Clostridium difficile infe
ction (CDI) is the major
cause of antibioti
c-asso
ciated diarrhea and pseudomembranous
colitis, a disease asso
ciated with signifi
cant morbidity and mortality. The disease is mostly of noso
comial origin, with elderly patients undergoing anti-mi
crobial therapy being parti
cularly at risk.
C. difficile produ
ces two large toxins: Toxin A (T
cdA) and Toxin B (T
cdB). The two toxins a
ct synergisti
cally to damage and impair the
coloni
c epithelium, and are primarily responsible for the pathogenesis asso
ciated with CDI. The feasibility of toxin-based va
ccination against
C. difficile is being vigorously investigated. A va
ccine based on formaldehyde-ina
ctivated Toxin A and Toxin B (toxoids) was reported to be safe and immunogeni
c in healthy volunteers and is now undergoing evaluation in
clini
cal effi
ca
cy trials. In order to eliminate
cytotoxi
c effe
cts, a
chemi
cal ina
ctivation step must be in
cluded in the manufa
cturing pro
cess of this toxin-based va
ccine. In addition, the large-s
cale produ
ction of highly toxi
c antigens
could be a
challenging and
costly pro
cess.
Vaccines based on non-toxic fragments of genetically engineered versions of the toxins alleviate most of these limitations. We have evaluated a vaccine assembled from two recombinant fragments of TcdB and explored their potential as components of a novel experimental vaccine against CDI. Golden Syrian hamsters vaccinated with recombinant fragments of TcdB combined with full length TcdA (Toxoid A) developed high titer IgG responses and potent neutralizing antibody titers. We also show here that the recombinant vaccine protected animals against lethal challenge with C. difficile spores, with efficacy equivalent to the toxoid vaccine. The development of a two-segment recombinant vaccine could provide several advantages over toxoid TcdA/TcdB such as improvements in manufacturability.