引用

在发达国家，艰难梭菌是引起医院内抗生素相关腹泻的头号原因。历史上，发病机理主要归结为两种同源糖化毒素，毒素- a (TcdA)和毒素- b (TcdB)。然而，在过去十年中，出现了高毒力的艰难梭菌流行菌株(B1/NAP1/027)，并与发病率和死亡率的增加有关。毒性增加归因于多种因素，包括:A-和b -毒素的产生增加;二元毒素(CDT)的产生;以及毒性更强的TcdB变异(TcdB(027))的出现。TcdB(027)对细胞的细胞毒性更强;对动物造成更大的组织损伤和毒性;并且在抗原性上不同于历史上的TcdB(TcdB(003))。因此，广泛的保护性疫苗和治疗性抗体策略可能针对TcdA、TcdB变体和CDT。 To facilitate the generation of multivalent toxin-based C. difficile vaccines and therapeutic antibodies, we have generated fusion proteins constructed from the receptor binding domains (RBD) of TcdA, TcdB(003), TcdB(027) and CDT. Herein, we describe the development of a trivalent toxin (T-toxin) vaccine (CDTb/TcdB(003)/TcdA) and quadravalent toxin (Q-toxin) vaccine (CDTb/TcB(003)/TcdA/TcdB(027)) fusion proteins that retain the protective toxin neutralizing epitopes. Active immunization of mice or hamsters with T-toxin or Q-toxin fusion protein vaccines elicited the generation of toxin neutralizing antibodies to each of the toxins. Hamsters immunized with the Q-toxin vaccine were broadly protected against spore challenge with historical C. difficile 630 (toxinotype 0/ribotype 003) and epidemic NAP1 (toxinotype III/ribotype 027) strains. Fully human polyclonal antitoxin IgG was produced by immunization of transgenic bovine with these fusion proteins. In passive transfer studies, mice were protected against lethal toxin challenge. Hamsters treated with human antitoxin IgG were completely protected when challenged with historical or epidemic strains of C. difficile. The use of chimeric fusion proteins is an attractive approach to producing multivalent antitoxin vaccines and therapeutic polyclonal antibodies for prevention and treatment of C. difficile infections (CDI).