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CTXphi immunity: application in the development of cholera vaccines.

ABSTRACT: CTXphi is a filamentous bacteriophage that encodes cholera toxin, the principal virulence factor of Vibrio cholerae. CTXphi is unusual among filamentous phages because it encodes a repressor and forms lysogens. CTXphi can infect the existing live-attenuated V. cholerae vaccine strains derived from either the El Tor or classical V. cholerae biotypes and result in vaccine reversion to toxinogenicity. Intraintestinal CTXphi transduction assays were used to demonstrate that El Tor biotype strains of V. cholerae are immune to infection with the El Tor-derived CTXphi, whereas classical strains are not. The El Tor CTXphi repressor, RstR, was sufficient to render classical strains immune to infection with the El Tor CTXphi. The DNA sequences of the classical and El Tor CTXphi repressors and their presumed cognate operators are highly diverged, whereas the sequences that surround this "immunity" region are nearly identical. Transcriptional fusion studies revealed that the El Tor RstR mediated repression of an El Tor rstA-lacZ fusion but did not repress a classical rstA-lacZ fusion. Likewise, the classical RstR only repressed a classical rstA-lacZ fusion. Thus, similar to the mechanistic basis for heteroimmunity among lambdoid phages, the specificity of CTXphi immunity is based on the divergence of the sequences of repressors and their operators. Expression of the El Tor rstR in either El Tor or classical live-attenuated V. cholerae vaccine strains effectively protected these vaccines from CTXphi infection. Introduction of rstR into V. cholerae vaccine strains should enhance their biosafety.

SUBMITTER: Kimsey HH

PROVIDER: S-EPMC22729 | biostudies-literature | 1998 Jun

REPOSITORIES: biostudies-literature

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CTXphi immunity: application in the development of cholera vaccines.

Kimsey H H HH Waldor M K MK

Proceedings of the National Academy of Sciences of the United States of America 19980601 12

CTXphi is a filamentous bacteriophage that encodes cholera toxin, the principal virulence factor of Vibrio cholerae. CTXphi is unusual among filamentous phages because it encodes a repressor and forms lysogens. CTXphi can infect the existing live-attenuated V. cholerae vaccine strains derived from either the El Tor or classical V. cholerae biotypes and result in vaccine reversion to toxinogenicity. Intraintestinal CTXphi transduction assays were used to demonstrate that El Tor biotype strains of ...[more]

PMID: 9618534

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Project description:BackgroundKilled whole-cell oral cholera vaccines (kOCVs) are becoming a standard cholera control and prevention tool. However, vaccine efficacy and direct effectiveness estimates have varied, with differences in study design, location, follow-up duration, and vaccine composition posing challenges for public health decision making. We did a systematic review and meta-analysis to generate average estimates of kOCV efficacy and direct effectiveness from the available literature.MethodsFor this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Review Library on July 9, 2016, and ISI Web of Science on July 11, 2016, for randomised controlled trials and observational studies that reported estimates of direct protection against medically attended confirmed cholera conferred by kOCVs. We included studies published on any date in English, Spanish, French, or Chinese. We extracted from the published reports the primary efficacy and effectiveness estimates from each study and also estimates according to number of vaccine doses, duration, and age group. The main study outcome was average efficacy and direct effectiveness of two kOCV doses, which we estimated with random-effect models. This study is registered with PROSPERO, number CRD42016048232.FindingsSeven trials (with 695 patients with cholera) and six observational studies (217 patients with cholera) met the inclusion criteria, with an average two-dose efficacy of 58% (95% CI 42-69, I2=58%) and effectiveness of 76% (62-85, I2=0). Average two-dose efficacy in children younger than 5 years (30% [95% CI 15-42], I2=0%) was lower than in those 5 years or older (64% [58-70], I2=0%; p<0·0001). Two-dose efficacy estimates of kOCV were similar during the first 2 years after vaccination, with estimates of 56% (95% CI 42-66, I2=45%) in the first year and 59% (49-67, I2=0) in the second year. The efficacy reduced to 39% (13 to 57, I2=48%) in the third year, and 26% (-46 to 63, I2=74%) in the fourth year.InterpretationTwo kOCV doses provide protection against cholera for at least 3 years. One kOCV dose provides at least short-term protection, which has important implications for outbreak management. kOCVs are effective tools for cholera control.FundingThe Bill & Melinda Gates Foundation.

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CTXphi immunity: application in the development of cholera vaccines.

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CTXphi immunity: application in the development of cholera vaccines.

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