Development of a universal DISC vaccine strategy against congenital cytomegalovirus

摘要 先天性巨细胞病毒（cCMV）是存活新生儿听力损失和认知障碍的主要原因。一 疫苗是一个高度优先事项，但有效的疫苗需要超过自然恢复期的保护水平。 免疫力，因为再感染的风险由多个菌株的HCMV。豚鼠是唯一一个 cCMV的动物模型，在幼仔中具有与人类相似的疾病。以前的研究表明，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， 可以作为中和抗体靶抗原。与HCMV的一个重要相关性是GPCMV编码 病毒嗜性/进入非成纤维细胞所必需的功能性基于gH的五聚体复合物（PC）， 发病机制和cCMV。以前，两个非复制能力衣壳突变体GPCMV的效力 评价了DISC（缺陷性传染性单循环）疫苗株：（1）缺乏PC（DISCI）;（2）编码 PC（DISCII）。DISCII在中和上皮细胞上的病毒方面更成功，并且完全保护了 当妊娠动物用野生型病毒攻毒时的cCMV。然而，一个重大挑战是， DISC疫苗策略仍有待实现的能力是保护免受：（1）多株病毒 挑战，这是一个成功的HCMV疫苗的绝对必要;（2）提供保护， 自然感染途径。新分离的GPCMV毒株（CRV）将被纳入研究， 多株病毒攻毒。改良的GPCMV DISC疫苗株将提高免疫原性， 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 使用第一只基因敲除（IFNLR 1）豚鼠来评估IFN III在塑造免疫中的重要性 反应总体中心假设是DISC疫苗策略可以提供更大的保护 与恢复期免疫相比，可完全保护免受多种病毒株的侵害， 自然感染途径，但疫苗需要全面的CMV基因表达，这是潜在缺乏的 在基于IE 1突变体的DISC疫苗株中。拟议的研究将提供一个加速的时间轴， 针对cCMV的DISC疫苗策略的现实评估。

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.