Human Antibody against Shiga Toxin 2 Administered to Piglets after the Onset of Diarrhea Due to Escherichia coli O157:H7 Prevents Fatal Systemic Complications

Abstract

Infection of children with Shiga toxin (Stx)-producing Escherichia coli (STEC) can lead to hemolytic-uremic syndrome (HUS) in 5 to 10% of patients. Stx2, one of two toxins liberated by the bacterium, is directly linked with HUS. We have previously shown that Stx-specific human monoclonal antibodies protect STEC-infected animals from fatal systemic complications. The present study defines the protective antibody dose in relation to the time of treatment after the onset of diarrhea in infected gnotobiotic piglets. Using the mouse toxicity model, we selected 5C12, an antibody specific for the A subunit, as the most effective Stx2 antibody for further characterization in the piglet model in which piglets developed diarrhea 16 to 40 h after bacterial challenge, followed by fatal neurological symptoms at 48 to 96 h. Seven groups of piglets received doses of 5C12 ranging from 6.0 mg/kg to 0.05 mg/kg of body weight, administered parenterally 48 h after bacterial challenge. The minimum fully protective antibody dose was 0.4 mg/kg, and the corresponding serum antibody concentration in these piglets was 0.7 g (؎0.5)/ml, measured 7 to 14 days after administration. Of 40 infected animals which received Stx2 antibody treatment of >0.4 mg/kg, 34 (85%) survived, while only 1 (2.5%) of 39 placebo-treated animals survived. We conclude that the administration of the Stx2-specific antibody was protective against fatal systemic complications even when it was administered well after the onset of diarrhea. These findings suggest that children treated with this antibody, even after the onset of bloody diarrhea, may be equally protected against the risk of developing HUS.

Rapid Detection of Shiga Toxin-Producing Escherichia coli by Optical Immunoassay

“…In addition, we observed that the OIA method was more sensitive than the EIA (14). In addition, therapies such as humanized monoclonal antibodies that can be passively administered to protect against Shiga toxins are in development (5,13). Once these therapies are available, at-risk patients who have been identified by rapid toxin detection methods can be treated promptly, since the efficacy of such interventions is likely to be proportional to the speed with which therapy is administered.…”

Nitric oxide inhibits Shiga-toxin synthesis by enterohemorrhagic Escherichia coli

“…In this contribution different approaches have aimed to neutralize Stx by the use of pharmacological compounds (26), specific antibodies (27,28), or recombinant bacteria expressing globotriaosylceramide-3 (29). Herein, we present NO, a critical mediator of the host mucosal innate immune response, as a potent inhibitor of Stx2 synthesis by EHEC.…”

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

“…Research in this field is still ongoing, but to date, the results have been disappointing [111] . Another option for the future is to treat patients during the diarrheal phase with monoclonal antibodies against Shiga toxin [112] . In December 2005, the United States Food and Drug Administration (FDA) approved orphan drug status for 2 chimerical anti-Stx antibodies.…”