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Beta-Glucan oligosaccharide enhances CD8(+) T cells immune response induced by a DNA vaccine encoding hepatitis B virus core antigen.

ABSTRACT: DNA vaccination can induce specific CD8(+) T cell immune response, but the response level is low in large mammals and human beings. Coadministration of an adjuvant can optimize protective immunity elicited by a DNA vaccine. In this study, we investigated the effect of a synthetic glucohexaose (beta-glu6), an analogue of Lentinan basic unit, on specific CD8(+) T cell response induced by a DNA vaccine encoding HBcAg (pB144) in mice. We found that beta-glu6 promoted the recruitment and maturation of dendritic cells, enhanced the activation of CD8(+) and CD4(+) T cells and increased the number of specific CD8(+)/IFN-gamma(+) T cells in lymphoid and nonlymphoid tissues in mice immunized by pB144. Immunization with pB144 and beta-glu6 increased the anti-HBc IgG and IgG2a antibody titer. These results demonstrate that beta-glu6 can enhance the virus-specific CTL and Th1 responses induced by DNA vaccine, suggesting beta-glu6 as a candidate adjuvant in DNA vaccination.

SUBMITTER: Wang J

PROVIDER: S-EPMC2896713 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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beta-Glucan oligosaccharide enhances CD8(+) T cells immune response induced by a DNA vaccine encoding hepatitis B virus core antigen.

Wang Jing J Dong Shengfu S Liu Chunhong C Wang Wei W Sun Shuhui S Gu Jianxin J Wang Yuan Y Boraschi Diana D Qu Di D

Journal of biomedicine & biotechnology 20100610

DNA vaccination can induce specific CD8(+) T cell immune response, but the response level is low in large mammals and human beings. Coadministration of an adjuvant can optimize protective immunity elicited by a DNA vaccine. In this study, we investigated the effect of a synthetic glucohexaose (beta-glu6), an analogue of Lentinan basic unit, on specific CD8(+) T cell response induced by a DNA vaccine encoding HBcAg (pB144) in mice. We found that beta-glu6 promoted the recruitment and maturation o ...[more]

PMID: 20625506

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Project description:Background & aimsParticulate hepatitis B core antigen (HBcoreAg) is a potent immunogen used as a vaccine carrier platform. HBcoreAg produced in E. coli encapsidates random bacterial RNA (bRNA). Using the heterologous protein-prime, viral-vector-boost therapeutic hepatitis B vaccine TherVacB, we compared the properties of different HBcoreAg forms. We explored how the content of HBcoreAg modulates antigen stability, immunogenicity, and antiviral efficacy.MethodsbRNA was removed from HBcoreAg by capsid disassembly, followed by reassembly in the absence or presence of specific nucleic acid-based adjuvants poly I:C or CpG. The morphology and structure of empty, bRNA-containing and adjuvant-loaded HBcoreAg were monitored by electron microscopy and nuclear magnetic resonance spectroscopy. Empty, bRNA-containing or adjuvant-loaded HBcoreAg were applied together with HBsAg and with or without nucleic acid-based external adjuvants within the TherVacB regimen in both wild-type and HBV-carrier mice.ResultsWhile HBcoreAg retained its structure upon bRNA removal, its stability and immunogenicity decreased significantly. Loading HBcoreAg with nucleic acid-based adjuvants re-established stability of the capsid-like antigen. Immunization with poly I:C- or CpG-loaded HBcoreAg induced high antibody titers against co-administered HBsAg. When applied within the TherVacB regimen, they activated vigorous HBcoreAg- and HBsAg-specific T-cell responses in wild-type and HBV-carrier mice, requiring a significantly lower dose of adjuvant compared to externally added adjuvant. Finally, immunization with adjuvant-loaded HBcoreAg mixed with HBsAg led to long-term control of persistent HBV replication in the HBV-carrier mice.ConclusionAdjuvant-loaded HBcoreAg retained capsid integrity and stability, was as immunogenic in vivo as externally adjuvanted HBcoreAg, requiring lower adjuvant levels, and supported immunity against co-administered, non-adjuvanted HBsAg. Thus, adjuvant-loaded HBcoreAg represents a promising novel platform for vaccine development.Impact and implicationsHepatitis B core antigen (HBcoreAg) recapitulates the capsid of the HBV that hosts the viral genome. Produced recombinantly, it is not infectious but emerges as a potent immunogen in vaccine development. In this preclinical study, we show that loading HBcoreAg with defined nucleic-acid-based adjuvants on the one hand stabilizes the HBcoreAg with standardized capsid content and, on the other hand, efficiently promotes the immunity of HBcoreAg and a co-administered antigen, allowing for reduced adjuvant doses. Therefore, adjuvant-loaded HBcoreAg not only serves as an encouraging option for therapeutic hepatitis B vaccines, but could also act as an efficient adjuvant delivery system for other types of vaccine.

Project description:Helicobacter pylori lipopolysaccharide promotes chronic gastric colonisation through O-antigen host mimicry and resistance to mucosal antimicrobial peptides mediated primarily by modifications of the lipid A. The structural organisation of the core and O-antigen domains of H. pylori lipopolysaccharide remains unclear, as the O-antigen attachment site has still to be identified experimentally. Here, structural investigations of lipopolysaccharides purified from two wild-type strains and the O-antigen ligase mutant revealed that the H. pylori core-oligosaccharide domain is a short conserved hexasaccharide (Glc-Gal-DD-Hep-LD-Hep-LD-Hep-KDO) decorated with the O-antigen domain encompassing a conserved trisaccharide (-DD-Hep-Fuc-GlcNAc-) and variable glucan, heptan and Lewis antigens. Furthermore, the putative heptosyltransferase HP1284 was found to be required for the transfer of the third heptose residue to the core-oligosaccharide. Interestingly, mutation of HP1284 did not affect the ligation of the O-antigen and resulted in the attachment of the O-antigen onto an incomplete core-oligosaccharide missing the third heptose and the adjoining Glc-Gal residues. Mutants deficient in either HP1284 or O-antigen ligase displayed a moderate increase in susceptibility to polymyxin B but were unable to colonise the mouse gastric mucosa. Finally, mapping mutagenesis and colonisation data of previous studies onto the redefined organisation of H. pylori lipopolysaccharide revealed that only the conserved motifs were essential for colonisation. In conclusion, H. pylori lipopolysaccharide is missing the canonical inner and outer core organisation. Instead it displays a short core and a longer O-antigen encompassing residues previously assigned as the outer core domain. The redefinition of H. pylori lipopolysaccharide domains warrants future studies to dissect the role of each domain in host-pathogen interactions. Also enzymes involved in the assembly of the conserved core structure, such as HP1284, could be attractive targets for the design of new therapeutic agents for managing persistent H. pylori infection causing peptic ulcers and gastric cancer.

Dataset Information

Beta-Glucan oligosaccharide enhances CD8(+) T cells immune response induced by a DNA vaccine encoding hepatitis B virus core antigen.

Publications

beta-Glucan oligosaccharide enhances CD8(+) T cells immune response induced by a DNA vaccine encoding hepatitis B virus core antigen.

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