Live Attenuated Human
            <i>Salmonella</i>
            Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity

Galen, James E.; Buskirk, Amanda D.; Tennant, Sharon M.; Pasetti, Marcela F.

doi:10.1128/ecosalplus.esp-0010-2016

Cited by 34 publications

(41 citation statements)

References 111 publications

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“…Advances in molecular biology have allowed the design of attenuated mutants preserving adequate immunogenicity while preventing persistent infection. In order to limit undesired reactogenicity, targeted attenuation can be performed with both virulent and metabolic genes (143,144), resulting in mutations affecting functionality or through complete gene disruption. This has led to the development of several candidate vaccines orally administered and currently tested in phase 2 clinical trials, such as, for example, M01ZH09 (Ty2; aroC ssaV mutants), CVD909 (aroC aroD htrA mutants), and Ty800 (phoP phoQ mutants) (145,146).…”

Section: Recent Developments In Human Vaccinationmentioning

confidence: 99%

Vaccination against Salmonella Infection: the Mucosal Way

Gayet¹,

Bioley²,

Rochereau³

et al. 2017

Microbiol Mol Biol Rev

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subspecies includes several serovars infecting both humans and other animals and leading to typhoid fever or gastroenteritis. The high prevalence of associated morbidity and mortality, together with an increased emergence of multidrug-resistant strains, is a current global health issue that has prompted the development of vaccination strategies that confer protection against most serovars. Currently available systemic vaccine approaches have major limitations, including a reduced effectiveness in young children and a lack of cross-protection among different strains. Having studied host-pathogen interactions, microbiologists and immunologists argue in favor of topical gastrointestinal administration for improvement in vaccine efficacy. Here, recent advances in this field are summarized, including mechanisms of bacterial uptake at the intestinal epithelium, the assessment of protective host immunity, and improved animal models that closely mimic infection in humans. The pros and cons of existing vaccines are presented, along with recent progress made with novel formulations. Finally, new candidate antigens and their relevance in the refined design of anti- vaccines are discussed, along with antigen vectorization strategies such as nanoparticles or secretory immunoglobulins, with a focus on potentiating mucosal vaccine efficacy.

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Section: Recent Developments In Human Vaccinationmentioning

confidence: 99%

Vaccination against Salmonella Infection: the Mucosal Way

Gayet¹,

Bioley²,

Rochereau³

et al. 2017

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

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“…Alternative vaccine candidates currently in phase I and phase II studies have been generated by targeting virulence genes related to acid resistance, stress response, osmolarity and invasion. These gene targets are combined with gene deletions resulting in limited intracellular replication [ 24 ] . In most STY vaccine candidates, deleted genes attenuate infection.…”

Section: Introductionmentioning

confidence: 99%

“…In most STY vaccine candidates, deleted genes attenuate infection. A notable exception is the constitutive expression of the STY-specific [ 82 ] immune-capsule suppressing regulator [ 78 ] tviA gene [ 24 ]. Despite the development of several vaccine strains against STY, no strategy confers long-term protection in a cost-effective manner.…”

Section: Introductionmentioning

confidence: 99%

Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes Aimed at Evading Host Mucosal Immune Defense During Early Infection of Human Intestinal Tissue

et al. 2018

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Commensal microorganisms influence a variety of host functions in the gut, including immune response, glucose homeostasis, metabolic pathways and oxidative stress, among others. This study describes how Salmonella Typhi, the pathogen responsible for typhoid fever, uses similar strategies to escape immune defense responses and survive within its human host. To elucidate the early mechanisms of typhoid fever, we performed studies using healthy human intestinal tissue samples and “mini-guts,” organoids grown from intestinal tissue taken from biopsy specimens. We analyzed gene expression changes in human intestinal specimens and bacterial cells both separately and after colonization. Our results showed mechanistic strategies that S. Typhi uses to rearrange the cellular machinery of the host cytoskeleton to successfully invade the intestinal epithelium, promote polarized cytokine release and evade immune system activation by downregulating genes involved in antigen sampling and presentation during infection. This work adds novel information regarding S. Typhi infection pathogenesis in humans, by replicating work shown in traditional cell models, and providing new data that can be applied to future vaccine development strategies.

