Phase 1 clinical trial of live attenuated Shigella dysenteriae type-1 ΔicsA Δent Δfep ΔstxA:HgR oral vaccine SC599 in healthy human adult volunteers

Sadorge, Christine; Ndiaye, Anna Julienne Selbé; Beveridge, Nathalie; Frazer, Schale; Giemza, Rafaela; Jolly, Nathalie; Johnson, Julie; Liddy, Helen; Cosgrove, Catherine; Allavena, Paola; Mantovani, Alberto; Béchet, Stéphane; Fontaine-Thompson, Annick; Griffin, George E.; Dupont, Francis; Sansonetti, Philippe J.; Lewis, David J. M.

doi:10.1016/j.vaccine.2007.11.024

Cited by 18 publications

(12 citation statements)

References 48 publications

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“…Other strategies for the development of vaccines to prevent S. dysenteriae 1 disease that have advanced to clinical trials include an S. dysenteriae type 1 O-antigen LPS polysaccharidecarrier protein conjugate that was immunogenic in volunteers (9,46,51) and two live attenuated S. dysenteriae 1 vaccine strains, including strains SC599 (with mutations in icsA, ent, fep, and stxA::hgR) and WRSd1 (harboring mutations in virG and stxAB) (32,48). Both of these live vaccines were well tolerated and moderately immunogenic, inducing anti-S. dysenteriae 1 LPS IgA antigen-secreting cell (ASC) responses in approximately 50% and 60% of volunteers, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Both of these live vaccines were well tolerated and moderately immunogenic, inducing anti-S. dysenteriae 1 LPS IgA antigen-secreting cell (ASC) responses in approximately 50% and 60% of volunteers, respectively. The SC599 vaccine strain retained the stxB gene; however, antiStxB responses were not measured (48). These studies have paved the way for the evaluation of a new generation of live attenuated S. dysenteriae 1 vaccines.…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…Fasting volunteers ingested 120 ml of 2% sodium bicarbonate buffer, followed 5 min later by 30 ml 2% (w/v) bicarbonate solution containing the assigned vaccine dose or no vaccine (placebo). SC599 vaccine was an attenuated Shigella dysenteriae strain, described elsewhere [29]. Quantification by Elispot of circulating IgA-ASC (antibody secreting cells) was performed on days 0, 7, 9 and 11 after vaccination and responders to the vaccine were defined as exhibiting ≥20 LPS-specific IgA ASC/10 6 PBMC.…”

Section: Methodsmentioning

confidence: 99%

MAIT Cells Detect and Efficiently Lyse Bacterially-Infected Epithelial Cells

et al. 2013

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Mucosal associated invariant T cells (MAIT) are innate T lymphocytes that detect a large variety of bacteria and yeasts. This recognition depends on the detection of microbial compounds presented by the evolutionarily conserved major-histocompatibility-complex (MHC) class I molecule, MR1. Here we show that MAIT cells display cytotoxic activity towards MR1 overexpressing non-hematopoietic cells cocultured with bacteria. The NK receptor, CD161, highly expressed by MAIT cells, modulated the cytokine but not the cytotoxic response triggered by bacteria infected cells. MAIT cells are also activated by and kill epithelial cells expressing endogenous levels of MRI after infection with the invasive bacteria Shigella flexneri. In contrast, MAIT cells were not activated by epithelial cells infected by Salmonella enterica Typhimurium. Finally, MAIT cells are activated in human volunteers receiving an attenuated strain of Shigella dysenteriae-1 tested as a potential vaccine. Thus, in humans, MAIT cells are the most abundant T cell subset able to detect and kill bacteria infected cells.

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“…The vaccine was well tolerated with only mild constitutional symptoms and was minimally shed in stool; however, serum antibody titers were modest or absent [78,79]. In this strain, three deletions have been introduced: DicsA/virG, Dent fep fes (genes encoding the enterochelin system), and DstxA, the gene encoding the catalytic subunit of Shiga toxin.…”

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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Phase 1 clinical trial of live attenuated Shigella dysenteriae type-1 ΔicsA Δent Δfep ΔstxA:HgR oral vaccine SC599 in healthy human adult volunteers

Cited by 18 publications

References 48 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

MAIT Cells Detect and Efficiently Lyse Bacterially-Infected Epithelial Cells

Live-Attenuated Shigella Vaccines. Is Encouraging Good Enough?

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