Development of a universal DISC vaccine strategy against congenital cytomegalovirus

针对先天性巨细胞病毒的通用 DISC 疫苗策略的开发

基本信息

批准号：
10386763
负责人：
ALISTAIR MCGREGOR
金额：
$ 66.83万
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：
2021
资助国家：
美国
起止时间：
2021-04-07 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386763
关键词：
Acquired Immunodeficiency Syndrome Amniotic Sac Animal Model Animals Antibodies Antigen Targeting Antigens Capsid Cavia Cell Line Cells Clinic Complex Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Development Disease Epithelial Epithelial Cells Evaluation Fetus Fibroblasts Gene Expression Glycoproteins Guinea pig cytomegalovirus Human Immune Immune response Immunity Immunocompromised Host Impaired cognition Individual Infection Innate Immune Response Interferons Intervention Mental Retardation Morbidity - disease rate Newborn Infant PDGFRA gene Pathogenesis Pathogenicity Patients Population Pregnancy Proteins Research Research Personnel Risk Route Shapes Study models T cell response TimeLine Transplantation Vaccine Design Vaccines Viral Virus Virus Diseases Visual impairment base cell type congenital cytomegalovirus deafness guinea pig model hearing impairment immunogenicity improved in utero insight knockout animal knockout gene macrophage mortality mutant neutralizing antibody novel pathogen pregnant pup receptor renal epithelium response trophoblast unvaccinated vaccine immunogenicity vaccine strategy vaccine trial virus tropism

项目摘要

ABSTRACT Congenital CMV (cCMV) is a leading cause of hearing loss and cognitive impairment in surviving newborns. A vaccine is a high priority but an effective vaccine needs to exceed protection levels of natural convalescent immunity because of the risk of re-infection by multiple strains of HCMV. The guinea pig is the only small animal model for cCMV with disease in pups similar to humans. Previously it was demonstrated that guinea pig cytomegalovirus (GPCMV) encodes functionally similar essential viral glycoprotein complexes to HCMV, which can act as neutralizing antibody target antigens. An important correlation with HCMV is that GPCMV encodes a functional gH based pentamer complex (PC) necessary for virus tropism/entry to non-fibroblast cells, pathogenesis and cCMV. Previously, the efficacy of two non-replication competent capsid mutant GPCMV DISC (Defective Infectious Single Cycle) vaccine strains were evaluated: (1) lacking PC (DISCI); (2) encoding PC (DISCII). DISCII was more successful in neutralizing virus on epithelial cells and fully protected against cCMV when pregnant animals were challenged with wild type virus. However, a significant challenge that remains to be attained is the ability of a DISC vaccine strategy to protect against: (1) multistrain virus challenge, which is an absolute necessity for a successful HCMV vaccine; (2) provide protection against natural routes of infection. A newly isolated GPCMV strain (CRV) will be included in the studies to enable multistrain virus challenge. Modified GPCMV DISC vaccine strain will be improved for immunogenicity and correlates of immune protection determined. An important leap in the guinea pig model studies is that we will employ the first gene knockout (IFNLR1) guinea pig to evaluate the importance of IFN III in shaping immune response. The overall central hypothesis is that the DISC vaccine strategy can provide greater protection against cCMV compared to convalescent immunity and can fully protect against multiple strains of virus and natural routes of infection but vaccine requires comprehensive CMV gene expression that is potentially lacking in IE1 mutant based DISC vaccine strains. The proposed studies will provide an accelerated timeline for the realistic evaluation of a DISC vaccine strategy against cCMV.

抽象的先天性CMV（CCMV）是尚存新生儿中听力损失和认知障碍的主要原因。一个疫苗是高度优先级，但有效的疫苗需要超过自然康复的保护水平免疫力是由于多种HCMV菌株再感染的风险。豚鼠是唯一的小与人类类似的幼犬中CCMV的动物模型。以前证明了豚鼠巨细胞病毒（GPCMV）编码功能相似的必需病毒糖蛋白复合物与HCMV 可以充当中和抗体靶抗原。与HCMV的重要相关性是GPCMV编码一种基于功能性GH的五聚体复合物（PC），用于病毒对流/进入非纤维细胞细胞，发病机理和CCMV。以前，两个非复制能胜任的衣壳突变体GPCMV的功效评估了椎间盘（传染性单周期缺陷）疫苗菌株：（1）缺乏PC（disci）；（2）编码 PC（discii）。 discii在中和上皮细胞上的病毒方面更为成功，并完全保护 CCMV怀孕的动物被野生型病毒挑战。但是，这是一个重大挑战还有待实现的尚有椎间盘疫苗策略预防的能力：（1）多病毒病毒挑战，这是成功的HCMV疫苗的绝对必要性；（2）提供防止自然感染途径。研究中将包括新分离的GPCMV菌株（CRV），以实现多种病毒挑战。修饰的GPCMV椎间盘疫苗菌株将改善免疫原性和确定免疫保护的相关性。豚鼠模型研究的一个重要飞跃是我们将使用第一个基因敲除（IFNLR1）豚鼠来评估IFN III在塑造免疫中的重要性回复。总体核心假设是，光盘疫苗策略可以提供更大的保护与CCMV相比，与康复免疫相比，可以完全防止多种病毒菌株和自然感染途径，但疫苗需要全面的CMV基因表达，这可能缺乏在IE1基于IE1突变体的椎间盘疫苗菌株中。拟议的研究将为加速时间表对CCMV的光盘疫苗策略的现实评估。