Health Protection Agency, Porton Down, Salisbury, Wilts, United Kingdom.
Infect Immun. 2012 Feb;80(2):875-82. doi: 10.1128/IAI.05684-11. Epub 2011 Dec 5.
Treatment of Clostridium difficile is a major problem as a hospital-associated infection which can cause severe, recurrent diarrhea. The currently available antibiotics are not effective in all cases and alternative treatments are required. In the present study, an ovine antibody-based platform for passive immunotherapy of C. difficile infection is described. Antibodies with high toxin-neutralizing titers were generated against C. difficile toxins A and B and were shown to neutralize three sequence variants of these toxins (toxinotypes) which are prevalent in human C. difficile infection. Passive immunization of hamsters with a mixture of toxin A and B antibodies protected them from a challenge with C. difficile spores in a dose-dependent manner. Antibodies to both toxins A and B were required for protection. The administration of toxin A and B antibodies up to 24 h postchallenge was found to reduce significantly the onset of C. difficile infection compared to nonimmunized controls. Protection from infection was also demonstrated with key disease isolates (ribotypes 027 and 078), which are members of the hypervirulent C. difficile clade. The ribotype 027 and 078 strains also have the capacity to produce an active binary toxin and these data suggest that neutralization of this toxin is unnecessary for the management of infection induced by these strains. In summary, the data suggest that ovine toxin A and B antibodies may be effective in the treatment of C. difficile infection; their potential use for the management of severe, fulminant cases is discussed.
艰难梭菌感染是一种严重的医院相关性感染，可导致严重、反复的腹泻，其治疗是一个主要问题。目前可用的抗生素并非对所有病例均有效，需要替代疗法。本研究描述了一种基于羊抗体的艰难梭菌感染被动免疫治疗平台。针对艰难梭菌毒素 A 和 B 产生了具有高毒素中和效价的抗体，并证明它们能中和在人类艰难梭菌感染中流行的三种毒素序列变体（毒素型）。用毒素 A 和 B 抗体混合物对仓鼠进行被动免疫，可使其在一定剂量范围内免受艰难梭菌孢子的挑战。保护作用需要两种毒素的抗体。与未免疫对照相比，在挑战后 24 小时内给予毒素 A 和 B 抗体可显著减少艰难梭菌感染的发病。用关键疾病分离株（ribotype 027 和 078）也证明了这种保护作用，这些分离株属于高毒力艰难梭菌 clade。ribotype 027 和 078 菌株也有产生活性二元毒素的能力，这些数据表明，中和这种毒素对于管理这些菌株引起的感染是不必要的。总之，这些数据表明，羊毒素 A 和 B 抗体可能对治疗艰难梭菌感染有效；讨论了其在治疗严重、暴发性病例中的潜在用途。
