Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo.
Genomic analysis of chimeric human cytomegalovirus vaccine candidates derived from strains Towne and Toledo.
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DOI：
10.1007/s11262-017-1452-0
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发表时间：
2017-08
期刊：
影响因子：
1.6
通讯作者：
Davison AJ
中科院分区：
文献类型：
--
作者：
Suárez NM;Lau B;Kemble GM;Lee R;Mocarski ES;Wilkinson GWG;Adler SP;McVoy MA;Davison AJ
人巨细胞病毒(HCMV)是免疫功能低下患者的一种重要的机会致病因子，也是先天性出生缺陷的主要原因。20世纪90年代，通过将高传代汤恩株的基因组片段替换为低传代托莱多株的基因组片段，构建了四种嵌合病毒，目的是获得仍然安全但比过度减毒的汤恩疫苗更具免疫原性的减毒活疫苗候选疫苗。这些嵌合体在HCMV血清阴性的人类志愿者身上被发现是安全的，但在诱导血清转换的能力方面存在显著差异。这表明嵌合体特有的遗传差异影响了体内复制或持续的能力，以及随后诱导抗体反应的能力。为了确定Towne和Toledo序列之间的特定基因组断裂点，并确定在构建嵌合体的过程中是否发生了自发突变或重排，确定了完整的基因组序列。没有观察到重大的缺失或重排，尽管发现了一些意想不到的突变。然而，嵌合体的遗传含量与疫苗诱导的HCMV特异性体液或细胞免疫反应的报道水平之间没有明显的关联，这表明多个基因决定因素可能影响免疫原性。除了揭示四种候选疫苗的基因组结构外，这项研究还为探索人类巨细胞病毒衰减的遗传学提供了机会。这些结果可能对未来优化免疫原性和有效性的安全活疫苗或复制缺陷疫苗的设计有价值。
Human cytomegalovirus (HCMV) is an important opportunistic pathogen in immunocompromised patients and a major cause of congenital birth defects when acquired in utero. In the 1990s, four chimeric viruses were constructed by replacing genome segments of the high passage Towne strain with segments of the low passage Toledo strain, with the goal of obtaining live attenuated vaccine candidates that remained safe but were more immunogenic than the overly attenuated Towne vaccine. The chimeras were found to be safe when administered to HCMV-seronegative human volunteers, but to differ significantly in their ability to induce seroconversion. This suggests that chimera-specific genetic differences impacted the ability to replicate or persist in vivo and the consequent ability to induce an antibody response. To identify specific genomic breakpoints between Towne and Toledo sequences and establish whether spontaneous mutations or rearrangements had occurred during construction of the chimeras, complete genome sequences were determined. No major deletions or rearrangements were observed, although a number of unanticipated mutations were identified. However, no clear association emerged between the genetic content of the chimeras and the reported levels of vaccine-induced HCMV-specific humoral or cellular immune responses, suggesting that multiple genetic determinants are likely to impact immunogenicity. In addition to revealing the genome organization of the four vaccine candidates, this study provided an opportunity to probe the genetics of HCMV attenuation in humans. The results may be valuable in the future design of safe live or replication-defective vaccines that optimize immunogenicity and efficacy.
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影响因子：
3.8
作者：
Davison, AJ;Dolan, A;Hayward, GS
通讯作者：
Hayward, GS
DOI：
10.1099/vir.0.018994-0
发表时间：
2010-06
期刊：
The Journal of general virology
影响因子：
--
作者：
Dargan DJ;Douglas E;Cunningham C;Jamieson F;Stanton RJ;Baluchova K;McSharry BP;Tomasec P;Emery VC;Percivalle E;Sarasini A;Gerna G;Wilkinson GW;Davison AJ
通讯作者：
Davison AJ
影响因子：
3.1
作者：
PLOTKIN, SA;FURUKAWA, T;HUYGELEN, C
通讯作者：
HUYGELEN, C
影响因子：
6.4
作者：
ADLER, SP;STARR, SE;BEST, AM
通讯作者：
BEST, AM
影响因子：
39.2
作者：
QUINNAN, GV;DELERY, M;HILLEMAN, MR
通讯作者：
HILLEMAN, MR