Development and Evaluation of Vaccines based on Fimbrial Adhesins of Escherichia coli

With most pathogens acquiring resistance to currently used drugs, the development and formulation of vaccines against predominant infectious diseases has taken centre stage. Bacterial pathogens utilize a wide variety of virulence factors that are critical for disease, and therefore make attractive vaccine candidates. Fimbriae are one type of these virulence factors and mediate adherence to host tissues. Since preventing attachment of a bacterial pathogen is often adequate to render it non-virulent, antiadhesin antibodies can play an important role in the protection against infection. The aim of this Ph.D. thesis therefore concerned the design, construction and evaluation of recombinant anti-adhesin vaccines. The major research focus lay on the use of live-attenuated Salmonella vaccine strains as vectors to express and deliver fimbrial receptor-binding domains. We have chosen to focus our research on two fimbriae: type 1 and F17a fimbriae. Both fimbriae play a role in the initial stages of infection and sufficient structural information is present to identify their receptor-binding domains. Type 1 fimbriae, although present on most Enterobacteriaceae, are specific virulence factors of avian pathogenic E. coli (APEC) and uropathogenic E. coli (UPEC). The adhesin of type 1 fimbriae, FimH, allows binding to epithelial cells of the respiratory tract of poultry and the bladder of mammals. F17a fimbriae are found on certain bovine enterotoxigenic E. coli (ETEC) strains that inflict severe diarrhea in new-borne calves, and their adhesin, F17a-G, mediates attachment to the intestinal epithelium of calves. As the FimH and F17a-G adhesins are unstable in the absence of their chaperones, due to the incomplete Ig fold of the pillin domain, we used constructs covering only the receptor-binding