Repeated Dose Toxicity Study of a Live Attenuated Oral Cholera Vaccine in Sprague Dawley Rats
Received 22 May 2009; accepted 20 July 2009.
Background and Aims
A live attenuated vaccine candidate against human cholera has been developed from the genetically modified Vibrio cholerae O1, biotype El Tor, serotype Ogawa, 638 strain. Previous single dose toxicity and local tolerance studies have demonstrated that the product is innocuous in Sprague Dawley rats by oral route and single dose. The present paper describes a repeated dose toxicity study using a further dose compared to the proposed clinical schedule.
Methods
Sprague Dawley rats (140–180g) were treated with two doses of the vaccine candidate with a dedicated placebo formulation or were not treated at all (controls). The test products were inoculated at a 21-day interval. Animals were observed daily, body weight was determined weekly and food and water intakes were measured every other day. Three and 14 days after the last inoculation, groups of rats were humanely sacrificed, bled and macroscopically examined. Blood samples were taken for hematology, serum biochemistry and to determine the vibriocide antibody titers. A comprehensive list of tissue and organ samples was taken for microscopic studies.
Results
There was no mortality and no animal showed any clinical symptoms. Food and water intake, body weight, and hematological and biochemical variables did not show differences of toxicological and/or statistical relevance among the experimental groups. Macroscopic examination did not demonstrate any alterations and there were no histological findings of toxicological significance.
Conclusions
The vaccine was considered potentially safe for human use as indicated by the results in Sprague Dawley rats.
aDepartment of Animal Models and Preclinical Studies, Finlay Institute, Siboney, Playa, Habana, Cuba
bDepartment of Molecular Biology, Vice-Presidency of Research, Finlay Institute, Siboney, Playa, Habana, Cuba
cDepartment of Technological Development, Vice-Presidency of Development, Finlay Institute, Siboney, Playa, Habana, Cuba
dDepartment of Bacteriology, Vice-Presidency of Quality Assurance, Finlay Institute, Siboney, Playa, Habana, Cuba
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ABSTRACT