Developement of live attenuated anti-Shigella vaccine based on molecular pathogenesis studies

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Bacillary dysentery, caused by Shigella, is a significant cause of serious enteric illness in the world, particularly in developing countries. Efficacious vaccines are thus urgently needed. Several promising vaccine candidates are at various levels of investigations, but to date none is available for public health purposes. Recently genetic and molecular basis of the pathogenicity of Shigella and host responses to the bacterial virulence factors have been elucidated, that have made it possible to construct a live attenuated vaccine based on rational strategies. The genes required at a certain known step of infection process can be selectively mutated to impair the interaction with intestinal epithelial cells and/or survive within intestinal tissues in general. Based on the genetic and molecular studies on Shigella pathogenic properties, we have constructed and evaluated a virG thyA double mutant of S.flexneri serotype 2a for utilization as a candidate live attenuated oral vaccine against bacillary dysentery. virG is required for spreading into adjacent epithelial cells and thyA essential for the multiplication of the invading bacteria. These mutations were introduced by insertional inactivation with Tn10 followed by counterselection for a tetracycline-sensitive derivative. This double mutant completely protected guinea pigs from provoking keratoconjunctivitis. It also appeared safe when administered intragastrically to cynomolgus monkeys and gave an incomplete but highly significant protection against a challenge by the homologous wild type shigella flexneri strain as judged by bacteriological, histopathological and immunological examinations.