Towards Development of a Non-Toxigenic Clostridioides difficile Oral Spore Vaccine against Toxigenic C. difficile.
Towards Development of a Non-Toxigenic Clostridioides difficile Oral Spore Vaccine against Toxigenic C. difficile.
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DOI：
10.3390/pharmaceutics14051086
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发表时间：
2022-05-19
期刊：
影响因子：
5.4
通讯作者：
Griffin, Ruth
中科院分区：
文献类型：
--
作者：
Hughes, Jaime;Aston, Carl;Kelly, Michelle L.;Griffin, Ruth
艰难梭菌是一种机会性肠道病原体，可引起严重结肠炎，并因其毒素 TcdA 和 TcdB 导致显着的发病率和死亡率。两种肌内类毒素疫苗进入了 III 期试验，并在全身强烈诱导毒素中和抗体，但未能在结肠中提供针对原发性艰难梭菌感染 (CDI) 的局部保护。或者，通过口服免疫，可以直接靶向回肠（主要免疫诱导部位）以在大肠中提供保护。肠道共生、非产毒艰难梭菌 (NTCD) 此前已在动物模型中作为口服疫苗进行测试，用于将工程化毒素嵌合体自然递送至小肠，并成功诱导毒素中和抗体。我们研究了是否可以进一步利用 NTCD 来诱导抗体，阻止艰难梭菌与上皮细胞的粘附，从而靶向发病机制的第一阶段。在 NTCD 菌株 T7 中，定植因子 CD0873 和 TcdB 结构域过表达。用重组菌株 T7-0873 或 T7-TcdB 的孢子口服免疫仓鼠后，研究了肠道和全身反应。 T7-0873 疫苗接种成功诱导了肠道抗体，显着降低了产毒艰难梭菌与 Caco-2 细胞的粘附，并且这些反应也反映在血清中。现在需要对 NTCD 进行额外的工程来进一步开发这种疫苗。
Clostridioides difficile is an opportunistic gut pathogen which causes severe colitis, leading to significant morbidity and mortality due to its toxins, TcdA and TcdB. Two intra-muscular toxoid vaccines entered Phase III trials and strongly induced toxin-neutralising antibodies systemically but failed to provide local protection in the colon from primary C. difficile infection (CDI). Alternatively, by immunising orally, the ileum (main immune inductive site) can be directly targeted to confer protection in the large intestine. The gut commensal, non-toxigenic C. difficile (NTCD) was previously tested in animal models as an oral vaccine for natural delivery of an engineered toxin chimera to the small intestine and successfully induced toxin-neutralising antibodies. We investigated whether NTCD could be further exploited to induce antibodies that block the adherence of C. difficile to epithelial cells to target the first stage of pathogenesis. In NTCD strain T7, the colonisation factor, CD0873, and a domain of TcdB were overexpressed. Following oral immunisation of hamsters with spores of recombinant strain, T7-0873 or T7-TcdB, intestinal and systemic responses were investigated. Vaccination with T7-0873 successfully induced intestinal antibodies that significantly reduced adhesion of toxigenic C. difficile to Caco-2 cells, and these responses were mirrored in sera. Additional engineering of NTCD is now warranted to further develop this vaccine.
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