Nieuwenhuizen Natalie E, Kulkarni Prasad S, Shaligram Umesh, Cotton Mark F, Rentsch Cyrill A, Eisele Bernd, Grode Leander, Kaufmann Stefan H E
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Serum Institute of India Pvt. Ltd., Pune, India.
Front Immunol. 2017 Sep 19;8:1147. doi: 10.3389/fimmu.2017.01147. eCollection 2017.
The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from . Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔ:: (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.
唯一获得许可的抗结核病疫苗卡介苗（BCG）可预防严重的肺外结核病，但对该疾病最常见的形式——肺结核几乎无效。马克斯·普朗克感染生物学研究所对卡介苗进行了基因改造，通过用来自的溶菌酶编码基因取代脲酶C编码基因来提高其免疫原性。溶菌酶在酸性pH值下会破坏吞噬体膜。脲酶C参与了容纳卡介苗的吞噬体的中和过程。其缺失可使吞噬体快速酸化并促进吞噬溶酶体融合。结果，BCGΔ::（VPM1002）促进细胞凋亡和自噬，并有助于将分枝杆菌抗原释放到细胞质中。在临床前研究中，VPM1002比卡介苗更有效且更安全。该疫苗已授权给Vakzine Projekt Management，后来又 sublicense 给了世界上最大的疫苗生产商印度血清研究所私人有限公司。该疫苗已在德国和南非通过了I期临床试验，证明了其在年轻人中的安全性和免疫原性。它也在南非健康新生儿的IIa期随机临床试验中成功进行了测试，目前正在对暴露于HIV和未暴露于HIV的新生儿进行IIb期研究。一项II/III期临床试验将于2017年在印度开始，以评估对结核病复发的疗效。VPMl002的目标适应症是新生儿免疫以预防结核病以及成人暴露后免疫以预防结核病复发。此外，一项针对非肌肉浸润性膀胱癌患者的I期试验已经完成，II期试验正在进行中。本综述描述了VPM1002从设计到临床评估的发展过程。
