Date Published: March 19, 2008
Publisher: Public Library of Science
Author(s): Audrey Tanghe, Jean-Pierre Dangy, Gerd Pluschke, Kris Huygen, Pamela L. C. Small
Abstract: Vaccination with plasmid DNA encoding Ag85A from M. bovis BCG can partially protect C57BL/6 mice against a subsequent footpad challenge with M. ulcerans. Unfortunately, this cross-reactive protection is insufficient to completely control the infection. Although genes encoding Ag85A from M. bovis BCG (identical to genes from M. tuberculosis) and from M. ulcerans are highly conserved, minor sequence differences exist, and use of the specific gene of M. ulcerans could possibly result in a more potent vaccine. Here we report on a comparison of immunogenicity and protective efficacy in C57BL/6 mice of Ag85A from M. tuberculosis and M. ulcerans, administered as a plasmid DNA vaccine, as a recombinant protein vaccine in adjuvant or as a combined DNA prime-protein boost vaccine. All three vaccination formulations induced cross-reactive humoral and cell-mediated immune responses, although species-specific Th1 type T cell epitopes could be identified in both the NH2-terminal region and the COOH-terminal region of the antigens. This partial species-specificity was reflected in a higher—albeit not sustained—protective efficacy of the M. ulcerans than of the M. tuberculosis vaccine, particularly when administered using the DNA prime-protein boost protocol.
Partial Text: Buruli ulcer (BU), also known as Bairnsdale ulcer, is an infectious, necrotizing skin disease caused by Mycobacterium ulcerans (M. ulcerans) occurring mostly in tropical and subtropical areas. Cases have been reported in several countries in West and Central Africa, in Central and South America, in Southeast Asia and in Australia. BU is emerging as a serious health problem, especially in West Africa, where it is the third leading cause of mycobacterial disease in immunocompetent people, after tuberculosis and leprosy. In some countries in Africa, thousands of cases occur annually and in these areas BU has supplanted leprosy to become the second most important human mycobacterial disease. The natural history of M. ulcerans infection and subsequent development of BU is not completely elucidated. M. ulcerans bacteria have been found in endemic areas in stagnant water or slowly moving water sources and in aquatic snails and carnivorous insects ,. So far, person to person transmission has not been reported. The infection causes initially a painless nodular swelling which can eventually develop into an extensive necrotizing lesion. M. ulcerans has the particularity to produce a family of toxin molecules, the so-called mycolactone (ML), polyketides that can suppress the immune system and destroy skin, underlying tissue and bone, causing severe deformities –. ML suppresses the in vitro TNF-α production by murine macrophages infected with M. ulcerans (4) and it strongly affects the maturation and the migratory properties of DC . On the other hand, ML does not seem to affect the production of the inflammatory cytokine MIP-2, involved in the recruitment of neutrophils (4). M. ulcerans has an initial intracellular infection stage but virulent ML producing strains induce apoptosis of the infected cells and can subsequently be found extracellularly ,. Only few Mycobacterium species produce mycolactone toxins . M. ulcerans isolates from different geographical areas produce different types of mycolactone, i.e. mycolactone A/B, C, D, E and F ,.
Buruli ulcer belongs to the family of neglected tropical diseases . In 1998 the first International Conference on Buruli Ulcer was organized in Côte d’Ivoire, expressing the poor knowledge about this disease and calling on the international scientific community to support control and research efforts. Currently, no specific vaccine exists against this disease. In 1957, Fenner demonstrated that a high degree of protection was conferred, in an experimental mouse model, against challenge infection with small doses of M. ulcerans by prior inoculation with M. ulcerans, M. balnei and M. bovis BCG (BCG). Footpad and intravenous BCG administration gave considerable protection against a small dose and a slight protection against a large dose of M. ulcerans given in the other footpad . More recently we have shown in a similar experimental mouse model that BCG vaccine protects to some extent against infection with M. ulcerans but that a booster vaccination with the same BCG vaccine does not increase the protective effect ,. In 1969, a clinical study performed in Uganda reported on a protection rate of 47% of the BCG vaccine. However, protection turned out to be short-lived and was only detected in the first 6 months following BCG vaccination . In 1976, Smith et al reported another BCG vaccination trial against Buruli ulcer in Uganda giving similar short lived (one year) protection rates of about 50% . Although not very effective at preventing the classical skin lesions of Buruli ulcer, the BCG vaccine seems to exert a significant protective effect against its severe, disseminated osteomyelitis form both in children and in adults ,.