Killed but metabolically active microbes: a new vaccine paradigm for eliciting effector T-cell responses and protective immunity
Killed but metabolically active microbes: a new vaccine paradigm for eliciting effector T-cell responses and protective immunity
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DOI：
10.1038/nm1276
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发表时间：
2005-08-01
期刊：
影响因子：
82.9
通讯作者：
Dubensky, TW
中科院分区：
文献类型：
--
作者：
Brockstedt, DG;Bahjat, KS;Dubensky, TW
我们开发了一类新的疫苗，基于杀死但代谢活性（KBMA）细菌，同时利用活疫苗的效力和杀死疫苗的安全性。我们去除了核苷酸切除修复（uvrAB）所需的基因，使基于微生物的疫苗对peptide和长波长紫外光的光化学灭活非常敏感。核苷酸切除修复突变体的菌落形成被罕见的随机分布的peptide交联所阻断，但细菌群体能够表达其基因，合成和分泌蛋白质。使用细胞内病原体单核细胞增多性李斯特菌作为模型平台，重组peptide灭活的Lm Delta uvrAB疫苗诱导有效的CD4（+）和CD8（+）T细胞应答，并在感染性疾病模型中保护小鼠免受病毒攻击，并在小鼠癌症模型中提供治疗益处。作为重组疫苗平台或作为病原体本身的修饰形式使用的微生物KBMA疫苗可广泛用于治疗传染病和癌症。
We developed a new class of vaccines, based on killed but metabolically active (KBMA) bacteria, that simultaneously takes advantage of the potency of live vaccines and the safety of killed vaccines. We removed genes required for nucleotide excision repair (uvrAB), rendering microbial-based vaccines exquisitely sensitive to photochemical inactivation with psoralen and long-wavelength ultraviolet light. Colony formation of the nucleotide excision repair mutants was blocked by infrequent, randomly distributed psoralen crosslinks, but the bacterial population was able to express its genes, synthesize and secrete proteins. Using the intracellular pathogen Listeria monocytogenes as a model platform, recombinant psoralen-inactivated Lm Delta uvrAB vaccines induced potent CD4(+) and CD8(+) T-cell responses and protected mice against virus challenge in an infectious disease model and provided therapeutic benefit in a mouse cancer model. Microbial KBMA vaccines used either as a recombinant vaccine platform or as a modified form of the pathogen itself may have broad use for the treatment of infectious disease and cancer.