CMV pentameric complex based vaccine strategies for prevention of congenital CMV

基于 CMV 五聚体复合物的预防先天性 CMV 的疫苗策略

• 批准号: 9382991
• 负责人: ALISTAIR MCGREGOR
• 金额: $ 30.33万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9382991
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Adenoviruses; Adverse effects; Animal Model; Antibodies; Antibody Response; Antigen Targeting; Antigens; Antiviral Agents; Attenuated; Blood Vessels; CD4 Positive T Lymphocytes; Cavia; Cells; Clinical; Clinical Trials; Complex; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Development; Disease; Effectiveness; Endothelial Cells; Epithelial; Epithelial Cells; Evaluation; Fetus; Fibroblasts; Glycoproteins; Goals; Guinea pig cytomegalovirus; Homologous Gene; Human; Immune response; Immunocompromised Host; Individual; Intervention; Macaca mulatta; Mental Retardation; Modeling; Morbidity - disease rate; Myeloid Cells; Newborn Infant; Pathway interactions; Patients; Phase; Placenta; Population; Prevention; Prevention strategy; Proteins; Recombinants; Risk; Species Specificity; Structure; Study models; Subunit Vaccines; T cell response; T-Lymphocyte; Time; Transplantation; Tropism; Vaccinated; Vaccines; Viral; Viral Antibodies; Viral Proteins; Virus; Virus Diseases; base; cell type; congenital cytomegalovirus; congenital infection; deafness; defective adenoviral vector; effective intervention; fetal; immunogenic; in utero; interest; macrophage; monocyte; mortality; neutralizing antibody; nonhuman primate; pathogen; pre-clinical; prevent; public health priorities; recombinant adenovirus; resistant strain; response; secondary infection; synergism; therapy development; translational study; trophoblast; vaccine efficacy; vector-based vaccine

Abstract Development of a cytomegalovirus (CMV) vaccine is a major public health priority due to the risk of congenital infection. Clinical strains of human CMV (HCMV) differ from lab adapted virus as the clinical strains express a pentameric complex (PC) and retain the ability to infect epithelial and endothelial cells unlike lab strains which are limited to fibroblast cells. The mechanism of virus entry into epi/endothelial cells is different from the gB pathway of entry into fibroblast cells as it requires viral proteins gH/gL/UL128-131 forming an endocytic complex (PC) to enable viral cell entry. Importantly, transplacental CMV infection is highly dependent upon viral epithelial/endothelial tropism since the virus has to infect endothelial cells of blood vessels (maternal and fetal) as well as a layer of epithelial trophoplast cells that constitute part of the placenta. Neutralizing antibodies to the PC are potentially more important than antibodies to the immunodominant gB glycoprotein, since anti- PC antibodies are more effective in neutralizing virus on epi/endothelial cells compared to gB. Importantly, in convalescent patients high anti-PC titers are thought to be effective in preventing congenital CMV. Human CMV cannot be directly studied in an animal model because of species specificity. The guinea pig is the only small animal model that allows the study of congenital CMV but requires the use of species specific guinea pig CMV (GPCMV). In the guinea pig model for congenital CMV, we have defined a homolog pentameric complex as necessary for epithelial tropism, virus dissemination and congenital infection by GPCMV. Furthermore, the GPCMV homolog PC is highly immunogenic and generates antibodies that neutralize virus infection on epithelial cells. This pre-clinical translational study seeks to develop GPCMV PC specific vaccine strategies (either subunit or defective adenovirus vector based) to determine if a PC or PC subcomplex vaccine strategy can prevent congenital CMV in the guinea pig model. Importantly, as part of these studies we will evaluate the ability of PC vaccines to cross protect against congenital CMV from different GPCMV strains. Additionally, the synergy effect of gB and PC vaccine strategies will be evaluated. Finally, since in HCMV both gB and gH induce a CD4 T cell response, the protective impact of the T cell response will be evaluated.

抽象的 由于先天性的风险 感染。人类CMV（HCMV）的临床菌株与实验室适应病毒不同，因为临床菌株表达 与实验室菌株不同 仅限于成纤维细胞。病毒进入Epi/Epi/内皮细胞的机制与GB不同 进入成纤维细胞的途径，因为它需要病毒蛋白GH/GL/ul128-131形成内吞细胞 复合物（PC）使病毒细胞进入。重要的是，移植CMV感染高度依赖 病毒上皮/内皮性疗法，因为该病毒必须感染血管的内皮细胞（母体和孕妇和 胎儿）以及构成胎盘一部分的上皮滋养细胞。中和抗体 对于PC，PC比对免疫主导GB糖蛋白的抗体更重要，因为抗 与GB相比，PC抗体更有效地对Epi/内皮细胞上的病毒更有效。重要的是，在 康复患者高抗PC滴度被认为有效预防先天性CMV。人类 由于物种特异性，无法在动物模型中直接研究CMV。豚鼠是唯一的 允许研究先天性CMV但需要使用特定物种豚鼠的小动物模型 CMV（GPCMV）。在先天性CMV的豚鼠模型中，我们定义了同源五聚体络合物 GPCMV的上皮性向托管，病毒传播和先天性感染的必要条件。此外， GPCMV同源PC具有高度免疫原性，并产生抗体，使病毒感染在 上皮细胞。这项临床前翻译研究旨在开发GPCMV PC特定的疫苗策略 （基于亚基或有缺陷的腺病毒载体）确定PC或PC子复合疫苗策略是 可以防止豚鼠模型中的先天CMV。重要的是，作为这些研究的一部分，我们将评估 PC疫苗通过不同GPCMV菌株的先天性CMV跨性能的能力。另外， 将评估GB和PC疫苗策略的协同作用。最后，因为在HCMV中，GB和GH 诱导CD4 T细胞反应，将评估T细胞反应的保护作用。