A PLATFORM FOR A MULTI-VALENT DIARRHEA VACCINE
Campylobacter jejuni, Enterotoxigenic Escherichia coli (ETEC) and Shigella sp. are major causes of bacterial diarrhea worldwide. Approaches to C. jejuni and Shigella vaccines include conjugate vaccines in which C. jejuni capsular polysaccharides and Shigella lipopolysaccharides are conjugated to proteins. In the case of ETEC vaccines, most current approaches are based on recombinant proteins that are involved in virulence. Here, the creation of a multi-pathogen vaccine using ETEC proteins as conjugating partners for C. jejuni and Shigella polysaccharides is described. Three vaccines were synthesized in which two C. jejuni polysaccharides were conjugated to two recombinant ETEC adhesins based on CFA/I (CfaEB) and CS6 (CssBA), and LPS from Shigella flexneri was also conjugated to CfaEB. The glycoconjugates were made by first activating the polysaccharides through TEMPO-mediated oxidation  (selective/stoichiometric oxidation of primary alcohols) followed by ligation to the ETEC proteins by reductive amination or carbodiimide chemistry. The vaccines were immunogenic in mice as monovalent, bivalent and trivalent formulations. Importantly, functional antibodies capable of inducing hemaglutination inhibition (HAI) of a CFA/I expressing ETEC strain were induced in all vaccines containing CfaEB. These data suggest that conjugate vaccines could be a platform for a multi-pathogen, multi-serotype vaccine against the three major causes of diarrheal disease worldwide.
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