Development of an Acid-Resistant Salmonella Typhi Ty21a Attenuated Vector For Improved Oral Vaccine Delivery

Dharmasena, Madushini N.; Feuille, Catherine M.; Starke, Carly E.; Bhagwat, Arvind A.; Stibitz, Scott; Kopecko, Dennis J.

doi:10.1371/journal.pone.0163511

Cited by 17 publications

(18 citation statements)

References 47 publications

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“…A non-specific band was used as the loading control instead of a standard housekeeping protein since standard housekeeping protein overlapped in their position on the gel with the ETC complexes. The use of a non-specific band has been used in a wide variety of previous studies [ 41 – 45 ]. The difference in the non-specific band was examined across experimental groups and sampling locations similar to the manner in which the complexes were analyzed and no systematic difference was found across experimental groups or sampling locations.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study

et al. 2017

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Gastrointestinal (GI) symptoms are prevalent in autism spectrum disorder (ASD) but the pathophysiology is poorly understood. Imbalances in the enteric microbiome have been associated with ASD and can cause GI dysfunction potentially through disruption of mitochondrial function as microbiome metabolites modulate mitochondrial function and mitochondrial dysfunction is highly associated with GI symptoms. In this study, we compared mitochondrial function in rectal and cecum biopsies under the assumption that certain microbiome metabolites, such as butyrate and propionic acid, are more abundant in the cecum as compared to the rectum. Rectal and cecum mucosal biopsies were collected during elective diagnostic colonoscopy. Using a single-blind case-control design, complex I and IV and citrate synthase activities and complex I-V protein quantity from 10 children with ASD, 10 children with Crohn’s disease and 10 neurotypical children with nonspecific GI complaints were measured. The protein for all complexes, except complex II, in the cecum as compared to the rectum was significantly higher in ASD samples as compared to other groups. For both rectal and cecum biopsies, ASD samples demonstrated higher complex I activity, but not complex IV or citrate synthase activity, compared to other groups. Mitochondrial function in the gut mucosa from children with ASD was found to be significantly different than other groups who manifested similar GI symptomatology suggesting a unique pathophysiology for GI symptoms in children with ASD. Abnormalities localized to the cecum suggest a role for imbalances in the microbiome, potentially in the production of butyrate, in children with ASD.

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Section: Methodsmentioning

confidence: 99%

Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study

et al. 2017

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“…One method to achieve this is to protect the vaccine from the low pH of gastric acidity by integrating acid stabilization genes into it. We have done this successfully with a Ty21a- Shigella sonnei O-antigen bivalent vaccine, 54 , 55 and intend to do so for Ty21a-PA-01.…”

Section: Discussionmentioning

confidence: 99%

Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis

Sim

Osorio

et al. 2017

npj Vaccines

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The national blueprint for biodefense concluded that the United States is underprepared for biological threats. The licensed anthrax vaccine absorbed vaccine, BioThrax, requires administration of at least 3–5 intramuscular doses. The anthrax vaccine absorbed vaccine consists of complex cell-free culture filtrates of a toxigenic Bacillus anthracis strain and causes tenderness at the injection site and significant adverse events. We integrated a codon-optimized, protective antigen gene of B. anthracis (plus extracellular secretion machinery), into the chromosome of the licensed, oral, live-attenuated typhoid fever vaccineTy21a to form Ty21a-PA-01 and demonstrated excellent expression of the gene encoding protective antigen. We produced the vaccine in a 10-L fermenter; foam-dried and vialed it, and characterized the dried product. The vaccine retained ~50% viability for 20 months at ambient temperature. Sera from animals immunized by the intraperitoneal route had high levels of anti-protective antigen antibodies by enzyme-linked immunosorbent assay and anthrax lethal toxin-neutralizing activity. Immunized mice were fully protected against intranasal challenge with ~5 LD50 of B. anthracis Sterne spores, and 70% (7/10) of vaccinated rabbits were protected against aerosol challenge with 200 LD50 of B. anthracis Ames spores. There was a significant correlation between protection and antibody levels determined by enzyme-linked immunosorbent assay and toxin-neutralizing activity. These data provide the foundation for achievement of our ultimate goal, which is to develop an oral anthrax vaccine that is stable at ambient temperatures and induces the rapid onset of durable, high-level protection after a 1-week immunization regimen.

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“…Enteric pathogens including E. coli, L. monocytogenes, Shigella spp., and L. lactis can tolerate extreme acidic pH (below pH 2.5) because they possess the most potent acid resistance (AR) system known as GDAR (glutamatedependent acid resistance) pathway. Attenuated strains of ST and STm have limited acid tolerance and exhibit moderate immunogenicity (Dharmasena et al 2016a). By engineering AR components from Shigella spp., Dharmasena et al significantly (10 5fold) enhanced acid tolerance of attenuated ST-Ty21a (Dharmasena et al 2016a).…”

Section: Acid Resistancementioning

confidence: 99%

“…Attenuated strains of ST and STm have limited acid tolerance and exhibit moderate immunogenicity (Dharmasena et al 2016a). By engineering AR components from Shigella spp., Dharmasena et al significantly (10 5fold) enhanced acid tolerance of attenuated ST-Ty21a (Dharmasena et al 2016a).…”

Section: Acid Resistancementioning

confidence: 99%

Live-Attenuated Bacterial Vectors for Delivery of Mucosal Vaccines, DNA Vaccines, and Cancer Immunotherapy

Kumar

2019

Environmental Chemistry for a Sustainable World

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Vaccines save millions of lives each year from various life-threatening infectious diseases, and there are more than 20 vaccines currently licensed for human use worldwide. Moreover, in recent decades immunotherapy has become the mainstream therapy, which highlights the tremendous potential of immune response mediators, including vaccines for prevention and treatment of various forms of cancer. However, despite the tremendous advances in microbiology and immunology, there are several vaccine preventable diseases which still lack effective vaccines. Classically, weakened forms (attenuated) of pathogenic microbes were used as vaccines. Although the attenuated microbes induce effective immune response, a significant risk of reversion to pathogenic forms remains. While in the twenty-first

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Development of an Acid-Resistant Salmonella Typhi Ty21a Attenuated Vector For Improved Oral Vaccine Delivery

Cited by 17 publications

References 47 publications

Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study

Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study

Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis

Live-Attenuated Bacterial Vectors for Delivery of Mucosal Vaccines, DNA Vaccines, and Cancer Immunotherapy

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