BCG and M. smegmatis which express the immunodominant MU Ag85A. Priming with rBCG MU-Ag85A followed by an M. smegmatis MU-Ag85A boost strongly induced murine antigen-specific CD4+ T cells and elicited functional IFNγ-producing splenocytes which recognized MU-Ag85A peptide and whole M. ulcerans better than a BCG prime-boost vaccination. Strikingly, mice vaccinated with a single subcutaneous dose of BCG MU-Ag85A or prime-boost displayed significantly enhanced survival, reduced tissue pathology, and lower bacterial load compared to mice vaccinated with BCG. Importantly, this level of superior protection against experimental Buruli ulcer compared to BCG has not previously been achieved. These results suggest that use of BCG as a recombinant vehicle expressing MU antigens represents an effective Buruli ulcer vaccine strategy and warrants further antigen discovery to improve vaccine efficacy.
Highlights
Buruli ulcer (BU), the clinical manifestation of subcutaneous infection by Mycobacterium ulcerans (MU), is a highly disfiguring flesh-eating skin disease with significant associated morbidity [1,2,3,4,5]
Enhanced recombinant BCG (rBCG) Protection against Buruli ulcer resistance and toxicity warrant their replacement with efficacious vaccines
We demonstrate that a recombinant bacille Calmette–Guérin (BCG)-based vaccine expressing the immunodominant M. ulcerans Ag85A is capable of significantly enhancing protection in experimental Buruli ulcer compared to standard BCG, with a decrease in bacterial burden, pathology, and increase in survival
Summary
Buruli ulcer (BU), the clinical manifestation of subcutaneous infection by Mycobacterium ulcerans (MU), is a highly disfiguring flesh-eating skin disease with significant associated morbidity [1,2,3,4,5]. Infections are present worldwide, endemicity occurs in impoverished areas with below-average access to appropriate diagnosis and medical treatment. This condition disproportionately afflicts children, and over 50% of those affected are less than 15 years of age [9]. Due to the typically indolent and misleading nature of initial disease symptoms, skin ulceration is often allowed to progress to a point at which antibiotic treatment is ineffective in preventing further necrosis. At this stage, surgical removal of infected tissue and skin grafting is required. The mode of transmission, pathogenesis, and host immune responses to M. ulcerans infection are poorly understood, and there is currently no effective prophylactic vaccine available [13]
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