Construction, Characterization, and Animal Testing of WRSd1, a
            <i>Shigella dysenteriae</i>
            1 Vaccine

Venkatesan, Malabi M.; Hartman, Antoinette B.; Newland, John W.; Ivanova, Vessela S.; Hale, Thomas L.; McDonough, Marie; Butterton, Joan R.

doi:10.1128/iai.70.6.2950-2958.2002

Cited by 37 publications

(16 citation statements)

References 31 publications

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“…Activity of this potent toxin was eliminated from the vaccine strains by deleting the entire stxAB operon in strains CVD 1254 and CVD 1255 or by deleting stxA (that encodes the enzymatically active A subunit) in CVD 1256 and CVD 1257. Earlier investigators isolated S. dysenteriae 1 strains that lacked Shiga toxin activity following anaerobic growth on medium containing chlorate, which selects for bacteria that have lost the fnr locus via deletion of a 20-kb chromosomal region that includes stxAB (39,53). While this method was effective for isolating Shiga toxinnegative strains, the large chromosomal deletion consequent to the chlorate treatment includes the loss of other genes besides stxAB.…”

Section: Discussionmentioning

confidence: 99%

Live Attenuated Shigella dysenteriae Type 1 Vaccine Strains Overexpressing Shiga Toxin B Subunit

Grassel

Levine

et al. 2011

Infect Immun

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Shigella dysenteriae serotype 1 (S. dysenteriae 1) is unique among the Shigella species and serotypes in the expression of Shiga toxin which contributes to more severe disease sequelae and the ability to cause explosive outbreaks and pandemics. S. dysenteriae 1 shares characteristics with other Shigella species, including the capability of causing clinical illness with a very low inoculum (10 to 100 CFU) and resistance to multiple antibiotics, underscoring the need for efficacious vaccines and therapeutics. Following the demonstration of the successful attenuating capacity of deletion mutations in the guaBA operon in S. flexneri 2a vaccine strains in clinical studies, we developed a series of S. dysenteriae 1 vaccine candidates containing the fundamental attenuating mutation in guaBA. All strains are devoid of Shiga toxin activity by specific deletion of the gene encoding the StxA subunit, which encodes enzymatic activity. The StxB subunit was overexpressed in several derivatives by either plasmid-based constructs or chromosomal manipulation to include a strong promoter. All strains are attenuated for growth in vitro in the HeLa cell assay and for plaque formation and were safe in the Serény test and immunogenic in the guinea pigs. Each strain induced robust serum and mucosal anti-S. dysenteriae 1 lipopolysaccharide (LPS) responses and protected against wild-type challenge. Two strains engineered to overexpress StxB induced high titers of Shiga toxin neutralizing antibodies. These candidates demonstrate the potential for a live attenuated vaccine to protect against disease caused by S. dysenteriae 1 and potentially to protect against the toxic effects of other Shiga toxin 1-expressing pathogens.Within the genus Shigella, four species, including S. dysenteriae, S. flexneri, S. sonnei, and S. boydii, cause diarrheal disease and dysentery in humans. It is estimated that more than 160 million cases of shigellosis and 1

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Section: Discussionmentioning

confidence: 99%

Live Attenuated Shigella dysenteriae Type 1 Vaccine Strains Overexpressing Shiga Toxin B Subunit

Grassel

Levine

et al. 2011

Infect Immun

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“…Most importantly, the reduction does not coincide with a consistent decrease in acquired serum or mucosal immunity or protective capacity. Live attenuated vaccine strains, like SC602 (S. flexneri 2a), WRSS1 (S. sonnei), and WRSd1 (S. dysenteriae 1), have the loss of the virG(icsA) gene (8,17,47) as their primary attenuating feature. Although these vaccines are highly attenuated and immunogenic, they induce mild fever and diarrhea in an unacceptable percentage of human volunteers (reviewed in reference 48).…”

Section: Vol 78 2010 Characterization Of S Flexneri Msbb Mutants 409mentioning

confidence: 99%

Virulence, Inflammatory Potential, and Adaptive Immunity Induced by Shigella flexneri msbB Mutants

