Safety and immunogenicity of increasing doses of a Clostridium difficile toroid vaccine administered to healthy adults

Clostridium difficile is a major cause of nosocomial diarrhea in industrial ized countries. Although most illnesses respond to available therapy, infec tion can increase morbidity, prolong hospitalization, and produce life-thre atening colitis. Vaccines are being explored as an alternative means for pr otecting high-risk individuals. We assessed the safety, immunogenicity, and dose response of a parenteral vaccine containing C. difficile toxoids A an d B. Thirty healthy adults were assigned to receive four spaced inoculation s on days 1, 8, 30, and 60 with one of three doses of vaccine (6.25, 25, or 100 mug). At each dose level, subjects were randomized, in a double-blind fashion, to receive either the soluble toxoids (n = 5) or toxoids adsorbed to alum (n = 5). Subjects were monitored for clinical and immunologic respo nses to vaccination. Vaccination was generally well tolerated, with occasio nal, usually mild, systemic reactions (abdominal pain, arthralgia, and diar rhea). The most common local reaction, mild arm pain, was reported by all r ecipients of the toroid-alum formulation. Nearly all subjects (greater than or equal to 90%) developed vigorous serum antibody responses to both toxin s, as measured by immunoglobulin G (IgG) enzyme-linked immunosorbent assay and neutralization of cytotoxicity, whereas fecal IgA increases occurred in approximately 50%. Statistically significant effects of dose and formulati on on immunogenicity were not seen, although antibody levels tended to be h igher with the alum-adjuvanted formulations and with increasing doses of so luble toroid. Serum antibody responses among the toxoid-alum group appeared to plateau at 25 mug. We concluded that the C. difficile toxoid vaccine is safe and immunogenic in healthy volunteers. Further development as a proph ylactic vaccine or for producing C. difficile hyperimmune globulin is justi fied.