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“…Indeed, live attenuated Salmonella have multiple potential advantages as vaccine vectors and have been used to express foreign antigens against infectious diseases and cancers [20–22]. They directly target the intestinal M cells overlying the gut-associated lymphoid tissues (GALT) [21, 23–26], have large ‘carrying’ capacity [27] and are easy to manipulate both in the laboratory and at industrial scale. Although there is considerable experience with the attenuated S. typhi vaccine strain (Ty21a: Vivotif™) in the delivery of heterologous antigens [21, 28], far less is known about the potential of other Salmonella strains.…”

Section: Introductionmentioning

confidence: 99%

“…They directly target the intestinal M cells overlying the gut-associated lymphoid tissues (GALT) [21, 23–26], have large ‘carrying’ capacity [27] and are easy to manipulate both in the laboratory and at industrial scale. Although there is considerable experience with the attenuated S. typhi vaccine strain (Ty21a: Vivotif™) in the delivery of heterologous antigens [21, 28], far less is known about the potential of other Salmonella strains. Of direct relevance to the current work, Chen and colleagues used YS1646 to express a chimeric S. japonicum antigen that induced both strong antibody and cellular responses after repeated oral dosing and provided up to 62% protection in a murine challenge model [29].…”

Section: Introductionmentioning

confidence: 99%

Vaccination against the digestive enzyme Cathepsin B using a YS1646Salmonella entericaTyphimurium vector provides almost complete protection againstSchistosoma mansonichallenge in a mouse model

Hassan

Zelt

Perera

et al. 2019

Preprint

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24Schistosoma mansoni threatens hundreds of millions of people in >50 countries. Schistosomulae 25 migrate through the lung and adult worms reside adjacent to the intestinal mucosa. None of the 26 candidate vaccines in current development is designed to elicit a mucosal response. We have 27 repurposed an attenuated Salmonella enterica Typhimurium strain (YS1646) to produce such a 28 vaccine targeting Cathepsin B (CatB), a digestive enzyme important for parasite survival. 29 Promoter-Type 3 secretory signal pairs were screened for protein expression in vitro and 30 transfected into YS1646 to generate candidate vaccine strains. Two strains were selected for in 31 vivo evaluation (nirB_SspH1 and SspH1_SspH1). Female C57BL/6 mice were immunized twice, 32 3 weeks apart, using six strategies: i) saline gavage (control), ii) the 'empty' YS1646 vector orally 33 (PO) followed by intramuscular recombinant CatB (20g IM rCatB), iii) two doses of IM rCatB, 34 iv) two PO doses of YS1646-CatB, v) IM rCatB then PO YS1646-CatB and vi) PO YS1646-CatB 35 then IM rCatB. Serum IgG responses to CatB were monitored by ELISA. Three weeks after the 36 second dose, mice were challenged with 150 cercariae and sacrificed 7 weeks later to assess adult 37 worm and egg burden (liver and intestine), granuloma size and egg morphology. CatB-specific 38 IgG antibodies were low/absent in the control and PO only groups but rose substantially in other 39 groups (5898-6766ng/mL). The highest response was in animals that received nirB_SspH1 40 YS1646 PO then IM rCatB. In this group, reductions in worm and intestine/liver egg burden (vs. 41 control) were 93.1% and 79.5%/90.3% respectively (all P<.0001). Granuloma size was reduced in 42 all vaccinated groups (range 32.86-52.83 x10 3 m 2 ) and most significantly in the nirB_SspH1 + 43 CatB IM group (34.74±3.35 x10 3 m 2 vs. 62.22±6.08 x10 3 m 2 : vs. control P<.01). Many eggs in 44 the vaccinated animals had abnormal morphology. Targeting CatB using a multi-modality 45 approach can provide almost complete protection against S. mansoni challenge. 46 Author Summary 47 Schistosomiasis is a parasitic disease that affects over 250 million people worldwide and over 800 48 million are at risk of infection. Of the three main species, Schistosoma mansoni is the most widely 49 distributed and is endemic in the Caribbean, South America, Africa, and the Middle East. It causes 50 a chronic disease with severe negative effects on quality of life. Mass drug administration of 51 praziquantel is the only available course of action due to a current lack of vaccines. However, 52 praziquantel does not protect from reinfection. Therefore, a vaccine would be beneficial as a long-53 term solution to reduce morbidity and transmission of the disease. Our group has repurposed the 54 attenuated YS1646 strain of Salmonella Typhimurium as an oral vaccine vector for the digestive 55 enzyme Cathepsin B of S. mansoni. Oral vaccination followed by an intramuscular dose of 56 recombinant Cathepsin B lead to significant reduction...

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Live Attenuated Human Salmonella Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity

Cited by 34 publications

References 111 publications

Vaccination against Salmonella Infection: the Mucosal Way

Vaccination against Salmonella Infection: the Mucosal Way

Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes Aimed at Evading Host Mucosal Immune Defense During Early Infection of Human Intestinal Tissue

Vaccination against the digestive enzyme Cathepsin B using a YS1646Salmonella entericaTyphimurium vector provides almost complete protection againstSchistosoma mansonichallenge in a mouse model

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