Abstract
Melioidosis is an emerging infectious disease caused by Burkholderia pseudomallei and is associated with high morbidity and mortality rates in endemic areas. Antibiotic treatment is protracted and not always successful; even with appropriate therapy, up to 40% of individuals presenting with melioidosis in Thailand succumb to infection. In these circumstances, an effective vaccine has the potential to have a dramatic impact on both the scale and the severity of disease. Currently, no vaccines are licensed for human use. A leading vaccine candidate is the capsular polysaccharide consisting of a homopolymer of unbranched 1→3 linked 2-O-acetyl-6-deoxy-β-d-manno-heptopyranose. Here, we present the chemical synthesis of this challenging antigen using a novel modular disaccharide assembly approach. The resulting hexasaccharide was coupled to the nontoxic Hc domain of tetanus toxin as a carrier protein to promote recruitment of T-cell help and provide a scaffold for antigen display. Mice immunized with the glycoconjugate developed IgM and IgG responses capable of recognizing native capsule, and were protected against infection with over 120 × LD50 of B. pseudomallei strain K96243. This is the first report of the chemical synthesis of an immunologically relevant and protective hexasaccharide fragment of the capsular polysaccharide of B. pseudomallei and serves as the rational starting point for the development of an effective licensed vaccine for this emerging infectious disease.
Highlights
Melioidosis is a serious and often fatal disease caused by the Gram negative, facultative intracellular pathogen Burkholderia pseudomallei.[1]
The disease is prevalent in South-East Asia and Northern Australia, the area of endemicity is expanding rapidly as surveillance improves and cases are described in other countries
Antibiotic therapies are available for melioidosis, typically requiring several weeks of intravenous administration followed by orally delivered antibiotics which may last several months.[5]
Summary
Melioidosis is a serious and often fatal disease caused by the Gram negative, facultative intracellular pathogen Burkholderia pseudomallei.[1]. This work describes a novel approach to the chemical synthesis of a 1→3 linked 2-O-acetyl-6-deoxy-β-D-mannoheptopyranose hexasaccharide using a modular disaccharide assembly approach This hexasaccharide was covalently linked to a recombinant carrier protein to improve immunogenicity and the resulting glycoconjugate shown to stimulate production of antibodies specific for native CPS and to confer significant protection in mice following a challenge with a lethal dose of B. pseudomallei. All of the mice receiving the TetHc-SHCPS glycoconjugate had detectable levels of IgG and IgM recognizing native CPS, demonstrating that the synthetic approach utilized here successfully generated immunologically relevant glycoconjugates and the necessity for conjugation to a carrier protein for the development of detectable immune responses. The modular disaccharide strategy described is broadly applicable for synthesizing other glycans containing C-6 homologated monosaccharide units in general, and for those connected by 1,2-β-manno-configured glycosides in particular
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