et al. 2010

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The ability of genetically detoxified lipopolysaccharide (LPS) to stimulate adaptive immune responses is an ongoing area of investigation with significant consequences for the development of safe and effective bacterial vaccines and adjuvants. One approach to genetic detoxification is the deletion of genes whose products modify LPS. The msbB1 and msbB2 genes, which encode late acyltransferases, were deleted in the Shigella flexneri 2a human challenge strain 2457T to evaluate the virulence, inflammatory potential, and acquired immunity induced by strains producing underacylated lipid A. Consistent with a reduced endotoxic potential, S. flexneri 2a msbB mutants were attenuated in an acute mouse pulmonary challenge model. Attenuation correlated with decreases in the production of proinflammatory cytokines and in chemokine release without significant changes in lung histopathology. The levels of specific proinflammatory cytokines (interleukin-1␤ [IL-1␤], macrophage inflammatory protein 1␣ [MIP-1␣], and tumor necrosis factor alpha [TNF-␣]) were also significantly reduced after infection of mouse macrophages with either single or double msbB mutants. Surprisingly, the msbB double mutant displayed defects in the ability to invade, replicate, and spread within epithelial cells. Complementation restored these phenotypes, but the exact nature of the defects was not determined. Acquired immunity and protective efficacy were also assayed in the mouse lung model, using a vaccination-challenge study. Both humoral and cellular responses were generally robust in msbB-immunized mice and afforded significant protection from lethal challenge. These data suggest that the loss of either msbB gene reduces the endotoxicity of Shigella LPS but does not coincide with a reduction in protective immune responses.Shigellosis, or bacillary dysentery, is an acute colitis caused by Shigella flexneri, a gram-negative enteroinvasive bacterium that is transmitted to humans via the fecal-oral route. Shigella triggers its uptake into the M cells of the lower intestine, where they are taken up by the underlying antigen-presenting cells (macrophages and dendritic cells) (18). Shigella bacteria are released from macrophages after inducing cell death (12,29) and invade the surrounding enterocytes, where they begin to multiply and spread to adjacent cells. Effector proteins secreted through a molecular-needle-like complex called the type III secretion system (TTSS) mediate the processes of macrophage cytotoxicity, enterocyte invasion, and modulation of the host cell immune response. The TTSS and associated effector proteins are encoded on a large virulence plasmid that is present in all invasive strains of Shigella (46). During replication and dissemination in host cells, components of the bacterial cell wall (lipopolysaccharide [LPS] and peptidoglycan) are released, inducing proinflammatory cytokines and chemokines which activate the innate immune response (reviewed in reference 31). Although the immune mechanisms of protection remain relatively undef...

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“…WRSd1 is another S. dysenteriae 1 vaccine strain (deletion of icsA/virG, fnr, and stxAB genes) developed by WRAIR [81] from the wild-type strain 1617 that was isolated during a dysentery outbreak in Guatemala in 1969. This oral vaccine was evaluated (40 volunteers).…”

Section: Rational Selection Of Genesmentioning

confidence: 99%

Live-Attenuated Shigella Vaccines. Is Encouraging Good Enough?

Germani

Sansonetti

2010

Replicating Vaccines

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Several strategies have been used to develop vaccines against Shigella infection. Among these, the most tested has been the construction of live attenuated, orally administered vaccine candidates in which defined mutations were introduced in specific genes. Two major options exist: (1) altering key metabolic pathways affecting bacterial growth in tissues or (2) knocking out virulence genes selected upon their expected capacity to affect one or several key steps of the infectious process. In certain cases, the two options have been combined.Live-attenuated Shigella vaccine candidates have shown great promise. They elicited, in general, significant immune responses when administered orally to volunteers. They have the capacity to confer protection by eliciting both mucosal and systemic immune responses, particularly the intestinal production of secretory IgAs directed against the O-antigens, a series of complex surface sugars accounting for the bacterial serotypes, which are known to mediate protection following natural infection. These responses have been measured by evaluating antibody-secreting cells, serum antibody levels, and fecal IgA to O-antigens and individual virulencerelated protein antigens for a dozen of vaccine candidates. Live-attenuated vaccines also offer the potential to elicit strong IFN-g responses, a cytokine that is known to provide protection against Shigella infection. With regard to possible T-cell-mediated responses, much basic research is still warranted to optimize vaccine approaches. Owing to the wide range of Shigella serotypes and subtypes, there is a priori a need for a multivalent vaccine representing the prevalent species and serotypes. The barrier to the use of live vaccine candidates against shigellosis is the issue of multivalency and indications for an average to poor immune responses observed in infants and children in endemic areas. In addition, identification of the correlates of protection is needed to accelerate the development of these vaccines.

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Construction, Characterization, and Animal Testing of WRSd1, a Shigella dysenteriae 1 Vaccine

Cited by 37 publications

References 31 publications

Live Attenuated Shigella dysenteriae Type 1 Vaccine Strains Overexpressing Shiga Toxin B Subunit

Live Attenuated Shigella dysenteriae Type 1 Vaccine Strains Overexpressing Shiga Toxin B Subunit

Virulence, Inflammatory Potential, and Adaptive Immunity Induced by Shigella flexneri msbB Mutants

Live-Attenuated Shigella Vaccines. Is Encouraging Good Enough?

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