Elucidation of the full genetic information of Japanese rubella vaccines and the genetic changes associated with in vitro and in vivo vaccine virus phenotypes
Elucidation of the full genetic information of Japanese rubella vaccines and the genetic changes associated with in vitro and in vivo vaccine virus phenotypes
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DOI：
10.1016/j.vaccine.2011.01.016
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发表时间：
2011-02-24
期刊：
影响因子：
5.5
通讯作者：
Komase, Katsuhiro
中科院分区：
文献类型：
--
作者：
Otsuki, Noriyuki;Abo, Hitoshi;Komase, Katsuhiro
风疹是一种轻微的疾病，其特征是低热和麻疹样皮疹，但在怀孕期间患有风疹的母亲所生的新生儿会导致先天性缺陷。在日本，野生型风疹病毒株在各种类型的培养细胞中多次传代后，开发了5种风疹减毒活疫苗。在实验感染的动物中不能引发抗风疹病毒抗体被用作日本风疹疫苗的体内标记表型。所有日本风疹疫苗病毒都表现出温度敏感（ts）表型，在高温下复制非常差。我们确定了三种日本风疹疫苗（Matsuba，TCRB 19和Matsuura）的全基因组序列，从而完成了所有五种日本风疹疫苗的测序。此外，测定了三种疫苗祖细胞的全基因组序列。比较核苷酸序列分析揭示了在通过实验室传代生产期间引入TO-336和Matsuura疫苗的基因组中的突变。涉及病毒P150非结构蛋白衍生肽的细胞表达的分析显示，N1159 S突变赋予TO-336疫苗TS表型，并且P150蛋白酶结构域的热稳定性降低是某些风疹疫苗病毒TS表型的原因。疫苗病毒的ts表型与它们不能在动物中引起体液免疫应答没有必然的联系。因此，这些疫苗不能在动物中引起体液应答的分子机制比以前认为的涉及ts表型作为主要原因的机制更复杂。(C)2011爱思唯尔有限公司保留所有权利。
Rubella is a mild disease characterized by low-grade fever, and a morbilliform rash, but causes congenital defects in neonates born from mothers who suffered from rubella during the pregnancy. After many passages of wild-type rubella virus strains in various types of cultured cells, five live attenuated rubella vaccines were developed in Japan. An inability to elicit anti-rubella virus antibodies in experimentally infected animals was used as an in vivo marker phenotype of Japanese rubella vaccines. All Japanese rubella vaccine viruses exhibit a temperature-sensitive (ts) phenotype, and replicate very poorly at a high temperature. We determined the entire genome sequences of three Japanese rubella vaccines (Matsuba, TCRB19, and Matsuura), thereby completing the sequencing of all five Japanese rubella vaccines. In addition, the entire genome sequences of three vaccine progenitors were determined. Comparative nucleotide sequence analyses revealed mutations that were introduced into the genomes of the TO-336 and Matsuura vaccines during their production by laboratory passaging. Analyses involving cellular expression of viral P150 nonstructural protein-derived peptides revealed that the N1159S mutation conferred the ts phenotype on the TO-336 vaccine, and that reduced thermal stability of the P150 protease domain was a cause of the ts phenotype of some rubella vaccine viruses. The ts phenotype of vaccine viruses was not necessarily correlated with their inability to elicit humoral immune responses in animals. Therefore, the molecular mechanisms underlying the inability of these vaccines to elicit humoral responses in animals are more complicated than the previously considered mechanism involving the ts phenotype as the major cause. (C) 2011 Elsevier Ltd. All rights reserved.