Multi-faceted Approach to Vaccine Development Against Escherichia coli O157:H7
Uniformed Services University Of The Health Sciences Bethesda United States
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Enterohemorrhagic Escherichia coli EHEC O157H7 was first recognized as a human pathogen in the early 1980s when it was isolated from the stools of individuals with bloody diarrhea who had ingested undercooked hamburger. We now know that cattle are asymptomatic intestinal carriers of O157H7 and the principal source of transmission to people. The primary adhesin of O157H7, intimin, is required for the organism to colonize cattle. Additionally, EHEC can produce one or more types of potent Shiga toxins Stx that are responsible for the damage to renal microvasculature that can lead to the development of the life-threatening post-infection sequela, the hemolytic uremic syndrome HUS. The goal of our research is to develop a vaccine against EHEC that can reduce transmission of the organism from cattle to humans and also prevent toxin-mediated disease in infected individuals. Ideally, such a vaccine would induce mucosal anti-intimin IgA antibodies that block adherence of the bacteria to the gut and serum anti-Stx IgG antibodies that neutralize toxin activity. It was recently reported that intimin expressing tobacco cells, when used in a parenteral-prime-oral boost immunization scheme, reduced the colonization of O157H7 in mice. Further efforts to express intimin in corn are described here as well as are my efforts to design and evaluate prototype immunogens against Stxs. For the latter purpose, I initially demonstrated that genetic toxoids are viable vaccine candidates, and confirmed the hypothesis that a multivalent vaccine for both Stx 1 and 2 is required. Next, I made a plant-based Stx2 toxoid vaccine, fed it to mice, and demonstrated that it protected them from intoxication after oral challenge with an Stx-producing E. coli strain.