Optimized Vaccines Against Congenital Infection and Maternal Reinfection with CMV

 描述（由申请方提供）：感染后对人巨细胞病毒（HCMV）的免疫力是复杂的，不能完全防止新毒株的再激活和再感染。虽然在免疫功能正常的成年人中通常无症状，但如果发生经胎盘传播，孕妇的感染或再感染可能对发育中的胎儿造成破坏。由于先天性CMV感染导致的终身残疾，如感音神经性听力损失（SNHL），了解保护发育中胎儿的宿主防御决定因素对于开发有效的孕前疫苗至关重要。一种含佐剂的糖蛋白B（gB）疫苗的临床试验显示对育龄期的年轻女性具有保护作用，但免疫力下降和有效性不高（约50%），需要考虑其他亚单位策略。最近的证据表明，CMV蛋白的五聚体复合物（PC）（gH/gL/UL 128/UL 130/UL 131）可能是比gB更引人注目的诱导保护性抗体应答的疫苗靶标。这是由于观察到抗PC抗体有效地阻断病毒进入上皮细胞、内皮细胞和白细胞。此外，这些抗体的获得与原发性CMV感染妇女的胎儿传播风险降低相关。为了确定基于PC的疫苗是否提供比基于gB的疫苗所赋予的针对先天性CMV传播的保护更上级的保护，我们将在先天性CMV感染的豚鼠模型中使用这些蛋白质的豚鼠CMV（GPCMV）同源物比较MVA载体的gB和PC疫苗。除了比较母体和幼仔死亡率、先天性GPCMV感染和妊娠期间高剂量GPCMV攻毒后病毒载量的大小（目的1）等终点外，我们还将比较这些疫苗在妊娠期间低剂量攻毒后提供SNHL保护的能力（目的2）。本研究将代表产前疫苗预防先天性CMV诱导的尿道炎和SNHL的首次动物模型评价。我们还将解决CMV疫苗中第二个非常复杂的领域，即解决怀孕期间再次感染的现象。越来越清楚的是，尽管有孕前免疫力，但妇女可以再次感染新的HCMV毒株，这些毒株可以传播给胎儿，导致损伤。因此，在目标3中，我们将利用新发现的GPCMV毒株CIDMTR毒株在豚鼠中进行再感染研究建模。我们将测试MVA-PC疫苗接种是否可以提供上级保护相比，gB疫苗，防止再次感染和随后的胎儿传播母鼠孕前免疫的异型株，ATCC（22122）菌株。由于大多数先天性CMV感染发生在非原发性母体感染的背景下，这些研究将大大推进该领域，并阐明育龄妇女对CMV疫苗的要求。

 DESCRIPTION (provided by applicant): Immunity to human cytomegalovirus (HCMV) following infection is complex, and not fully protective against reactivation and reinfection with new strains. Although generally asymptomatic in immunocompetent adults, infection or reinfection in pregnant women can be devastating to the developing fetus if transplacental transmission occurs. Because of the lifelong disabilities caused by congenital CMV infection, such as sensorineural hearing loss (SNHL), understanding the host defense determinants that protect the developing fetus is critical, toward the goal of developing an effective preconception vaccine. Clinical trials of an adjuvanted glycoprotein B (gB) vaccine showed protection in young women of childbearing age, but waning immunity and modest efficacy (~50%) necessitate consideration of other subunit strategies. Recent evidence suggests that the pentameric complex (PC) of CMV proteins (gH/gL/UL128/UL130/UL131) may be a more compelling vaccine target for induction of protective antibody responses than gB. This stems from the observations that antibodies to the PC potently block virus entry into epithelial and endothelial cells and leukocytes. Moreover, acquisition of these antibodies correlates with a reduced risk of fetal transmission in women with primary CMV infection. To address whether a PC-based vaccine provides superior protection against congenital CMV transmission to that conferred by a gB-based vaccine, we will compare MVA- vectored gB and PC vaccines in the guinea pig model of congenital CMV infection, using the guinea pig CMV (GPCMV) homologs of these proteins. In addition to comparing the endpoints of maternal and pup mortality, congenital GPCMV infection, and magnitude of viral load following high-dose GPCMV challenge during pregnancy (aim 1), we will compare these vaccines for their ability to confer protection against SNHL (aim 2) following low-dose challenge during pregnancy. This study will represent the first animal model evaluation of a prenatal vaccine to prevent congenital CMV-induced labyrinthitis and SNHL. We will also address a second area of significant complexity in CMV vaccines, namely, addressing the phenomena of re-infection during pregnancy. It has become increasingly clear that, in spite of preconception immunity, women can become re-infected with new strains of HCMV, and these strains can be transmitted to the fetus, leading to injury. Therefore, in aim 3, we will utilze a newly discovered strain of GPCMV, the CIDMTR strain, to model re- infection studies in the guinea pig. We will test whether MVA-PC vaccination can provide superior protection compared to gB vaccine against re-infection and subsequent fetal transmission in dams with preconception immunity to a heterotypic strain, the ATCC (22122) strain. Since most congenital CMV infections occur in the context of non-primary maternal infections, these studies will substantially advance the field, and clarify what is required of a CMV vaccine in women of childbearing age.