Optimized Vaccines Against Congenital Infection and Maternal Reinfection with CMV

 描述(由申请人提供)：感染后对人类巨细胞病毒(HCMV)的免疫是复杂的，不能完全预防新毒株的重新激活和再次感染。虽然在具有免疫能力的成年人中一般没有症状，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毁灭性的影响。由于先天性CMV感染会导致终生残疾，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早孕疫苗的目标至关重要。一种佐剂糖蛋白B(GB)疫苗的临床试验显示，在育龄的年轻女性中有保护作用，但免疫力减弱和适度的疗效(~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(PC)(Gh/gl/UL128/UL130/UL131)可能是比GB更有吸引力的保护性抗体反应的疫苗靶点。这源于观察到，针对PC的抗体有效地阻止病毒进入上皮细胞、内皮细胞和白细胞。此外，在患有CMV原发感染的妇女中，获得这些抗体与降低胎儿传播风险相关。为了说明基于PC的疫苗是否对先天性CMV传播提供了比基于GB的疫苗更好的保护，我们将在先天性CMV感染的豚鼠模型中比较MVA载体的GB和PC疫苗，使用这些蛋白的豚鼠CMV(GPCMV)同源物。除了比较母婴死亡率、先天GPCMV感染和孕期大剂量GPCMV攻击后病毒载量(目标1)的终点外，我们还将比较这些疫苗在孕期低剂量攻击后对SNHL(AIM 2)的保护能力。这项研究将是对预防先天性CMV诱导的迷路炎和SNHL的产前疫苗的第一次动物模型评估。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，尽管有先入为主的免疫力，女性可能会再次感染新的HCMV毒株，这些毒株可能会传播给胎儿，导致伤害。因此，在目标3中，我们将利用一种新发现的GPCMV毒株，CIDMTR毒株，来模拟豚鼠的再感染研究。我们将测试MVA-PC疫苗是否可以提供比GB疫苗更好的保护，防止对异型毒株ATCC(22122)株有预先免疫的母体再次感染和随后的胎儿传播。由于大多数先天性巨细胞病毒感染发生在非原发母体感染的背景下，这些研究将极大地推进这一领域，并澄清育龄妇女接种巨细胞病毒疫苗的必要性。

 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.