Subunit vaccines for Shigella flexneri, Salmonella typhimurium, Burkholderia pseudomallei, Yersenia pestis and Pseudomonas aeruginosa.

University of Kansas
posted on 06/29/2010

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Virulence of all five bacterial pathogen species requires a Type Three Secretion System (TTSS). The TTSS is a supramolecular assembly consisting of a basal body and an extracellular needle-like structure composed of more than 20 unique proteins. The apparatus acts as a molecular conduit which is responsible for the translocation of effector proteins into a eukaryotic host, subverting normal cell function. Researchers at the University of Kansas have identified two groups of TTSS proteins relevant to vaccine development. These TTSS proteins are commonly referred to as needle and tip proteins. The representative proteins from each bacterial species do not all share high sequence homology although the analogues are structurally and functionally related. The Needle Proteins: MxiH (Shigella flexneri), Prgl (Salmonella typhimurium), BsaL (Burkholderia pseudomallei), YscF (Yersenia pestis) and PscF (Pseudomonas aeroginosa) are small (< 10 kDa), hydrophilic proteins with low iso-electric points (pl) which readily oligomerize when expressed in their wildtype form. The proteins can be rendered mono-disperse when the 5 C-terminal residues are truncated. Both the monomer and the oligomer represent potential vaccine antigens. The Tip Proteins: IpaD (Shigella flexneri), SipD (Salmonella typhimurium), BipD (Burkholderia pseudomallei), LcrV (Yersenia pestis), PcrV (Pseudomonas aeroginosa) are approximately 37 kDa proteins with low pls. Published work on the Shigella flexneri system has reported the localization of IpaD to the needle tip during infection, where it controls the secretion of effector proteins. It has also been established that anti-IpaD antibodies are capable of neutralizing bacterial invasion. Similar to this, LcrV, the tip protein from the Yersenia species, has been established as protective. Researchers at the University of Kansas have extensively studied the solution stability of each of these protein antigens, investigated numerous formulation aspects and have proven the antigenicity of both the Shigella (MxiH and IpaD) and Salmonella (Prgl and SipD) proteins.

Subunit vaccines for Shigella flexneri, Salmonella typhimurium, Burkholderia pseudomallei, Yersenia pestis and Pseudomonas aeruginosa.

The identified antigens are ideal vaccine candidates, as they are necessary for bacterial virulence and are surface exposed. This approach is considered safer than whole bacteria (attenuated or killed) vaccine approaches. Other subunit vaccine concepts have not been proven effective.