Novartis Vaccines and Diagnostics SRL, Siena, Italy.
Infect Immun. 2013 Aug;81(8):2851-60. doi: 10.1128/IAI.01341-12. Epub 2013 May 28.
Clostridium difficile is a spore-forming bacterium that can reside in animals and humans. C. difficile infection causes a variety of clinical symptoms, ranging from diarrhea to fulminant colitis. Disease is mediated by TcdA and TcdB, two large enterotoxins released by C. difficile during colonization of the gut. In this study, we evaluated the ability of recombinant toxin fragments to induce neutralizing antibodies in mice. The protective efficacies of the most promising candidates were then evaluated in a hamster model of disease. While limited protection was observed with some combinations, coadministration of a cell binding domain fragment of TcdA (TcdA-B1) and the glucosyltransferase moiety of TcdB (TcdB-GT) induced systemic IgGs which neutralized both toxins and protected vaccinated animals from death following challenge with two strains of C. difficile. Further characterization revealed that despite high concentrations of toxin in the gut lumens of vaccinated animals during the acute phase of the disease, pathological damage was minimized. Assessment of gut contents revealed the presence of TcdA and TcdB antibodies, suggesting that systemic vaccination with this pair of recombinant polypeptides can limit the disease caused by toxin production during C. difficile infection.
艰难梭菌是一种能在动物和人类中存活的产芽孢细菌。艰难梭菌感染会引起各种临床症状，从腹泻到暴发性结肠炎不等。疾病是由 TcdA 和 TcdB 介导的，这两种大型肠毒素是艰难梭菌在肠道定植过程中释放的。在这项研究中，我们评估了重组毒素片段在小鼠中诱导中和抗体的能力。然后，在仓鼠疾病模型中评估了最有希望的候选物的保护效果。虽然一些组合观察到了有限的保护作用，但 TcdA 的细胞结合结构域片段（TcdA-B1）和 TcdB 的葡糖基转移酶部分（TcdB-GT）的共同给药诱导了系统 IgG，这些 IgG 中和了两种毒素，并保护接种疫苗的动物免受两种艰难梭菌菌株的攻击而死亡。进一步的特征分析表明，尽管在疾病的急性阶段，接种疫苗的动物的肠道腔中有高浓度的毒素，但病理损伤最小化。对肠道内容物的评估显示存在 TcdA 和 TcdB 抗体，这表明用这对重组多肽进行全身接种可以限制艰难梭菌感染期间毒素产生引起的疾病。
