title: Protection against Experimental Melioidosis with a Synthetic manno-Heptopyranose Hexasaccharide Glycoconjugate.
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.
authors.affiliation: Defence Science and Technology Laboratory , Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Scott
authors.affiliation: Corden Pharma International Inc. (formerly Ancora Pharmaceuticals Inc.) , Woburn, Massachusetts 01801 United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Christ
authors.affiliation: Defence Science and Technology Laboratory , Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: George
authors.affiliation: Defence Science and Technology Laboratory , Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors.forename: Margaret G M
authors.initials: MG
authors.lastname: Stokes
authors.affiliation: Corden Pharma International Inc. (formerly Ancora Pharmaceuticals Inc.) , Woburn, Massachusetts 01801 United States.
authors.forename: Gregory J S
authors.initials: GJ
authors.lastname: Lohman
authors.affiliation: Corden Pharma International Inc. (formerly Ancora Pharmaceuticals Inc.) , Woburn, Massachusetts 01801 United States.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Corden Pharma International Inc. (formerly Ancora Pharmaceuticals Inc.) , Woburn, Massachusetts 01801 United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jones
authors.affiliation: College of Life and Environmental Sciences, University of Exeter , Exeter, Devon EX4 4QD, United Kingdom.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Titball
authors.affiliation: Defence Science and Technology Laboratory , Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Atkins
authors.affiliation: Corden Pharma International Inc. (formerly Ancora Pharmaceuticals Inc.) , Woburn, Massachusetts 01801 United States.
authors.forename: A Stewart
authors.initials: AS
authors.lastname: Campbell
authors.affiliation: Defence Science and Technology Laboratory , Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors.forename: Joann L
authors.initials: JL
authors.lastname: Prior
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000737:chemistry / Q000276:immunology; D016957:Burkholderia pseudomallei / Q000276:immunology / Q000502:physiology; D005260:Female; D006001:Glycoconjugates / Q000737:chemistry* / Q000276:immunology*; D008358:Mannose / Q000737:chemistry*; D008554:Melioidosis / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D001428:Bacterial Vaccines; D006001:Glycoconjugates; D009844:Oligosaccharides; D008358:Mannose