Recombinant lipoprotein-based vaccine candidates against C. difficile infections

Journal of Biomedical Science

Pele Chong¹  Leung-Kei Siu²  Hsin-Wei Chen²  Shih-Jen Liu²  Kuang-Nan Hsiao²  Chih-Hsiang Leng²  Shu-Pei Lien²  Chia-Wei Wu²  Jui-Hsin Huang³ 

[1] Graduate Institute of Immunology, China Medical University, Taichung, Taiwan;Vaccine R&D Center, National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan;Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan

关键词: Adjuvant;    Toll-like receptor agonist;    Lipoprotein;    Receptor binding domain;    C. difficile toxins;    Antibiotic-associated pseudo-membranous colitis;   

Others  :  1225527
DOI  :  10.1186/s12929-015-0171-x

 received in 2015-04-09, accepted in 2015-07-29,  发布年份 2015

【 摘 要 】

Background

Opportunistically nosocomial infections in hospitalized patients are often related to Clostridium difficile infections (CDI) due to disruption of the intestinal micro-flora by antibiotic therapies during hospitalization. Clostridial exotoxins A and B (TcdA and TcdB) specifically bind to unknown glycoprotein(s) in the host intestine, disrupt the intestinal barrier leading to acute inflammation and diarrhea. The C-terminal receptor binding domain of TcdA (A-rRBD) has been shown to elicit antibody responses that neutralize TcdA toxicity in Vero cell cytotoxicity assays, but not effectively protect hamsters against a lethal dose challenge of C. difficile spores. To develop an effective recombinant subunit vaccine against CDI, A-rRBD was lipidated (rlipoA-RBD) as a rational design to contain an intrinsic adjuvant, a toll-like receptor 2 agonist and expressed in Escherichia coli.

Results

The purified rlipoA-RBD was characterized immunologically and found to have the following properties: (a) mice, hamsters and rabbits vaccinated with 3 μg of rlipoA-RBD produced strong antibody responses that neutralized TcdA toxicity in Vero cell cytotoxicity assays; furthermore, the neutralization titer was comparable to those obtained from antisera immunized either with 10 μg of TcdA toxoid or 30 μg of A-rRBD; (b) rlipoA-RBD elicited immune responses and protected mice from TcdA challenge, but offered insignificant protection (10 to 20 %) against C. difficile spores challenge in hamster models; (c) only rlipoA-RBD formulated with B-rRBD consistently confers protection (90 to 100 %) in the hamster challenge model; and (d) rlipoA-RBD was found to be 10-fold more potent than A-rRBD as an adjuvant to enhancing immune responses against a poor antigen such as ovalbumin.

Conclusion

These results indicate that rlipoA-RBD formulated with B-rRBD could be an excellent vaccine candidate for preclinical studies and future clinical trials.

【 授权许可】

   
2015 Huang et al.

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