Clostridium difficile Vaccine and Serum Immunoglobulin G Antibody Response to Toxin A

Abstract

There is a strong association between serum antibody responses to toxin A and protection against Clostridium difficile diarrhea. A parenteral C. difficile toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G (IgG) in the sera of healthy volunteers. After vaccination, the concentrations of anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations that were associated with protection in previous clinical studies. Furthermore, the median concentration of serum anti-toxin A IgG in the test group was 50-fold higher than the previous threshold. These findings support the feasibility of using a vaccine to protect high-risk individuals against C. difficile-associated diarrhea and colitis.Clostridium difficile is the most commonly known cause of nosocomial infectious diarrhea in industrialized countries (2, 9). Rates of C. difficile infection in high-risk hospital patients receiving antibiotics are as high as 31% (11,15,19). The clinical presentation of C. difficile colitis ranges from mild diarrhea to fulminant pseudomembranous colitis (2, 9). However, approximately half of the patients who are colonized by toxin-producing strains of C. difficile are asymptomatic carriers (11,15).Two recent clinical studies demonstrated that high concentrations of anti-toxin A immunoglobulin G (IgG) antibody in serum were associated with protection against C. difficile-associated diarrhea and colitis (11,12). In the first study, infected patients with serum anti-toxin A IgG concentrations of greater than 3 enzyme-linked immunosorbent assay (ELISA) units (EU) were 48-fold more likely to become asymptomatic carriers than patients with lower concentrations of anti-toxin A antibody (11). In the second study, patients who developed high concentrations of serum anti-toxin A IgG during initial episodes of C. difficile-associated diarrhea were 48-fold less likely to suffer a recurrence than those who did not show an anti-toxin A antibody response (12). These findings provide further evidence that active or passive immunization against C. difficile toxins may be effective in preventing C. difficile-associated diarrhea and colitis (1,3,5,10,13,17,20).Kotloff et al. reported recently their experience using a parenteral C. difficile vaccine containing toxoids A and B administered to healthy adult volunteers (7). To our knowledge, this is the only candidate C. difficile vaccine that has been tested in human studies. The vaccine was produced from a culture filtrate of C. difficile strain ATCC 43255 as previously described (7). Briefly, toxins A and B were partially purified by ammonium sulfate precipitation and application to an S300 Sephacryl size exclusion column, followed by inactivation with formaldehyde. The total protein concentration of the vaccine was 0.52 mg per ml, of which toxins A and B comprised about 44% at a 1.5:1 toxin A-to-toxin B ratio. Both toxoid A and toxoid B were included in the C. difficile vaccine based on preclinical observations which indicated that both toxin A and toxin B m...

Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections

“…In one study of hospitalized patients with CDI, those who developed RCDI had lower levels of immunoglobulin G (IgG) antibody to toxin A ( 82 ). In another, three patients who were given a vaccine to clear C. diffi cile developed an IgG response to toxin A ( 83 ).…”

The host immune response to Clostridium difficile infection

“…The only candidate vaccine to progress to phase II human clinical trials is a formalin-inactivated toxoid A and B vaccine that induced a high serum-antitoxin antibody response and showed success in treating patients with recurrent CDI [Aboudola et al 2003;Kotloff et al 2001;Sougioultzis et al 2005]. Recent improvements in the purity of this toxoid vaccine and coadministration with aluminium hydroxide adjuvant resulted in robust seroconversion for anti-TcdA and anti-TcdB in a phase I randomized, placebocontrolled study on healthy volunteers and an effective dose has been defined for use in further clinical trials [Greenberg et al 2012].…”

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

“…Vaccines targeting the C. difficile toxins include toxoids [19][20][21][22][23] and toxin fragments. [24][25][26][27][28][29] Formaldehyde-inactivated native C. difficile toxins have been reported to be well tolerated and able to induce protective immunity in CDI in humans.…”