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Published on: December 19, 2020
Protection against Experimental Melioidosis with a Synthetic manno-Heptopyranose Hexasaccharide Glycoconjugate
Andrew E Scott1, William J Christ2, Alison J George1
1Defence Science and Technology Laboratory , Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
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.
Insights
An effective vaccine against melioidosis, a serious bacterial infection, is crucial. Scientists chemically synthesized a key component of the Burkholderia pseudomallei capsule, creating a promising vaccine candidate that protected mice from infection.
Area of Science:
- Chemical synthesis
- Vaccinology
- Immunology
Background:
- Melioidosis, caused by Burkholderia pseudomallei, is a significant emerging infectious disease with high mortality.
- Current antibiotic treatments for melioidosis are lengthy and often unsuccessful, highlighting the need for alternative interventions like vaccines.
Purpose of the Study:
- To chemically synthesize a specific hexasaccharide fragment of the Burkholderia pseudomallei capsular polysaccharide.
- To develop a glycoconjugate vaccine candidate for melioidosis by coupling the synthesized antigen to a carrier protein.
Main Methods:
- Novel modular disaccharide assembly approach for chemical synthesis of the hexasaccharide antigen.
- Coupling of the synthesized hexasaccharide to the Hc domain of tetanus toxin.
- Immunization of mice with the resulting glycoconjugate vaccine candidate.
Main Results:
- Successful chemical synthesis of an immunologically relevant hexasaccharide fragment of the B. pseudomallei capsule.
- Glycoconjugate immunization induced IgM and IgG responses recognizing the native capsule.
- Vaccinated mice demonstrated significant protection against lethal B. pseudomallei challenge (over 120 × LD50).
Conclusions:
- The chemical synthesis provides a viable route to a key B. pseudomallei antigen for vaccine development.
- The synthesized glycoconjugate is a promising vaccine candidate, demonstrating immunogenicity and protective efficacy in a mouse model.
- This work represents a critical step towards an effective licensed vaccine for melioidosis.
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