Genomic Analysis, Phenotype, and Virulence of the Historical Brazilian Smallpox Vaccine Strain IOC: Implications for the Origins and Evolutionary Relationships of Vaccinia Virus
Genomic Analysis, Phenotype, and Virulence of the Historical Brazilian Smallpox Vaccine Strain IOC: Implications for the Origins and Evolutionary Relationships of Vaccinia Virus
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DOI：
10.1128/jvi.01833-15
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发表时间：
2015-12-01
影响因子：
5.4
通讯作者：
Damaso, Clarissa R.
中科院分区：
文献类型：
--
作者：
Medaglia, Maria Luiza G.;Moussatche, Nissin;Damaso, Clarissa R.
1980年，在使用不同毒株的牛痘病毒(VACV；痘病毒科)进行密集接种计划后，天花被宣布根除。VACV毒株IOC(VACV-IOC)是巴西主要疫苗生产商在天花根除计划期间生产的天花疫苗的种子株。然而，人们对这种第一代疫苗的生物学和免疫学特征以及系统发育关系知之甚少。在这项工作中，我们对VACV-IOC的两个克隆进行了全面的表征。这两个克隆在感染小鼠中的毒力都很低，并诱导了对致命性感染的保护性免疫反应，与特许疫苗ACAM2000和亲本毒株VACV-IOC的反应相当。全基因组测序显示存在几个可能无功能的片段毒力基因，如F1L、B13R、C10L、K3L和C3L。最值得注意的是，基因组末端结构分析支持的系统发育推断提供了VACV系统发育中一个新的、独立的簇的证据，该簇由VACV-IOC、巴西野毒株坎塔加洛(CTGV)和Serro 2病毒以及马痘病毒组成，马痘病毒是一种类似VACV的病毒，被认为是VACV谱系的祖先。我们的数据有力地支持了这样的假设，即CTGV样病毒代表着与VACV-IOC平行进化的野生VACV，该病毒是从最近的共同祖先分离而来的，可能是与马痘病毒有关的古代天花疫苗株。我们的数据与有趣的历史调查一起，回顾了VACV的起源，并提出了古代和现存VACV毒株之间新的进化关系，主要是马痘病毒、VACV-IOC/CTGV样病毒和Dryvax株。重要的是，用于根除天花的第一代疫苗的不良反应率是当前卫生保健标准所不能接受的。此外，这些疫苗在基因上是异质性的，由VACV准物种池组成。因此，寻找集低致病性、免疫保护和遗传同质性于一体的新一代天花疫苗是极其重要的。此外，VACV毒株的系统发育关系和起源是相当模糊的。我们展示了VACV-IOC的两个克隆的特征，VACV-IOC是一种独特的天花疫苗毒株，有助于在巴西根除天花。免疫原性和降低的毒力使IOC克隆成为替代第二代天花疫苗的良好选择。更重要的是，本研究揭示了VACV-IOC、自然界中建立的野生VACV和类祖先马痘病毒之间的系统发育关系。我们的数据扩展了对VACV谱系起源和进化联系的讨论。
Smallpox was declared eradicated in 1980 after an intensive vaccination program using different strains of vaccinia virus (VACV; Poxviridae). VACV strain IOC (VACV-IOC) was the seed strain of the smallpox vaccine manufactured by the major vaccine producer in Brazil during the smallpox eradication program. However, little is known about the biological and immunological features as well as the phylogenetic relationships of this first-generation vaccine. In this work, we present a comprehensive characterization of two clones of VACV-IOC. Both clones had low virulence in infected mice and induced a protective immune response against a lethal infection comparable to the response of the licensed vaccine ACAM2000 and the parental strain VACV-IOC. Full-genome sequencing revealed the presence of several fragmented virulence genes that probably are nonfunctional, e.g., F1L, B13R, C10L, K3L, and C3L. Most notably, phylogenetic inference supported by the structural analysis of the genome ends provides evidence of a novel, independent cluster in VACV phylogeny formed by VACV-IOC, the Brazilian field strains Cantagalo (CTGV) and Serro 2 viruses, and horsepox virus, a VACV-like virus supposedly related to an ancestor of the VACV lineage. Our data strongly support the hypothesis that CTGV-like viruses represent feral VACV that evolved in parallel with VACV-IOC after splitting from a most recent common ancestor, probably an ancient smallpox vaccine strain related to horsepox virus. Our data, together with an interesting historical investigation, revisit the origins of VACV and propose new evolutionary relationships between ancient and extant VACV strains, mainly horsepox virus, VACV-IOC/CTGV-like viruses, and Dryvax strain.IMPORTANCEFirst-generation vaccines used to eradicate smallpox had rates of adverse effects that are not acceptable by current health care standards. Moreover, these vaccines are genetically heterogeneous and consist of a pool of quasispecies of VACV. Therefore, the search for new-generation smallpox vaccines that combine low pathogenicity, immune protection, and genetic homogeneity is extremely important. In addition, the phylogenetic relationships and origins of VACV strains are quite nebulous. We show the characterization of two clones of VACV-IOC, a unique smallpox vaccine strain that contributed to smallpox eradication in Brazil. The immunogenicity and reduced virulence make the IOC clones good options for alternative second-generation smallpox vaccines. More importantly, this study reveals the phylogenetic relationship between VACV-IOC, feral VACV established in nature, and the ancestor-like horsepox virus. Our data expand the discussion on the origins and evolutionary connections of VACV lineages.