Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge
Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge
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DOI：
10.1073/pnas.0401165101
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发表时间：
2004-03-30
影响因子：
11.1
通讯作者：
Moss, B
中科院分区：
文献类型：
--
作者：
Wyatt, LS;Earl, PL;Moss, B
改良的安卡拉牛痘病毒（MVA），在> 30年前作为高度减毒的候选天花疫苗开发，从1974代中再克隆，并评估安全性和免疫原性。MVA的复制在大多数哺乳动物细胞中受损，我们发现患有严重联合免疫缺陷病的小鼠在接种MVA时保持健康，MVA的致死剂量是来自许可的Dryvax疫苗种子的牛痘病毒的1,000倍。在肌内接种MVA的BALB/c小鼠中，以剂量依赖性方式诱导病毒特异性CD 8（+）T细胞和针对纯化的病毒粒子和细胞内和细胞外感染形式的牛痘病毒的膜蛋白组分的抗体。接种MVA一次或两次后，T细胞数和抗体滴度等于或超过经皮注射Dryvax诱导的T细胞数和抗体滴度。MVA和Dryvax诱导的抗体具有中和作用，并抑制病毒在培养细胞中的传播。此外，接种疫苗的小鼠被保护免受致病性牛痘病毒的致死性鼻内攻击。不能产生抗体的B细胞缺陷小鼠和不能表达MHC I类分子以产生CD 8（+）T细胞应答的β 2-微球蛋白缺陷小鼠也通过MVA进行保护性接种。相比之下，CD 4或MHC II类表达降低的小鼠和MHC II类限制性活性缺陷的双敲除小鼠受到的保护较差或未受到保护。这项研究证实了MVA的安全性，并证明了重叠的免疫应答保护了正常和部分免疫缺陷的动物，这是该候选天花减毒疫苗的一个令人鼓舞的结果。
Modified vaccinia virus Ankara (MVA), developed > 30 years ago as a highly attenuated candidate smallpox vaccine, was recloned from a 1974 passage and evaluated for safety and immunogenicity. Replication of MVA is impaired in most mammalian cells, and we found that mice with severe combined immunodeficiency disease remained healthy when inoculated with MVA at 1,000 times the lethal dose of vaccinia virus derived from the licensed Dryvax vaccine seed. In BALB/c mice inoculated intramuscularly with MVA, virus-specific CD8(+) T cells and antibodies to purified virions and membrane protein components of the intracellular and extracellular infectious forms of vaccinia virus were induced in a dose-dependent manner. After one or two inoculations of MVA, the T cell numbers and antibody titers equaled or exceeded those induced by percutaneous injection of Dryvax. Antibodies induced by MVA and Dryvax were neutralizing and inhibited virus spread in cultured cells. Furthermore, vaccinated mice were protected against lethal intranasal challenge with a pathogenic vaccinia virus. B cell-deficient mice unable to generate antibodies and beta(2)-microglobulin-deficient mice unable to express MHC class I molecules for a CD8(+) T cell response were also protectively vaccinated by MVA. In contrast, mice with decreased CD4 or MHC class II expression and double-knockout mice deficient in MHC class land II-restricted activities were poorly protected or unprotected. This study confirmed the safety of MVA and demonstrated that the overlapping immune responses protected normal and partially immune-deficient animals, an encouraging result for this candidate attenuated smallpox vaccine.