Clostridium difficile Vaccine for Preventing Infection in Patients Undergoing Elective Treatment in a Healthcare Facility

C. diff, an anaerobic spore-forming bacterium, has been linked to antibiotic overuse, and CDI is on the rise in hospitals across the United States, Canada, Europe, and Japan.1,2 Although antimicrobial therapy remains the current standard for treating CDI, its use can paradoxically result in development of even more resistant strains of bacteria.3,4 This, combined with the high rate of C. diff relapse, suggests that nonantibiotic toxin-based interventions to prevent or treat the infection are needed. In the case of chronic relapsing CDI, continued antibiotic treatment might be replaced by fecal transplantation from a healthy donor to recolonize the patient's colon with nonpathogenic bacteria. Researchers are also investigating nonantimicrobial treatment options to prevent CDI recurrence and reduce the use of antibiotics.5

Sanofi-Pasteur is developing ACAM-CDIFF, a toxoid vaccine composed of inactivated C. diff toxins A and B.2 It is in clinical development to prevent and treat C. diff-associated diarrhea (CDAD).2 Toxins A and B are single-subunit exotoxins (i.e., toxic substances secreted by the organism) capable of binding host cells, translocating into host cells, and catalyzing pathogenic cellular reactions.6 Toxins cause epithelial cells in the colon to lose their barrier function by disrupting tight junctions and increasing cell membrane permeability. This can lead to diarrhea and severe inflammation.6 Preclinical studies suggest that antibodies against both toxins are required for full protection against C. diff-associated diarrhea.6 ACAM-CDIFF is intended for preventing primary CDI in at-risk adults, such as those undergoing prolonged hospitalization or long-term care in a nursing home or who have comorbidities that require chronic antibiotic use.2 ACAM-CDIFF is currently administered in phase II clinical trials as a 0.5 mL intramuscular injection on days 0, 7, and 30.7

In January 2013, Sanofi announced in a company portfolio update that it expects the vaccine to enter phase III clinical trials in the third quarter of 2013 in patients at high risk of CDI.8 Results of one ongoing phase II trial (National Clinical Trials identifier: NCT01230957) evaluating the vaccine in a population of middle-aged to elderly individuals at risk of C. diff exposure because of impending hospitalization or residence in a care facility are expected in July 2014. An additional phase II study evaluated the vaccine in patients with a new diagnosis of CDI (National Clinical Trials identifier: NCT00772343).9 Although this trial was completed in July 2012, results have not yet been reported. In October 2010, FDA granted ACAM-CDIFF fast-track designation for treating C. diff-associated diarrhea10 FDA's fast-track program is designed to facilitate the development and expedite the review of new drugs and vaccines...