An attenuated LC16m8 smallpox vaccine: Analysis of full-genome sequence and induction of immune protection
An attenuated LC16m8 smallpox vaccine: Analysis of full-genome sequence and induction of immune protection
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DOI：
10.1128/jvi.79.18.11873-11891.2005
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发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Kojima, A
中科院分区：
文献类型：
--
作者：
Morikawa, S;Sakiyama, T;Kojima, A
天花生物恐怖主义的潜在威胁使得低毒力牛痘病毒疫苗的开发迫在眉睫。1975年，从世界卫生组织天花根除计划中使用的李斯特菌株开发了一种减毒LC 16m8（m8）疫苗，但未用于地方性天花。今天，没有疫苗可以用天花病毒测试在人类中的功效，并且对痘病毒的主要细胞内成熟病毒体（IMV）和次要细胞外包膜病毒体（EEV）群体的免疫保护机制知之甚少。在这里，我们确定了m8，父母LC 16 mO（mO），和祖父母李斯特（LO）株的全基因组序列，并分析了它们的进化关系。序列分析和PCR分析表明，m8是LO的后代，除了EEV包膜基因B5 R被破坏外，m8几乎保留了所有的痘苗病毒开放阅读框架。根据该基因组背景，尽管缺乏抗B5R和抗EEV抗体，m8通过单次接种在小鼠中诱导针对高致病性牛痘WR病毒的100%保护。主要由IMV组成的m8疫苗的免疫原性和引发功效与完整的EEV亲本mO和祖父母LO疫苗一样高。因此，用10（7）PFU m8接种的小鼠在WR攻击后产生低水平的抗B5 R抗体，这可能是因为通过接种诱导的强免疫快速清除表达B5 R的WR EEV。这些结果表明，尽管针对EEV的免疫水平不可检测，但用m8 IMV引发提供了有效的保护。
The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10(7) PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.