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：
8270164
负责人：
ALISTAIR MCGREGOR
金额：
$ 14.24万
依托单位：
UNIVERSITY OF MINNESOTA
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 2013-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270164
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

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. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant mortality and morbidity in immunocompromised populations including transplant and AIDS patients and the fetus in utero. Congenital CMV infection causes mental retardation and deafness in surviving newborn. CMV is the most common AIDS related secondary infection. There is no vaccine to CMV. Although current antivirals are available for transplant and AIDS patients these result in the emergence of resistant strains that cause disease. Additionally, antiviral drug toxic side effects preclude their use in the prevention of congenital CMV.

说明（由申请人提供：由于存在先天性感染的风险，巨细胞病毒 (CMV) 疫苗的开发是一项主要的公共卫生优先事项。CMV 致病性临床毒株与实验室适应毒株的不同之处在于，它们保留了感染上皮细胞和内皮细胞的能力根据胎盘的结构，内皮细胞可能是病毒通过胎盘转移到胎儿的潜在重要位点。细胞与进入成纤维细胞的 gB 途径不同，因为它需要病毒蛋白 gH/gL/UL128-131 形成内吞复合物才能使病毒细胞进入，豚鼠是唯一允许研究先天性 CMV 的小动物模型。我们最近研究了复制受损的活 GPCMV 疫苗的使用，该疫苗需要补充细胞系来产生感染性病毒。禁用传染性单周期（DISC）疫苗策略产生的病毒可以感染细胞以表达一系列病毒抗原并诱导免疫反应，但不会产生传染性病毒。这种疫苗策略在豚鼠中具有高度免疫原性，可产生针对重要病毒抗原的抗体和 T 细胞反应。然而，我们最初的 DISC 疫苗缺乏新鉴定的人类 CMV UL128-131 (GP128-131) 同源基因座。因此，这种疫苗策略缺乏针对潜在 GPCMV 内吞复合物产生免疫反应的能力。在本申请中，我们建议定义 GPCMV 进入内皮细胞的要求，并另外开发第二代 DISC 疫苗，其携带诱导针对外皮/内皮细胞病毒感染的有效中和免疫反应所需的基本抗原。作为第二代 DISC 疫苗策略的一部分，该病毒将进一步减毒，以增加免疫原性，并通过敲除 pp71 同源物来降低病毒建立潜伏期的能力。将研究第二代 DISC 疫苗预防先天性 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功效。公共卫生相关性：巨细胞病毒 (CMV) 是一种普遍存在的病原体，可导致免疫功能低下人群（包括移植患者、艾滋病患者以及子宫内胎儿）显着死亡和发病。先天性巨细胞病毒感染会导致幸存新生儿智力低下和耳聋。 CMV 是最常见的艾滋病相关继发感染。没有针对 CMV 的疫苗。尽管目前的抗病毒药物可用于移植患者和艾滋病患者，但这些药物会导致导致疾病的耐药菌株的出现。此外，抗病毒药物的毒副作用使其无法用于预防先天性巨细胞病毒。