Safety and immunogenicity of WRSd1, a live attenuated Shigella dysenteriae type 1 vaccine candidate

McKenzie, Robin; Venkatesan, Malabi M.; Wolf, Marcia K.; Islam, Dilara; Grahek, Shannon; Jones, Andrea M.; Bloom, Arlene; Taylor, David N.; Hale, Thomas L.; Bourgeois, A. Louis

doi:10.1016/j.vaccine.2008.03.079

Cited by 36 publications

(28 citation statements)

References 24 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%

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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“…mg species below the detection limit within 20 h. Amongst four species and many subtypes of Shigella, S. dysenteriae 1 is the only Shigella that causes epidemics and pandemics, distinguished by high fever, cramps, seizures, bloody diarrhoea and dysentery, and haemolytic uraemic syndrome, and shows enormously high fatality rates amongst children and adults (Sur et al, 2004;Pozsgay et al, 2007;McKenzie et al, 2008;Barman et al, 2011). S. dysenteriae 1 causes recurrent disease in Asian countries such as India and Bangladesh (Dutta et al, 2003;von Seidlein et al, 2006;Emch et al, 2008).…”

Section: Time (H)mentioning

confidence: 99%

Intracellular and membrane-damaging activities of methyl gallate isolated from Terminalia chebula against multidrug-resistant Shigella spp.

Acharyya

Sarkar

Saha

et al. 2015

Journal of Medical Microbiology

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Shigella spp. (Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei ) cause bacillary dysentery (shigellosis), which is characterized by bloody mucous diarrhoea. Although a variety of antibiotics have been effective for treatment of shigellosis, options are becoming limited due to globally emerging drug resistance. In the present study, in vitro antibacterial activity of methyl gallate (MG) isolated from Terminalia chebula was determined by performing MIC, minimal bactericidal concentration (MBC) and time-kill kinetic studies. Bacterial membrane-damaging activity of MG was determined by membrane perturbation and transmission electron microscopy (TEM). Cellular drug accumulation, cell infection and assessment of intracellular activities of MG and reference antibiotics were performed using HeLa cell cultures. The bactericidal activity of MG against multidrug-resistant (MDR) Shigella spp. in comparison with other commonly used drugs including fluoroquinolone was demonstrated here. TEM findings in the present study revealed that MG caused the total disintegration of inner and outer membranes, and leakage of the cytoplasmic contents of S. dysenteriae. The level of accumulation of MG and tetracycline in HeLa cells incubated for 24 h was relatively higher than that of ciprofloxacin and nalidixic acid (ratio of intracellular concentration/extracellular concentration of antibiotic for MG and tetracycline.ciprofloxacin and nalidixic acid). The viable number of intracellular S. dysenteriae was decreased in a timedependent manner in the presence of MG (46MBC) and reduced to zero within 20 h. The significant intracellular activities of MG suggested that it could potentially be used as an effective antibacterial agent for the treatment of severe infections caused by MDR Shigella spp.

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“…It produces both LT and ST and expresses colonization factor I (CFA/I) (9). ETEC H10407 induces acute, watery diarrhea in otherwise healthy, ETEC-naïve subjects when they are challenged with Ն10 8 CFU of bacteria (18,20). The majority of ETEC H10407 challenge studies to date have utilized challenge inocula of 10 9 CFU in order to ensure diarrheal attack rates of Ͼ70%, which are needed to achieve statistical significance during small volunteer studies.…”

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confidence: 99%

Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines

Harro

Chakraborty

Feller

et al. 2011

Clin. Vaccine Immunol.

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Enterotoxigenic Escherichia coli (ETEC) is a leading bacterial cause of infectious diarrhea in infants and adults living in developing countries and accounts for approximately 30% of traveler's diarrhea in visitors to these regions (6, 21, 23-26, 28, 29, 35). ETEC strains vary in their pathogenicity as a result of differences in the expression of heat-labile toxin (LT), heatstable toxin (ST), and several colonization factors (CFAs) that are associated with attachment and colonization in the gut (23,31). For more than 40 years, human challenge models have been the mainstay for the clinical evaluation of ETEC pathogenesis and immunology (7,15) and for the assessment of the therapeutic and protective efficacy of antibiotics (2), probiotics (4), and candidate vaccines (18,19). The recent availability of new resources for ETEC vaccine development has renewed interest in ETEC challenge models. A model with a reliably high attack rate (AR) could provide a vehicle for the evaluation and screening of vaccine efficacy before expensive, longterm field trials are conducted in areas where ETEC is endemic or among at-risk travelers.

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Safety and immunogenicity of WRSd1, a live attenuated Shigella dysenteriae type 1 vaccine candidate

Cited by 36 publications

References 24 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

Intracellular and membrane-damaging activities of methyl gallate isolated from Terminalia chebula against multidrug-resistant Shigella spp.

Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines

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