Immunization against clostridium difficile disease

Abstract

The invention provides active and passive immunization methods for preventing and treating Clostridium difficile infection, which involve percutaneous administration of C. difficile toxin-neutralizing polyclonal immune globulin, C. difficile toxoids, or combinations thereof. Also provided by the invention are C. difficile toxoids, C. difficile toxin-neutralizing polyclonal immune globulin, and methods of identifying subjects that produce C. difficile toxin-neutralizing polyclonal immune globulin.

Description

[0001] This is a continuation of U.S. Ser. No. 10 / 737,270, filed Dec. 16, 2003 (pending), which is a continuation-in-part of U.S. Ser. No. 09 / 815,452, filed Mar. 22, 2001 (U.S. Pat. No. 6,680,168), which is a continuation of U.S. Ser. No. 09 / 176,076, filed Oct. 20, 1998 (U.S. Pat. No. 6,214,341 B1), which claims priority from U.S. Ser. No. 60 / 062,522, filed on Oct. 20, 1997 (abandoned).BACKGROUND OF THE INVENTION [0002] This invention relates to methods and compositions for preventing and treating Clostridium difficile disease. [0003]Clostridium difficile, a toxin-producing Gram-positive bacterium, invades the intestinal tracts of patients whose normal intestinal flora is suppressed due to treatment with broad-spectrum antibiotics. The bacterial toxins cause varying degrees of damage to the large intestinal (i.e., colonic) epithelium, and cause a spectrum of illnesses, ranging from mild diarrhea to severe colitis. Because antibiotic treatment induces the onset of C. difficile diseas...

AI Technical Summary

Benefits of technology

[0007] The invention provides methods of treating Clostridium difficile disease in human patients. These methods involve percutaneously (e.g., intramuscularly, intravenously, or intraperitoneally) administering to a patient human C. difficile polyclonal immune globulin that neutralizes both Toxin A and Toxin B (hereinafter “immune globulin”) (e.g., 0.01-100 mg / kg body weight). These methods can also include percutaneous administration of a clostridial toxin or toxoid to a patient, to stimulate an anti-C. difficile immune response in the patient. When administered as treatment in affected individuals, the injected immune globulin will also prevent relapse.

[0009] The invention also provides methods of preventing or treating symptomatic C. difficile infection in human patients, which involve percutaneously administering a clostridial (e.g., C. difficile) toxin or toxoid to a patient, in the presence or absence of an adjuvant, such as alum. Patients treated by these methods can have or be at risk of developing, for example, recurrent C. difficile associated diarrhea (CDAD). An additional method included in the invention involves administering C. difficile immune globulin, as described above, to rapidly treat or protect a patient, while simultaneously administering toxoid for long-term, active protection by means of stimulation of the patient's immune system.

[0016] The invention provides several advantages. For example, treatment using the methods of the invention specifically results in inactivation of C. difficile bacterial toxins, without affecting normal intestinal flora. Both C. difficile Toxin A and Toxin B are involved in human disease, and the immunotherapy methods of the invention can be used to target both of these molecules. Recovery using immunotherapy is more rapid than antimicrobial therapy, which targets vegetative bacteria, rather than directing toxin neutralization. The specific neutralization of toxin activity has the advantage of specifically and rapidly inactivating the cause of tissue damage. In addition, a single dose of C. difficile immune globulin, administered percutaneously (e.g., intramuscularly, intravenously, or intraperitoneally), can be used in the methods of the invention, rather than the repeating dosing required for oral administration (Lyerly et al., Infect. Immun. 59:2215-2218, 1991). Further, the overall dose of C. difficile immune globulin administered percutaneously is lower than the dose required in oral methods, due to the longer half life of injected antibodies, compared to orally administered antibodies (hours vs. weeks or months). Specific antibody therapy also permits continuation of treatment of underlying conditions with antibiotics, which may otherwise have to be withdrawn to permit reconstitution of the intestinal flora and recovery from C. difficile infection. Also, treatment using the methods of the invention prevents the emergence of antibiotic-resistant bacteria. In particular, C. difficile disease has been traditionally treated with vancomycin and metronidizole, and use of vancomycin has led to the emergence of vancomycin-resistant enterococcus. Similar problems may be arising from metronidizole treatment. In addition, as is described further below, the methods of the invention have been shown to be effective in patients with recurrent disease (e.g., recurrent C. difficile associated diarrhea (CDAD)), which otherwise is difficult to manage and requires prolonged therapy with metronidazole or vancomycin. Further, C. difficile is cultured in the methods of the invention in medium that lacks complex animal products, such as nervous system products, e.g., the animal products in Brain Heart Infusion medium. Media containing such complex animal products have been found to contain the bovine spongiform encephalopathy (BSE) prion. Thus, in not using such medium, the invention provides safety against infection by such agents.

Problems solved by technology

Both toxins are lethal to animals when administered systemically.

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