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6-O-Branched Oligo-?-glucan-Based Antifungal Glycoconjugate Vaccines.

ABSTRACT: With the rapid growth in fungal infections and drug-resistant fungal strains, antifungal vaccines have become an especially attractive strategy to tackle this important health problem. ?-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. ?-Glucans have a conserved ?-1,3-glucan backbone with sporadic ?-1,3- or ?-1,6-linked short glucans as branches at the 6-O-positions, and the branches may play a critical role in their immunologic functions. To study the immunologic properties of branched ?-glucans and develop ?-glucan-based antifungal vaccines, three branched ?-glucan oligosaccharides with 6-O-linked ?-1,6-tetraglucose, ?-1,3-diglucose, and ?-1,3-tetraglucose branches on a ?-1,3-nonaglucan backbone, which mimic the structural epitopes of natural ?-glucans, were synthesized and coupled with keyhole limpet hemocyanin (KLH) to form novel synthetic conjugate vaccines. These glycoconjugates were proved to elicit strong IgG antibody responses in mice. It was also discovered that the number, size, and structure of branches linked to the ?-glucan backbone had a significant impact on the immunologic property. Moreover, antibodies induced by the synthetic oligosaccharide-KLH conjugates were able to recognize and bind to natural ?-glucans and fungal cells. Most importantly, these conjugates elicited effective protection against systemic Candida albicans infection in mice. Thus, branched oligo-?-glucans were identified as functional epitopes for antifungal vaccine design and the corresponding protein conjugates as promising antifungal vaccine candidates.

SUBMITTER: Liao G

PROVIDER: S-EPMC5668869 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines.

Liao Guochao G Zhou Zhifang Z Liao Jun J Zu Luning L Wu Qiuye Q Guo Zhongwu Z

ACS infectious diseases 20151230 2

With the rapid growth in fungal infections and drug-resistant fungal strains, antifungal vaccines have become an especially attractive strategy to tackle this important health problem. β-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. β-Glucans have a conserved β-1,3-glucan backbone with sporadic β-1,3- or β-1,6-linked short glucans as branches at the 6-O-positions, ...[more]

PMID: 27624963

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Project description:Background(1,3)-β-D-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis.MethodsThis was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-D-glucan was negative ((1,3)-β-D-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-D-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment.ResultsWe randomized 108 patients into the (1,3)-β-D-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1-3] in the (1,3)-β-D-glucan group vs. 10 days [6-13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94-8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-D-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-D-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23).ConclusionsIn critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-D-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population.Trial registrationClinicalTrials.gov, NCT03117439 , retrospectively registered on 18 April 2017.

Project description:Nontyphoidal Salmonellae, principally S. Typhimurium and S. Enteritidis, are a major cause of invasive bloodstream infections in sub-Saharan Africa with no vaccine currently available. Conjugation of lipopolysaccharide O-antigen to a carrier protein constitutes a promising vaccination strategy. Here we describe a rational process to select the most appropriate isolates of Salmonella as source of O-antigen for developing a bivalent glycoconjugate vaccine. We screened a library of 30 S. Typhimurium and 21 S. Enteritidis in order to identify the most suitable strains for large scale O-antigen production and generation of conjugate vaccines. Initial screening was based on growth characteristics, safety profile of the isolates, O-antigen production, and O-antigen characteristics in terms of molecular size, O-acetylation and glucosylation level and position, as determined by phenol sulfuric assay, NMR, HPLC-SEC and HPAEC-PAD. Three animal isolates for each serovar were identified and used to synthesize candidate glycoconjugate vaccines, using CRM197 as carrier protein. The immunogenicity of these conjugates and the functional activity of the induced antibodies was investigated by ELISA, serum bactericidal assay and flow cytometry. S. Typhimurium O-antigen showed high structural diversity, including O-acetylation of rhamnose in a Malawian invasive strain generating a specific immunodominant epitope. S. Typhimurium conjugates provoked an anti-O-antigen response primarily against the O:5 determinant. O-antigen from S. Enteritidis was structurally more homogeneous than from S. Typhimurium, and no idiosyncratic antibody responses were detected for the S. Enteritidis conjugates. Of the three initially selected isolates, two S. Typhimurium (1418 and 2189) and two S. Enteritidis (502 and 618) strains generated glycoconjugates able to induce high specific antibody levels with high breadth of serovar-specific strain coverage, and were selected for use in vaccine production. The strain selection approach described is potentially applicable to the development of glycoconjugate vaccines against other bacterial pathogens.

Dataset Information

6-O-Branched Oligo-?-glucan-Based Antifungal Glycoconjugate Vaccines.

Publications

6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines.

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