Immunization with a chimera between the B subunit of Shiga toxin type 2 and Brucella Lumazine Synthase confers total protection against Shiga toxins in mice

Abstract

The striking feature of Enterohemorrhagic Escherichia coli (EHEC) infections is the production of Shiga toxins (Stx) implicated in the development of the life-threatening hemolytic uremic syndrome (HUS). Despite the magnitude of the social impact of EHEC infections, no licensed vaccine or effective therapy is presently available for human use. One of the biggest challenges is to develop an effective and safe immunogen to ensure non toxicity but also a strong input to the immune system to induce long-lasting, high affinity antibodies with anti-Stx neutralizing capacity. The enzyme lumazine synthase from Brucella spp. (BLS) is a highly stable dimer of pentamers and a scaffold with enormous plasticity for displaying foreign antigens on it. Taking into account BLS advantages and the potential capacity of the B subunit of Stx2 (Stx2B) to induce antibodies that prevent Stx2 toxicity by blocking its entrance to the host cells, we engineered a new immunogen inserting Stx2B at the amino termini of BLS. The resulting chimera demonstrated a strong capacity to induce long-lasting humoral immune response in mice. The chimera induced antibodies with high neutralizing capacity for Stx2 and its variants. Moreover, immunized mice were completely protected against i.v. Stx2-challenge and weaned mice receiving an oral challenge with EHEC were completely protected by the transference of immune sera. We conclude that this novel immunogen represents a promising candidate for vaccine or antibody development with preventive or therapeutic ends, for use in HUS endemic areas or during future outbreaks caused by pathogenic strains of Stx-producing E. coli.