TLP01, an mshA mutant of Vibrio cholerae O139 as vaccine candidate against cholera

No commercially live vaccine against cholera caused by Vibrio cholerae O139 serogroup is available and it is currently needed. Virulent O139 strain CRC266 was genetically modified by firstly deleting multiple copies of the filamentous phage CTXφ, further tagging by insertion of the endoglucanase A c...

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Bibliographic Details
Published in:Microbes and infection 2012-09, Vol.14 (11), p.968-978
Main Authors: Ledón, Talena, Ferrán, Beatriz, Pérez, Celso, Suzarte, Edith, Vichi, Joivier, Marrero, Karen, Oliva, Reinaldo, Fando, Rafael
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antibodies, Bacterial - immunology
Attenuated
Bacterial Shedding
Base Sequence
Biofilms
Cholera
Cholera - immunology
Cholera - prevention & control
Cholera Vaccines - genetics
Cholera Vaccines - immunology
Cholera Vaccines - pharmacology
Clostridium thermocellum
Disease Models, Animal
Feces - microbiology
Fimbriae Proteins - genetics
Fimbriae Proteins - immunology
Intestinal Mucosa - immunology
Mannose-Binding Lectin - genetics
Mannose-Binding Lectin - immunology
Molecular Sequence Data
mshA mutant
Oral cholera vaccine
Rabbits
Rats
Rats, Sprague-Dawley
Sequence Alignment
Sequence Deletion - genetics
Statistics, Nonparametric
Vaccines, Attenuated - genetics
Vaccines, Attenuated - immunology
Vaccines, Attenuated - pharmacology
Vibrio cholerae
Vibrio Cholerae O139
Vibrio cholerae O139 - genetics
Vibrio cholerae O139 - immunology
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Summary:No commercially live vaccine against cholera caused by Vibrio cholerae O139 serogroup is available and it is currently needed. Virulent O139 strain CRC266 was genetically modified by firstly deleting multiple copies of the filamentous phage CTXφ, further tagging by insertion of the endoglucanase A coding gene from Clostridium thermocellum into the hemagglutinin/protease gene and finally deleting the mshA gene, just to improve the vaccine biosafety. One of the derived strains designated as TLP01 showed full attenuation and good colonizing capacity in the infant mouse cholera model, as well as highly immunogenic properties in the adult rabbit and rat models. Since TLP01 lacks MSHA fimbriae, it is refractory to infection with another filamentous phage VGJφ and therefore protected of acquiring CTXφ from a recombinant hybrid VGJφ/CTXφ. This strategy could reduce the possibilities of stable reversion to virulence out of the human gut. Furthermore, this vaccine strain was impaired to produce biofilms under certain culture conditions, which might have implications for the strain survival in natural settings contributing to vaccine biosafety as well. The above results has encouraged us to consider TLP01 as a live attenuated vaccine strain having an adequate performance in animal models, in terms of attenuation and immunogenicity, so that it fulfills the requirements to be evaluated in human volunteers.
ISSN:1286-4579
1769-714X
DOI:10.1016/j.micinf.2012.04.004