Development of an effective DISC vaccine strategy against congenital CMV

开发针对先天性 CMV 的有效 DISC 疫苗策略

基本信息

批准号：
8685114
负责人：
ALISTAIR MCGREGOR
金额：
$ 36.38万
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：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685114
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Animal Model Animals Antibodies Antibody Formation Antigen Targeting Antigens Antiviral Agents Attenuated Attenuated Vaccines Cavia Cell Line Cells Clinical Clinical Trials Comparative Study Complement Complex Coupled Cytomegalovirus Cytomegalovirus Vaccines Development Disabled Persons Disease Endothelial Cells Epithelial Cells Fetus Fibroblasts Future Generations Genes Glycoproteins Guinea pig cytomegalovirus Homologous Gene Human Immune response Immunocompromised Host Inactivated Vaccines Individual Infection Intervention Knock-out Life Mental Retardation Modeling Modification Morbidity - disease rate Newborn Infant Pathogenicity Pathway interactions Patients Phase III Clinical Trials Placenta Population Pre-Clinical Model Prevention Production Proteins Recombinants Research Risk Safety Serum Site Structure Subfamily lentivirinae Subunit Vaccines T cell response Testing Tetanus Helper Peptide Transplantation United States National Institutes of Health Vaccinated Vaccine Design Vaccines Viral Viral Antigens Viral Proteins Virus Virus Diseases base congenital cytomegalovirus congenital infection deafness design experience immunogenic immunogenicity improved in utero in vivo interest mortality neutralizing antibody novel pathogen prevent public health priorities resistant strain secondary infection tissue culture

Acquired Immunodeficiency Syndrome Adverse effects Animal Model Animals Antibodies Antibody Formation Antigen Targeting Antigens Antiviral Agents Attenuated Attenuated Vaccines Cavia Cell Line Cells Clinical Clinical Trials Comparative Study Complement Complex Coupled Cytomegalovirus Cytomegalovirus Vaccines Development Disabled Persons Disease Endothelial Cells Epithelial Cells Fetus Fibroblasts Future Generations Genes Glycoproteins Guinea pig cytomegalovirus Homologous Gene Human Immune response Immunocompromised Host Inactivated Vaccines Individual Infection Intervention Knock-out Life Mental Retardation Modeling Modification Morbidity - disease rate Newborn Infant Pathogenicity Pathway interactions Patients Phase III Clinical Trials Placenta Population Pre-Clinical Model Prevention Production Proteins Recombinants Research Risk Safety Serum Site Structure Subfamily lentivirinae Subunit Vaccines T cell response Testing Tetanus Helper Peptide Transplantation United States National Institutes of Health Vaccinated Vaccine Design Vaccines Viral Viral Antigens Viral Proteins Virus Virus Diseases base congenital cytomegalovirus congenital infection deafness design experience immunogenic immunogenicity improved in utero in vivo interest mortality neutralizing antibody novel pathogen prevent public health priorities resistant strain secondary infection tissue culture

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项目摘要

DESCRIPTION (provided by applicant: Development of a cytomegalovirus (CMV) vaccine is a major public health priority due to the risk of congenital infection. Pathogenic clinical strains o CMV differ from lab adapted strains in that they retain the ability to infect epithelial and endothelial cells. Based on the structure of the placenta endothelial cells could be a potentially important site for initiation of virus transfer across the placenta to the fetus. The mechanism of virus entry into epi/endothelial cells is different from the gB pathway of entry into fibroblast cels as it requires viral proteins gH/gL/UL128-131 forming an endocytic complex to enable viral cell entry. The guinea pig is the only small animal model that allows the study of congenital CMV by using species specific guinea pig CMV (GPCMV). We recently investigated the use of a replication-impaired live GPCMV vaccine that requires a complementing cell line for production of infectious virus. This disabled infectious single cycle (DISC) vaccine strategy results in a virs that can infect cells to express an array of viral antigens and induce an immune response but does not produce infectious virus. This vaccine strategy was highly immunogenic in guinea pigs producing antibody and T cell responses to important viral antigens. However, our original DISC vaccine lacked a newly identified homolog locus to human CMV UL128-131 (GP128-131). Consequently, this vaccine strategy lacks the ability to generate an immune response against a potential GPCMV endocytic complex. In this application we propose to define requirements for GPCMV entry into endothelial cells and additionally develop a 2nd generation DISC vaccine carrying the essential antigens necessary to induce an effective neutralizing immune response against viral infection of epi/endothelial cells. As part of this 2nd generation DISC vaccine strategy the virus will be further attenuated to increase immunogenicity and decrease the ability of the virus to establish latency by the knockout of the pp71 homolog. The ability of second generation DISC vaccines to protect against congenital GPCMV will be investigated and efficacy determined by comparing it with a recombinant gB vaccine strategy previously investigated in this model.

描述（由申请人提供：巨细胞病毒（CMV）疫苗的发展是主要的公共卫生优先事项，这是由于存在先天性感染的风险。致病性临床菌株O CMV与实验室适应性菌株的不同之处在于，由于它们保留了跨性的上皮细胞的能力，因此它们可以基于跨性别细胞的结构。胎儿进入表面/内皮细胞的机制与GB进入成纤维细胞的GH/GL/GL/UL128-131的途径不同于唯一的小动物模型研究了复制受损的Live GPCMV疫苗，该疫苗需要互补的细胞系来生产这种残疾的感染性单周期（盘）疫苗策略，导致病毒会导致病毒感染细胞以表达一系列病毒抗原并引起免疫反应，但不会产生感染性病毒。这种疫苗策略在产生抗体和对重要病毒抗原的T细胞反应的豚鼠中具有高度免疫原性。但是，我们的原始盘疫苗缺乏与人CMV UL128-131（GP128-131）的新鉴定的同源基因座。因此，该疫苗策略缺乏针对潜在的GPCMV内吞复合物产生免疫反应的能力。在此应用中，我们建议定义GPCMV进入内皮细胞的需求，并另外开发出第二代椎间盘疫苗，该烟丝疫苗携带必要的必需抗原，以诱导对Epi/内皮细胞病毒感染的有效中和免疫反应。作为第二代椎间盘疫苗策略的一部分，该病毒将进一步减弱，以提高免疫原性并降低病毒通过PP71同源物敲除确定潜伏期的能力。将研究第二代椎间盘疫苗预防先天GPCMV的能力，并通过将其与先前在此模型中研究的重组GB疫苗策略进行比较来确定其功效。