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：
10595098
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/10595098
关键词：
Acceleration 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 Cells Epithelium 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 Macrophage Mental Retardation Morbidity - disease rate Newborn Infant PDGFRA gene Pathogenesis Pathogenicity Patients Population Pregnancy Proteins Receptor Gene Research Research Personnel Risk Route Shapes Study models T cell response Transplantation Vaccine Design Vaccines Viral Virus Virus Diseases Visual impairment adaptive immune response cell type congenital cytomegalovirus deafness guinea pig model hearing impairment immunogenicity improved in utero insight knockout animal knockout gene mortality mutant neutralizing antibody novel pathogen pregnant pup receptor renal epithelium response timeline 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.

抽象的先天性巨细胞病毒 (cCMV) 是导致存活新生儿听力丧失和认知障碍的主要原因。一个疫苗是当务之急，但有效的疫苗需要超过自然恢复期的保护水平免疫力，因为存在多种 HCMV 毒株再次感染的风险。豚鼠是唯一的小 cCMV 动物模型，幼犬患有与人类相似的疾病。此前有研究表明，豚鼠巨细胞病毒 (GPCMV) 编码与 HCMV 功能相似的必需病毒糖蛋白复合物，可以作为中和抗体的靶抗原。与 HCMV 的一个重要关联是 GPCMV 编码病毒向性/进入非成纤维细胞所必需的基于功能性 gH 的五聚体复合物 (PC)，发病机制和 cCMV。此前，两种非复制能力衣壳突变体 GPCMV 的功效对DISC（缺陷传染性单周期）疫苗株进行了评估：（1）缺乏PC（DISCI）； (2)编码电脑（DISCII）。 DISCII 在中和上皮细胞上的病毒方面更成功，并能充分防止当怀孕动物受到野生型病毒攻击时，出现 cCMV。然而，一个重大挑战是 DISC 疫苗策略仍有待实现的能力是预防：(1) 多株病毒挑战，这对于成功的 HCMV 疫苗是绝对必要的； (2) 提供保护自然感染途径。研究中将包括一种新分离的 GPCMV 毒株 (CRV)，以实现多毒株病毒挑战。改良GPCMV DISC疫苗株的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 在塑造免疫方面的重要性回复。总体中心假设是 DISC 疫苗策略可以提供更大的保护与恢复期免疫相比，具有针对 cCMV 的免疫力，可充分防御多种病毒株，自然感染途径，但疫苗需要全面的 CMV 基因表达，而这可能是缺乏的在基于 IE1 突变体的 DISC 疫苗株中。拟议的研究将提供一个加速时间表针对 cCMV 的 DISC 疫苗策略的现实评估。