The molecular basis for the virulence of bacterial pathogens: implications for oral vaccine development

Dougan, Gordon

doi:10.1099/13500872-140-2-215

Cited by 46 publications

(23 citation statements)

References 12 publications

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“…The potential of live attenuated Salmonella strains to induce both humoral and cell-mediated immunity has prompted their use as carriers of genes derived from other organisms (4)(5)(6)18). Provided that the vectors retain the potential to protect against Salmonella infection, this strategy allows construction of bi-or multivalent vaccines, an attractive option for mass immunization programs in developing countries.…”

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confidence: 99%

Impact of Vector Priming on the Immunogenicity of RecombinantSalmonellaVaccines

Vindurampulle

Attridge

2003

Infect Immun

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There are conflicting reports concerning the impact of prior vector priming on the immunogenicity of recombinant-Salmonella-based vaccines. A comparison of experimental protocols identified two variables which might account for this inconsistency: the potential of the vector strain to colonize the murine gut-associated lymphoid tissue (GALT) and the nature of the foreign antigen subsequently delivered by the recombinant Salmonella construct. The former was investigated by constructing an aroA mutant of the Salmonella enterica serovar Stanley vector previously used in our laboratory. Although the introduction of an aroA mutation had surprisingly little effect on GALT colonization, it did reduce the strength of antilipopolysaccharide (anti-LPS) antibody responses and the impact of vector priming. Studies were also performed to ascertain the extent to which any observed hyporesponsiveness consequent upon vector priming might be determined by the characteristics of the foreign antigen. S. enterica serovar Stanley was used to deliver either of two Escherichia coli antigens, K88 pilus protein or the LT-B toxin subunit, to vector-primed mice. Both serum immunoglobulin G (IgG) and intestinal IgA responses to K88 were completely abolished, and those to LT-B were significantly reduced, as a consequence of vector priming. When similar experiments were performed with an aroA S. enterica serovar Dublin vector, responses to K88 were significantly reduced but those to LT-B were unaffected by vector priming. Paradoxically, a priming infection with this vector induced stronger anti-LPS antibody responses but was less likely to elicit a state of hyporesponsiveness to subsequently presented foreign antigen. The impact of vector priming thus depends on both the Salmonella strain used and the nature of the foreign antigen, but our present data strengthen concerns that preexisting antivector immunity represents a serious threat to the Salmonella-based vaccine strategy.

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Impact of Vector Priming on the Immunogenicity of RecombinantSalmonellaVaccines

Vindurampulle

Attridge

2003

Infect Immun

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“…The potential of live attenuated Salmonella strains to induce broad-based immune responses, including cell-mediated, humoral, and S-IgA Ab responses, has prompted their use as oral vaccine delivery vectors for recombinant proteins associated with virulence (1,5,6,29). Genes from bacteria, viruses, parasites, and mammalian species have been expressed in attenuated Salmonella strains; however, few studies have elucidated the immunological mechanisms for induction of immune responses to the expressed Ag.…”

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confidence: 99%

Peyer's Patches Are Required for Intestinal Immunoglobulin A Responses toSalmonellaspp

Hashizume

Togawa²,

Nochi

et al. 2008

Infect Immun

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“…However, the induction of potent CD8 T-cell responses to fight microbes or cancer remains a major challenge in vaccine development. Live attenuated bacteria (e.g., S. enterica, L. monocytogenes, and mycobacteria) have been widely used as vaccine carriers for foreign antigen display to induce cell-mediated immunity (9,21,37). In the past, the T3SS of S. enterica serovar Typhimurium became an attractive tool for heterologous protein delivery directly into the cytosol of macrophages and dendritic cells, resulting in vigorous antigen-specific CD8 T-cell priming and the induction of protective immunity against viruses, bacteria, and tumors (29,30,32,34).…”

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confidence: 99%

Superior Protective Immunity against Murine Listeriosis by Combined Vaccination with CpG DNA and RecombinantSalmonella entericaSerovar Typhimurium

et al. 2009

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Preexisting antivector immunity can severely compromise the ability of Salmonella enterica serovar Typhimurium live vaccines to induce protective CD8 T-cell frequencies after type III secretion system-mediated heterologous protein translocation in orally immunized mice. To circumvent this problem, we injected CpG DNA admixed to the immunodominant p60 217-225 peptide from Listeria monocytogenes subcutaneously into BALB/c mice and coadministered a p60-translocating Salmonella strain by the orogastric route. The distribution of tetramer-positive p60 217-225 -specific effector and memory CD8 T cells was analyzed by costaining of lymphocytes with CD62L and CD127. In contrast to the single oral application of recombinant Salmonella or single immunization with CpG and p60, in the spleens from mice immunized with a combination of both vaccine types a significantly higher level of p60-specific CD8 T cells with a predominance of the effector memory T-cell subset was detected. In vivo protection studies revealed that this CD8 T-cell population conferred sterile protective immunity against a lethal infection with L. monocytogenes. However, p60-specific central memory CD8 T cells induced by single vaccination with CpG and p60 were not able confer effective protection against rapidly replicating intracellular Listeria. In conclusion, we provide compelling evidence that the combination of Salmonella type III-mediated antigen delivery and CpG immunization is an attractive novel vaccination strategy to modulate CD8 differentiation patterns toward distinct antigen-specific T-cell subsets with favorable protective capacities.The type III secretion system (T3SS) of Salmonella enterica serovar Typhimurium can be used to target heterologous antigens directly into the cytosol of antigen-presenting cells (30,32,33). Our laboratory has reported that the single oral immunization of mice with a recombinant Salmonella strain expressing the translocated Yersinia outer protein E (YopE) fused to the immunodominant antigen p60 from Listeria monocytogenes results in the efficient induction of p60-specific CD8 T cells (33). In further experiments, we explored the possibility to induce enhanced levels of antigen-specific CD8 T cells by oral boost immunization using the same recombinant serovar Typhimurium strain (38). We demonstrated that the rapid clearance of the Salmonella vaccine carrier due to anti-Salmonella vector immunity after the second immunization prevents a significant elevation of T-lymphocyte numbers (38). In a more recent study, we showed that heterologous prime-boost immunizations using attenuated serovar Typhimurium and serovar Dublin strains for foreign antigen delivery can be used to bypass anti-Salmonella immunity resulting in enhanced antigen-specific CD8 T-cell induction (40). However, the translation of this heterologous prime-boost immunization approach from mice to man is not trivial due to the lack of S. enterica vaccine strains with different O antigens approved for use in humans.An alternative vaccination strategy to ...

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The molecular basis for the virulence of bacterial pathogens: implications for oral vaccine development

Cited by 46 publications

References 12 publications

Impact of Vector Priming on the Immunogenicity of RecombinantSalmonellaVaccines

Impact of Vector Priming on the Immunogenicity of RecombinantSalmonellaVaccines

Peyer's Patches Are Required for Intestinal Immunoglobulin A Responses toSalmonellaspp

Superior Protective Immunity against Murine Listeriosis by Combined Vaccination with CpG DNA and RecombinantSalmonella entericaSerovar Typhimurium

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