Plasmid stabilisation for use in Shigella vaccine development

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The global impact of Shigellosis

Species of Shigella are the leading cause of bacterial dysentery worldwide. Shigella bacteria invade the epithelium lining of the gut leading to diarrhoea and the clinical syndrome called shigellosis. Shigellosis particularly impacts young children living in low-income countries. Despite significant reductions in mortality during the past few decades, there are still over 150,000 deaths per year attributable to shigellosis.

There is currently no vaccine available to prevent Shigellosis

Based on clinical severity, antibiotic resistance and disease burden, shigellosis caused by Shigella species is a prime target for vaccine development. The development of a Shigella vaccine would contribute significantly towards reducing the burden of disease, especially in nations where delivery of effective antimicrobials is challenging. To provide effective coverage, any vaccine developed should elicit protection against the most epidemiologically important Shigella serotypes, one of which is S. sonnei. This species is the most important serotype in industrialised counties and accounts for ~23% of disease isolates in less wealthy countries. A type III secretion system located on the plasmid pINV is critical for the virulence of Shigella bacteria. This plasmid is naturally maintained in growing bacterial populations through a process called post-segregational killing that consists of a toxin-antitoxin system.

Unfortunately, growth of S. sonnei at 37°C in the laboratory results in loss of this plasmid with consequent loss of pathogen virulence. This reduces the effectiveness of a Shigella vaccine strain produced in the lab. Little is known about the mechanisms underlying the high rate of pINV plasmid loss in this pathogen.

Oxford researchers have developed a method to stabilise plasmid pINV

Researchers at the University of Oxford have developed a modified Shigella toxin-antitoxin system that super-stabilises the pINV plasmid in the bacterial host. This allows the construction of S. sonnei strains which retain their virulence in the lab. This will facilitate studies of a host to pathogen interactions and future vaccine development. Additionally, this technique can be used to improve plasmid stability in other species of bacteria which could have significant use in the development of other vaccines and for increasing the efficiency of biomanufacturing processes. The Oxford researchers have demonstrated that they can use the technique to increase the stability of low-copy number plasmids in E. coli which could significantly increase the efficiency of biomanufacturing proteins for therapeutic and other uses.

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Oxford University Innovation has filed a patent application based on this technology.

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