Evaluation of Protective CMV Vaccines in Rhesus Macaques

恒河猴保护性巨细胞病毒疫苗的评价

• 批准号: 7162536
• 负责人: Peter A Barry
• 金额: $ 35.97万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162536
• 关键词: Animals; Antigens; CMV glycoprotein B; California; Complex; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Disease; Equilibrium; Evaluation; Exposure to; Fetus; Formalin; Frequencies; Gene Expression; Generations; Glycoproteins; Horizontal Disease Transmission; Housing; Immune; Immune response; Immune system; Immunity; Immunization; Immunocompetent; Individual; Infection; Kinetics; Macaca; Macaca mulatta; Maintenance; Measures; Modeling; Monkeys; Natural History; Natural Immunity; Numbers; Organ; Outcome; Pathogenesis; Pattern; Phosphoproteins; Plasmids; Population; Primates; Probability; Research; Research Personnel; Risk; Route; Site; Testing; Vaccination; Vaccines; Vertical Disease Transmission; Virion; Virus; Virus Diseases; Virus Replication; congenital infection; cost; design; expression vector; fetal; genetic immunization strategies; immunosuppressed; novel; prevent; programs; subcutaneous; transmission process

DESCRIPTION (provided by applicant): Since human cytomegalovirus (HCMV) was first recognized as a threat to the developing fetus, there have been repeated calls for a vaccine that could protect from the damaging effects of HCMV infection in those at risk for HCMV disease. The long quest for a HCMV vaccine that could prevent congenital infection and fetal sequelae, as well as end-organ disease in immune compromised individuals, remains unfulfilled. The primary objective measure for evaluating the efficiency of any vaccine is whether protective levels of immunity are generated and sustained in the vaccinees. An important issue for HCMV is the definition of what constitutes protective immunity. Using a stringent threshold, an immune response can be considered protective only if the vaccinees are absolutely protected from infection following repeated exposure to virus. Alternatively, a vaccine could still be considered protective if the course of challenge virus infection was so dramatically altered that the potential for transmission (horizontal and vertical) and pathogenesis of challenge virus was essentially eliminated. The difference between the two involves the level of virus replication at the primary site of challenge and the extent of dissemination beyond. The former definition requires the generation and maintenance of sterilizing immunity with no spread of the virus. The latter does not, but it does require that the immune system maintain a lifelong restriction on replication of a virus with a complex natural history of persistence in immune competent hosts. The hypothesis is presented that immunization against CMV can generate protective immune responses, although the degree of protection (sterilizing versus limited dissemination) will be dependent on both the titer of challenge virus and the frequency of exposure. According to this hypothesis, immunization can protect completely against infrequent exposure to a low titer CMV challenge. Protection will become more variable as the titer and/or the frequency of exposure to challenge virus increases. Vaccination should shift the virus-host balance decidedly in favor of the host such that both reactivation and shedding are significantly diminished. The hypothesis will be tested in the rhesus macaque model of HCMV infection through the following Aims. (I) Genetic immunization of seronegative macaques with plasmid expression vectors for RhCMV gB, pp65, and IE1, followed by immunization with formalin-inactivated virus. (II) Subcutaneous challenge of vaccinees and controls by experimental inoculation with either high or low titers of RhCMV. (III) Immunization of macaques followed by challenge of vaccinees and controls by natural routes with natural titers of RhCMV by co-housing vaccinees with seropositive, virus-excreting macaques. (IV) Alterations of RhCMV gene expression patterns to induce novel protective immune responses. A CMV vaccine can be considered protective if it results in a dead-end infection. This proposal will stringently test whether a combination of genetic immunization and formalin-inactivated virus can effectively eliminate horizontal spread of RhCMV following either experimental or natural infection.

描述（由申请人提供）：自从人类巨细胞病毒 (HCMV) 首次被认为对发育中的胎儿构成威胁以来，人们一再呼吁开发一种疫苗，能够保护那些有 HCMV 疾病风险的人免受 HCMV 感染的破坏性影响。人们长期以来一直寻求一种能够预防先天性感染和胎儿后遗症以及免疫受损个体的终末器官疾病的 HCMV 疫苗，但这一目标仍未实现。评估任何疫苗有效性的主要客观指标是接种者是否产生并维持保护性免疫水平。 HCMV 的一个重要问题是保护性免疫的定义。使用严格的阈值，只有当疫苗接种者在反复接触病毒后绝对免受感染时，免疫反应才能被认为具有保护性。或者，如果攻击病毒感染的过程发生如此显着的改变，以至于攻击病毒的传播（水平和垂直）和发病机制的可能性基本上被消除，那么疫苗仍然可以被认为是具有保护性的。两者之间的差异涉及主要攻击位点的病毒复制水平和传播程度。前一个定义要求产生和维持消毒免疫力，而不传播病毒。后者不需要，但它确实要求免疫系统对病毒的复制保持终生限制，该病毒在具有免疫能力的宿主中具有复杂的持续自然史。提出的假设是，针对 CMV 的免疫可以产生保护性免疫反应，尽管保护程度（灭菌与有限传播）将取决于攻击病毒的滴度和暴露频率。根据这一假设，免疫接种可以完全防止偶尔暴露于低滴度 CMV 攻击。随着暴露于攻击病毒的滴度和/或频率的增加，保护将变得更加可变。疫苗接种应明显改变病毒与宿主的平衡，有利于宿主，从而显着减少重新激活和脱落。该假设将通过以下目标在 HCMV 感染的恒河猴模型中进行检验。 (I)用RhCMV gB、pp65和IE1的质粒表达载体对血清阴性猕猴进行遗传免疫，然后用福尔马林灭活病毒进行免疫。 (II) 通过用高滴度或低滴度的 RhCMV 实验接种对疫苗接种者和对照进行皮下攻击。 (III)对猕猴进行免疫，然后对接种者进行攻击，并通过将接种者与血清反应呈阳性、分泌病毒的猕猴共同饲养，以具有RhCMV自然滴度的自然途径进行对照。 (IV) 改变 RhCMV 基因表达模式以诱导新的保护性免疫反应。如果 CMV 疫苗导致死端感染，则可被认为具有保护作用。该提案将严格测试基因免疫和福尔马林灭活病毒的结合是否可以有效消除实验或自然感染后RhCMV的水平传播。