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

基本信息

批准号：
10162628
负责人：
ALISTAIR MCGREGOR
金额：
$ 30.2万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162628
关键词：
Acquired Immunodeficiency Syndrome Address Adenovirus Vector Adenoviruses Animal Model Antibodies Antibody Response Antigen Targeting Antigens Antiviral Agents Attenuated Blood Vessels CD4 Positive T Lymphocytes Cavia Cells Clinical Complex Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Development Disease Effectiveness Endothelial Cells Endothelium 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 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 early phase clinical trial effective intervention fetal immunogenic in utero interest macrophage monocyte mortality neutralizing antibody nonhuman primate pathogen porcine model pre-clinical prevent public health priorities recombinant adenovirus resistant strain secondary infection side effect synergism therapy development translational study trophoblast vaccine efficacy vector-based vaccine

项目摘要

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.

抽象的由于存在先天性疾病的风险，巨细胞病毒 (CMV) 疫苗的开发是一项重要的公共卫生优先事项感染。人类 CMV (HCMV) 临床毒株与实验室适应病毒不同，因为临床毒株表达五聚体复合物（PC）并保留感染上皮细胞和内皮细胞的能力，这与实验室菌株不同。仅限于成纤维细胞。病毒进入外皮/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 形成内吞复合体（PC）使病毒能够进入细胞。重要的是，经胎盘巨细胞病毒感染高度依赖于病毒上皮/内皮向性，因为病毒必须感染血管内皮细胞（母体和内皮细胞）胎儿）以及构成胎盘一部分的上皮滋养体细胞层。中和抗体 PC 的抗体可能比免疫显性 gB 糖蛋白的抗体更重要，因为抗与 gB 相比，PC 抗体在中和外皮/内皮细胞上的病毒方面更有效。重要的是，在恢复期患者高抗 PC 滴度被认为可有效预防先天性巨细胞病毒 (CMV)。人类由于物种特异性，CMV 无法在动物模型中直接研究。豚鼠是唯一允许研究先天性巨细胞病毒的小动物模型，但需要使用特定物种的豚鼠 CMV（GPCMV）。在先天性 CMV 豚鼠模型中，我们定义了同源五聚体复合物是上皮趋向性、病毒传播和 GPCMV 先天性感染所必需的。此外， GPCMV 同源物 PC 具有高度免疫原性，可产生中和病毒感染的抗体上皮细胞。这项临床前转化研究旨在开发 GPCMV PC 特异性疫苗策略（基于亚基或有缺陷的腺病毒载体）以确定 PC 或 PC 亚复合体疫苗策略可以预防豚鼠模型中的先天性巨细胞病毒。重要的是，作为这些研究的一部分，我们将评估 PC 疫苗交叉保护不同 GPCMV 毒株的先天性 CMV 的能力。此外，将评估 GB 和 PC 疫苗策略的协同效应。最后，因为在 HCMV 中 gB 和 gH 诱导 CD4 T 细胞反应，将评估 T 细胞反应的保护性影响。