Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8
Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8
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DOI：
10.1073/pnas.0406671102
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发表时间：
2005-03-15
影响因子：
11.1
通讯作者：
Shida, H
中科院分区：
文献类型：
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作者：
Kidokoro, M;Tashiro, M;Shida, H
高度减毒的LC 16 m8（m8）天花疫苗已在日本获得许可，因为其极低的神经毒力特征，与复制缺陷型牛痘病毒株相当。从1973年到1975年，m8被给予超过100，000名婴儿，其诱导的免疫水平与原始Lister菌株相似，没有任何严重的副作用。最近，我们观察到，m8自发回复到大空斑形成克隆，具有相当于的毒力LC 16 mO，亲本病毒株m8。在这里，我们报告说，B5 R基因是负责的逆转，我们可以构建一个更稳定的基因从m8删除B5 R病毒。候选疫苗的保护性免疫原性被证明与美国-许可产品Dryvax，并且在小鼠模型中比修饰的安卡拉牛痘上级得多。此外，疫苗株从未在严重联合免疫缺陷病小鼠中引起任何症状，即使在免疫保护实验中使用的剂量的1，000倍时也是如此，这与Dryvax接种严重联合免疫缺陷病小鼠诱导的致死性致病性形成对比。我们的研究结果表明，该疫苗株是一个很好的候选人作为一个合适的天花疫苗和载体病毒，B5 R是不是必不可少的保护性免疫对天花。
A highly attenuated LC16m8 (m8) smallpox vaccine has been licensed in Japan because of its extremely low neurovirulence profile, which is comparable to that of replication incompetent strains of vaccinia virus. From 1973 to 1975, m8 was administrated to >100,000 infants where it induced levels of immunity similar to that of the originating Lister strain, without any serious side effects. Recently, we observed that m8 reverts spontaneously to large plaque forming clones that possess virulence equivalent to that of LC16mO, a parental virus strain of m8. Here, we report that the B5R gene is responsible for the reversion, and that we could construct a more genetically stable virus by deleting B5R from m8. The protective immunogenicity of the vaccine candidate proved to be equivalent to that of the U.S.-licensed product Dryvax, and much superior to modified vaccinia Ankara in a mouse model. Furthermore, the vaccine strain never elicited any symptoms in severe combined immunodeficiency disease mice, even at a dose 1,000-fold greater than that used in the immune protection experiments, which is in contrast to the lethal pathogenicity induced by Dryvax inoculation of severe combined immunodeficiency disease mice. Our results suggest that this vaccine strain is a good candidate as a suitable smallpox vaccine and a vector virus, and that B5R is not essential for protective immunity against smallpox.