Ober B T, Brühl P, Schmidt M, Wieser V, Gritschenberger W, Coulibaly S, Savidis-Dacho H, Gerencer M, Falkner F G
Biomedical Research Center, Baxter BioScience/Vaccine AG, A-2304 Orth/Donau, Austria.
J Virol. 2002 Aug;76(15):7713-23. doi: 10.1128/jvi.76.15.7713-7723.2002.
Potent and safe vaccinia virus vectors inducing cell-mediated immunity are needed for clinical use. Replicating vaccinia viruses generally induce strong cell-mediated immunity; however, they may have severe adverse effects. As a vector for clinical use, we assessed the defective vaccinia virus system, in which deletion of an essential gene blocks viral replication, resulting in an infectious virus that does not multiply in the host. The vaccinia virus Lister/Elstree strain, used during worldwide smallpox eradication, was chosen as the parental virus. The immunogenicity and safety of the defective vaccinia virus Lister were evaluated without and with the inserted human p53 gene as a model and compared to parallel constructs based on modified vaccinia virus Ankara (MVA), the present "gold standard" of recombinant vaccinia viruses in clinical development. The defective viruses induced an efficient Th1-type immune response. Antibody and cytotoxic-T-cell responses were comparable to those induced by MVA. Safety of the defective Lister constructs could be demonstrated in vitro in cell culture as well as in vivo in immunodeficient SCID mice. Similar to MVA, the defective viruses were tolerated at doses four orders of magnitude higher than those of the wild-type Lister strain. While current nonreplicating vectors are produced mainly in primary chicken cells, defective vaccinia virus is produced in a permanent safety-tested cell line. Vaccines based on this system have the additional advantage of enhanced product safety. Therefore, a vector system was made which promises to be a valuable tool not only for immunotherapy for diseases such as cancer, human immunodeficiency virus infection, or malaria but also as a basis for a safer smallpox vaccine.
临床应用需要高效且安全的痘苗病毒载体来诱导细胞介导的免疫反应。复制型痘苗病毒通常能诱导强烈的细胞介导免疫反应；然而，它们可能会产生严重的不良反应。作为一种临床应用载体，我们评估了缺陷型痘苗病毒系统，在该系统中，一个必需基因的缺失会阻断病毒复制，从而产生一种在宿主体内不会增殖的感染性病毒。在全球天花根除行动中使用的痘苗病毒李斯特/埃尔斯特里株被选为亲本病毒。以插入人p53基因作为模型，评估了缺陷型痘苗病毒李斯特株在有无该基因情况下的免疫原性和安全性，并与基于改良安卡拉痘苗病毒（MVA）的平行构建体进行了比较，MVA是目前临床开发中重组痘苗病毒的“金标准”。缺陷型病毒诱导了高效的Th1型免疫反应。抗体和细胞毒性T细胞反应与MVA诱导的反应相当。缺陷型李斯特构建体的安全性在体外细胞培养以及免疫缺陷的SCID小鼠体内均得到了证实。与MVA类似，缺陷型病毒在比野生型李斯特株高四个数量级的剂量下仍能被耐受。虽然目前的非复制型载体主要在原代鸡细胞中生产，但缺陷型痘苗病毒是在经过安全性测试的永久细胞系中生产的。基于该系统的疫苗还具有提高产品安全性的额外优势。因此，构建了一种载体系统，它有望不仅成为癌症、人类免疫缺陷病毒感染或疟疾等疾病免疫治疗的宝贵工具，而且还可作为更安全的天花疫苗的基础。
