Novel Strategy for Animal Model Testing of HCMV Vaccines

HCMV 疫苗动物模型测试新策略

基本信息

批准号：
7229927
负责人：
Mark R. Schleiss
金额：
$ 21.07万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229927
关键词：
Adjuvant Animal Model Animals Bacterial Artificial Chromosomes Bacterial Chromosomes Cavia Chimera organism Chinese Hamster Ovary Cell Clinical Trials Competence Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Data Development Disease Enzyme-Linked Immunosorbent Assay Epitopes Escherichia coli Evaluation Gene Targeting Generations Genes Genetic Genome Glycoproteins Guinea pig cytomegalovirus Health Priorities Homologous Gene Human Immune response Immunization Infection MF59 Maternal Mortality Modeling Monitor Mutagenesis Outcome Patient currently pregnant Placenta Pregnancy Prevention Proteins Public Health Recombinants Sequence Homology Serum Shuttle Vectors Species Specificity Subunit Vaccines Technology Testing Vaccines Viral Viral Genome Viremia Virus base congenital infection homologous recombination human TYRP1 protein human disease immunogenic immunogenicity in utero in vivo insight mutant neutralizing antibody novel novel strategies pup recombinant virus research study tissue culture vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): A vaccine for prevention of congenital infection with human cytomegalovirus (HCMV) is an urgent public health priority. A subunit vaccine based on purified recombinant glycoprotein B (gB), expressed in Chinese hamster ovary (CHO) cells, is currently being tested in clinical trials. The rationale for this vaccine is based on observations that the majority of virus-neutralizing antibodies found in human convalescent sera are specific for this protein. The observation that purified, recombinant forms of guinea pig cytomegalovirus (GPCMV) gB are protective against infection and disease in the guinea pig model of congenital CMV infection lends credence to the hypothesis that HCMV gB vaccines might be efficacious against congenital infection. However, to date it has unfortunately been impossible to test the efficacy of the HCMV gB vaccine in an animal model, such as the GPCMV model. This is because the strict species-specificity of the respective CMVs makes it impossible to perform HCMV viral challenge experiments in guinea pigs, even though the human gB vaccine is immunogenic in these animals. Recently, however, the development of viral mutagenesis strategies based on the successful doing of CMV genomes as bacterial artificial chromosomes (BACs) in E. coli has represented a major advance in generating recombinant, chimeric viruses. It is now feasible to generate replication-competent GPCMVs with targeted insertions of heterologous HCMV genes into the viral genome. Against this backdrop, this proposal seeks to test the hypotheses that: 1) a novel, recombinant 'swap' mutant, expressing the HCMV gB protein in the context of the GPCMV genome, will retain replication competence and the ability to cause congenital infection and disease in vivo; and, 2) that purified, recombinant HCMV gB, administered with MF59 adjuvant, will protect against congenital infection and disease in pregnant animals challenged with the 'humanized' virus. These studies will represent the first efficacy test of a human CMV subunit vaccine in a small animal model of congenital CMV infection.

描述（由申请人提供）：预防人类巨细胞病毒（HCMV）先天性感染的疫苗是一项紧迫的公共卫生优先事项。一种基于在中国仓鼠卵巢 (CHO) 细胞中表达的纯化重组糖蛋白 B (gB) 的亚单位疫苗目前正在进行临床试验。这种疫苗的基本原理是基于观察，即在人类恢复期血清中发现的大多数病毒中和抗体都对该蛋白具有特异性。豚鼠巨细胞病毒 (GPCMV) gB 的纯化重组形式在先天性 CMV 感染的豚鼠模型中具有预防感染和疾病的保护作用，这一观察结果证实了 HCMV gB 疫苗可能对先天性感染有效的假设。然而，不幸的是，迄今为止，还无法在动物模型（例如 GPCMV 模型）中测试 HCMV gB 疫苗的功效。这是因为各个 CMV 的严格物种特异性使得不可能在豚鼠中进行 HCMV 病毒攻击实验，即使人 gB 疫苗在这些动物中具有免疫原性。然而，最近，基于在大肠杆菌中成功地将CMV基因组用作细菌人工染色体（BAC）的病毒诱变策略的发展代表了产生重组嵌合病毒的重大进展。现在可以通过将异源 HCMV 基因定向插入病毒基因组来生成具有复制能力的 GPCMV。在此背景下，本提案旨在测试以下假设：1）一种新型重组“交换”突变体，在 GPCMV 基因组背景下表达 HCMV gB 蛋白，将保留复制能力以及引起先天性感染和疾病的能力体内; 2) 纯化的重组 HCMV gB 与 MF59 佐剂一起施用，将保护受到“人源化”病毒攻击的怀孕动物免受先天性感染和疾病。这些研究将代表人类 CMV 亚单位疫苗在先天性 CMV 感染的小动物模型中的首次功效测试。