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

• 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
• 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

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.

描述（由申请方提供）：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的致病性临床菌株与实验室适应菌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。基于胎盘的结构，内皮细胞可能是启动病毒通过胎盘转移到胎儿的潜在重要位点。病毒进入表皮/内皮细胞的机制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/UL 128 -131形成内吞复合物以使病毒进入细胞。豚鼠是唯一允许通过使用种属特异性豚鼠CMV（GPCMV）来研究先天性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生产感染性病毒。这种失能的感染性单循环（DISC）疫苗策略导致病毒可以感染细胞以表达一系列病毒抗原并诱导免疫应答，但不产生感染性病毒。该疫苗策略在豚鼠中产生对重要病毒抗原的抗体和T细胞应答，具有高度免疫原性。然而，我们最初的DISC疫苗缺乏新鉴定的人CMV UL 128 -131（GP 128 -131）的同源基因座。因此，该疫苗策略缺乏产生针对潜在的GPCMV内吞复合物的免疫应答的能力。在本申请中，我们提出定义GPCMV进入内皮细胞的要求，并另外开发第二代DISC疫苗，该疫苗携带诱导针对表皮/内皮细胞病毒感染的有效中和免疫应答所必需的必需抗原。作为第二代DISC疫苗策略的一部分，将进一步减毒病毒以增加免疫原性并降低病毒通过pp 71同源物敲除建立潜伏期的能力。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该模型中研究的重组gB疫苗策略进行比较来确定疗效。 公共卫生关系：巨细胞病毒（CMV）是一种普遍存在的病原体，在免疫功能低下的人群中，包括移植和艾滋病患者以及子宫内的胎儿，会导致显著的死亡率和发病率。先天性巨细胞病毒感染可导致存活新生儿智力低下和耳聋。CMV是最常见的艾滋病继发感染。没有CMV疫苗。虽然目前的抗病毒药物可用于移植和艾滋病患者，但这些药物导致出现导致疾病的耐药菌株。此外，抗病毒药物的毒副作用使其无法用于预防先天性CMV。