A mycolactone based vaccine against buruli ulcer disease
Boakye-Appiah, J. K. (2023). A mycolactone based vaccine against buruli ulcer disease. (Unpublished Doctoral thesis, St George's, University of London)
Abstract
Background
Buruli ulcer (BU), a neglected necrotizing tropical skin disease caused by Mycobacterium ulcerans is the third most common Mycobacterial disease after TB and leprosy. Infections mostly occur in remote, rural areas of Central and West Africa, but also in Australia, Japan and Papua New Guinea. Notwithstanding the fact that more than 42,000 BU cases have been reported worldwide in 33 countries in the past decade, the actual disease burden is difficult to objectively assess considering the remoteness of affected populations and a lack of credible health systems data on the incidence of Buruli Ulcer in quite a significant number of the countries in which cases are known to occur. Most patients are children aged under 15 years and even though the disease is known to carry a low mortality risk, it bears a huge morbidity and economic burden with costs of treatment rising as high as $30,000 per patient in some cases. The condition usually presents as a painless nodule, a firm plaque, or edematous lesion, which soon ulcerates with characteristically undermined edges. Mycolactone, a toxin produced exclusively by M. ulcerans is the main pathological factor in the pathogenesis of Buruli ulcer. Being a neglected disease of the poor, access to surgical treatment is limited and the cost of treatment, a big disincentive. The thought of vaccine development is therefore taking centre-stage in attempts to control the disease.
This work focuses on the development of a mycolactone-based vaccine against Buruli ulcer. Previous attempts at developing a vaccine using closely related bacteria and subunit proteins have not been successful.
Methods
C57BL/6J black mice were immunized with synthetic mycolactone, mycolactone-deficient M ulcerans and purified enzyme proteins expressed in E. coli combined with selected adjuvants and delivery systems. Immunised mice were challenged with pathological M ulcerans and observed for footpad swelling. Various immunological assays were performed to understand the immune mechanisms underlying protection.
Results
When combined with the delivery platform YC NaMA, mycolactone was immunogenic at concentrations below 18ng/ml. The enzyme proteins were able to induce varying types and levels of immune response. Antibodies were developed to KRA and Ag85A. BURULIVAC, a composite vaccine construct comprising Mycolactone, KRA, Ag85A and Quil A conferred absolute protection against Buruli ulcer disease in mice over a 14-week period of observation. This was observed in mouse groups irrespective of whether or not mice had been primed with Delta, the mycolactone deficient strain of M ulcerans. Interleukin 10 emerged as a reliable correlate of protection.
Conclusion
With the right adjuvants and adequate doses, mycolactone and some of its polyketide synthase enzymes involved in its synthesis are able to produce good immune responses against Buruli ulcer and the immunosuppressive effects of mycolactone can be circumvented. BURULIVAC is a promising vaccine candidate against Buruli ulcer disease and must be explored further. This work focuses on the development of a mycolactone-based vaccine against Buruli ulcer.
Download (3MB) | Preview
Export
Downloads
Downloads per month over past year
Metadata
MetadataActions (login required)
Admin Login