Abstract
Clostridium difficile is considered to be one of the major cause of infectious diarrhea in healthcare systems worldwide. Symptoms of C. difficile infection are caused largely by the production of two cytotoxins: toxin A (TcdA) and toxin B (TcdB). Vaccine development is considered desirable as it would decrease the mounting medical costs and mortality associated with C. difficile infections. Biodegradable nanoparticles composed of poly-γ-glutamic acid (γ-PGA) and chitosan have proven to be a safe and effective antigen delivery system for many viral vaccines. However, few studies have used this efficient antigen carrier for bacterial vaccine development. In this study, we eliminated the toxin activity domain of toxin B by constructing a recombinant protein rTcdB consists of residues 1852-2363 of TcdB receptor binding domain. The rTcdB was encapsulated in nanoparticles composed of γ-PGA and chitosan. Three rounds of intraperitoneal vaccination led to high anti-TcdB antibody responses and afforded mice full protection mice from lethal dose of C. difficile spore challenge. Protection was associated with high levels of toxin-neutralizing antibodies, and the rTcdB-encapsulated NPs elicited a longer-lasting antibody titers than antigen with the conventional adjuvant, aluminum hydroxide. Significant reductions in the level of proinflammatory cytokines and chemokines were observed in vaccinated mouse. These results suggested that polymeric nanocomplex-based vaccine design can be useful in developing vaccine against C. difficile infections.
Highlights
Clostridium difficile is a Gram-positive, anaerobic spore-forming bacterium and is the leading cause of antibiotic-associated diarrhea within hospital settings worldwide (Ananthakrishnan, 2011)
We evaluated a nanoparticle vaccine consisted of recombinant TcdB receptor binding domains (RBDs) encapsulated by a mixture of chitosan and poly-γ-glutamic acid (γ-PGS) for the ability to induce neutralizing antibodies and to protect mice from lethal C. difficile spore challenge
As the immunogenicity of TcdB has been well studied, in order to evaluate the potential of using nanoparticles as C. difficile vaccine adjuvants, our vaccine design started with the expression of recombinant C. difficile toxin B RBD
Summary
Clostridium difficile is a Gram-positive, anaerobic spore-forming bacterium and is the leading cause of antibiotic-associated diarrhea within hospital settings worldwide (Ananthakrishnan, 2011). C. difficile Nanoparticle Vaccine antibiotic treatments, such as clindamycin, or alteration in the endogenous gastrointestinal flora are considered major risk factors for C. difficile infection (Bartlett, 2008; Ananthakrishnan, 2011). Treatment of CDI mainly relies on the use of metronidazole and vancomycin, increasing cases of treatment failure or multiple relapses have raised concern over the need for alternative treatments (Ananthakrishnan, 2011). C. difficile spores can be present in the hospital setting, multiple relapses are quite common and making effective treatment difficult (Johnson, 2009). In recent years alternative therapeutic approaches such as fecal material transplantation (FMT) have gained ground as being effective and patients experience fewer relapses due to the recolonization of the intestinal microbiota (Borgia et al, 2015).
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