Clostridium difficile TxAC314 and SLP-36kDa enhance the immune response toward a co-administered antigen

Abstract

This study evaluated the in vivo adjuvant activity of two peptides derived from Clostridium difficile: a fragment of the receptor-binding domain of toxin A (TxA C314 ) and a fragment of the 36 kDa surface-layer protein (SLP-36kDa) from strain C253. Their ability to affect the magnitude, distribution and polarization of the immune response against fibronectin-binding protein A (FnbpA), a protective vaccine antigen against Staphylococcus aureus, was evaluated using two different routes of immunization: intranasal and subcutaneous. It was shown that (i) the route of immunization affected the magnitude of the immune response; (ii) both peptides enhanced the production of circulating anti-FnbpA IgG and IgA; (iii) following mucosal immunization TxA C314 was more effective than SLP-36kDa at inducing antibody in the gastrointestinal tract; (iv) the adjuvant influenced the Th1/Th2 balance; and (v) TxA C314 was more effective than SLP-36kDa in inducing a cell-mediated response. These studies provide insight into the ability of different C. difficile-derived peptides to differentially affect and polarize the activity of the immune system and on their potential use as adjuvants in newly developed vaccines.

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

“…In our previous study 37 and consistent with others, 35,36 we indicated that the N-terminus of TcdB was able to elicit a protective antibody response. In contrast, the RBD of TcdA has potent adjuvant activity 40 , and has been used as vaccine candidates in several studies. 28,34,40 Therefore, we hypothesized that a fusion protein containing the N-terminus of TcdB and RBD of TcdA would be immunogenic and sufficient to induce protection against both toxins.…”

“…In contrast, the RBD of TcdA has potent adjuvant activity 40 , and has been used as vaccine candidates in several studies. 28,34,40 Therefore, we hypothesized that a fusion protein containing the N-terminus of TcdB and RBD of TcdA would be immunogenic and sufficient to induce protection against both toxins.…”

“…32 Moreover, the N terminus of TcdB is more conserved than its RBD. 38,39 In contrast, the RBD of TcdA has potent adjuvant activity, e.g., it has been reported that a TcdA receptor peptide fragment enhanced mucosal antibody responses in mice when coadministered with heterologous protective antigens 40 . The RBD of TcdA has been used as an immunogen in several studies.…”

“…The RBD of TcdA has been used as an immunogen in several studies. 28,34,40 In this study, we have generated a much simplified new chimeric protein, mTcd138, containing the GTD and CPD domains of TcdB and RBD of TcdA. mTcd138 was evaluated in mice and hamsters for its immunogenicity, and protection efficacy against CDI.…”

The host immune response to Clostridium difficile

“…Future vaccines to reduce or prevent colonization with C. difficile As a C. difficile toxoid vaccine is unlikely to affect colonization, alternative vaccine candidates are being explored that may reduce or prevent this first step in the pathogenesis of CDI (Brun et al, 2008;Ní Eidhin et al, 2008;Péchiné et al, 2007). Péchiné et al (2005a, b) have evaluated C. difficile surface proteins, including the flagellar cap protein FliD and Cwp84, as vaccine antigens in a human flora-associated mouse model.…”