Development Of A Live, Oral, Attenuated Vaccine Against El Tor Cholera

Taylor, David N.; Killeen, Kevin; Hack, Dallas C.; Kenner, Julie R.; Coster, Trinka S.; Beattie, David T.; Ezzell, John W.; Hyman, Tracy; Trofa, Andrew F.; Sjögren, Maria H.; Friedlander, Arthur M.; Mekalanos, John J.; Sadoff, Jerald C.

doi:10.1093/infdis/170.6.1518

Cited by 99 publications

(95 citation statements)

References 22 publications

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“…Volunteers inoculated with Peru-3 often developed selflimiting diarrhea, whereas diarrhea was not observed in volunteers who received Peru-15 (6,7). Similarly, we found that most (12/18) rabbits inoculated with Peru-3 developed diarrhea, whereas only 2 of 13 rabbits inoculated with Peru-15 exhibited diarrhea.…”

Section: Resultssupporting

confidence: 72%

“…Comparative analyses of vaccine candidates suggests that reactogenicity may be linked to V. cholerae's single polar flagellum and/or to bacterial motility. The vaccine strain Peru-3, a ctxA derivative of a Peruvian El Tor clinical isolate, caused diarrhea, whereas Peru-15, a spontaneously derived nonflagellated (nonmotile) derivative of Peru-3, did not (6,7). Both strains engendered protection against challenge with wild-type V. cholerae in human trials, suggesting that the lack of reactogenicity does not simply result from a failure of Peru-15 to colonize.…”

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confidence: 99%

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Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins

Rui

Ritchie

Bronson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cholera is a severe diarrheal disease caused by the motile Gramnegative rod Vibrio cholerae. Live-attenuated V. cholerae vaccines harboring deletions of the genes encoding cholera toxin have great promise for reducing the global burden of cholera. However, development of live vaccines has been hampered by the tendency of such strains to induce noncholeric reactogenic diarrhea in human subjects. The molecular bases of reactogenicity are unknown, but it has been speculated that reactogenic diarrhea is a response to V. cholerae's flagellum and/or the motility that it enables. Here, we used an infant rabbit model of reactogenicity to determine what V. cholerae factors trigger this response. We found that V. cholerae ctx mutants that produced flagellins induced diarrhea, regardless of whether the proteins were assembled into a flagellum or whether the flagellum was functional. In contrast, ∼90% of rabbits infected with V. cholerae lacking all five flagellin-encoding genes did not develop diarrhea. Thus, flagellin production, independent of flagellum assembly or motility, is sufficient for reactogenicity. The intestinal colonization and intraintestinal localization of the nonreactogenic flagellin-deficient strain were indistinguishable from those of a flagellated motile strain; however, the flagellin-deficient strain stimulated fewer mRNA transcripts coding for proinflammatory cytokines in the intestine. Thus, reactogenic diarrhea may be a consequence of an innate host inflammatory response to V. cholerae flagellins. Our results suggest a simple genetic blueprint for engineering defined nonreactogenic live-attenuated V. cholerae vaccine strains.animal model | cholera | innate immunity | diarrhea

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Section: Resultssupporting

confidence: 72%

mentioning

confidence: 99%

Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins

Rui

Ritchie

Bronson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…TCP production is essential to the ability of diverse O1 strains of V. cholerae to colonize infant mice (1,30). We therefore tested the four TCP Ϫ , non-O1, non-O139 strains for colonization in infant mice (Table 1), using the CTX Ϫ TCP ϩ O1 strain (Bah-2) as the reference strain (44). Whereas N16961 competed effectively with Bah-2 (competitive index ϭ 1.21), the TCP Ϫ control strain TCP-2 showed an Ϸ10-fold reduction in colonization.…”

Section: Tcp ؊ Non-o1 Non-o139 Strains Are Proficient For Colonizatimentioning

confidence: 99%

Genomic characterization of non-O1, non-O139 Vibrio cholerae reveals genes for a type III secretion system

Dziejman

Serruto²,

Tam³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

201

212

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Non-O1, non-O139 Vibrio cholerae can cause gastroenteritis and extraintestinal infections, but, unlike O1 and O139 strains of V. cholerae, little is known about the virulence gene content of non-O1, non-O139 strains and their phylogenetic relationship to other pathogenic V. cholerae. Comparative genomic microarray analysis of four pathogenic non-O1, non-O139 strains indicates that these strains are quite divergent from O1 and O139 strains. Genomic sequence analysis of a non-O1, non-O139 strain (AM-19226) that appeared particularly pathogenic in experimental animals suggests that this strain carries a type III secretion system (TTSS) that is related to the TTSS2 gene cluster found in a pandemic clone of Vibrio parahaemolyticus. The genes for this V. cholerae TTSS system appear to be present in many clinical and environmental non-O1, non-O139 strains, including at least one clone that is globally distributed. We hypothesize that the TTSS present in some pathogenic strains of non-O1, non-O139

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“…5,6 Two major strategies have been used to develop a cholera vaccine with long-term immunity: live-attenuated V. cholerae strains lacking the ability to produce CT 5,7,8 and killed whole cell toxogenic V. cholerae strains in combination with CTB. [7][8][9] Several live-attenuated vaccine candidates have been developed including CVD103-HgR, CVD111, CVD101, CVD103, Peru-14, and Peru-15, which have been used in the clinical trials.…”

mentioning

confidence: 99%

“…[7][8][9] Several live-attenuated vaccine candidates have been developed including CVD103-HgR, CVD111, CVD101, CVD103, Peru-14, and Peru-15, which have been used in the clinical trials. 5,6,8,10,11 These are single dose vaccines, which can elicit a high titer of serum vibriocidal antibodies because they can actively colonize the host intestinal lumen. 6,[12][13][14] The major defect of the engineered live vaccine strains is the probability of acquiring the enterotoxin gene through horizontal gene transfer.…”

mentioning

confidence: 99%