Novel vaccine to CMV based on a disc virus

描述（由申请人提供）：巨细胞病毒（CMV）是一种普遍存在的病原体，在免疫功能低下人群中引起显著的发病率和死亡率。目前，没有针对巨细胞病毒的有效疫苗。研制疫苗，特别是为育龄妇女研制疫苗，被认为是一项重要的公共卫生优先事项，因为有可能对胎儿造成先天性感染。这项应用建议使用缺乏必要基因的复制受损巨细胞病毒活疫苗。突变病毒能够在一个失败的病毒复制单周期中感染非互补细胞，但不能产生感染性病毒。我们假设，无论使用何种病毒剂量，针对巨细胞病毒的失能感染单周期（DISC）疫苗都是非致病性的，但却能高度免疫原性地诱导抗体和t细胞对一系列病毒抗原的反应。此外，我们建议通过在病毒基因组中引入主要中和抗原糖蛋白gB的第二拷贝，进一步增强这种DISC疫苗对抗巨细胞病毒的有效性。我们还假设，疫苗株与促炎细胞因子（IL-12）佐剂共同给药将使T细胞辅助型1 （Th1）免疫反应极化，以对抗病毒，从而产生细胞介导的免疫反应。与所有巨细胞病毒一样，人类巨细胞病毒是一种物种特异性病毒，因此必须研究动物巨细胞病毒在其各自宿主中的情况，以测试任何拟议的疫苗或抗病毒策略。在CMV的小动物模型中，只有豚鼠模型允许研究先天性感染。我们的长期目标是继续发展这一模型，以测试针对先天性感染的干预策略，特别是孕前疫苗。作为CMV DISC疫苗策略的原理证明，这些研究将在豚鼠模型中进行。该研究将确定对一系列CMV DISC候选疫苗株的抗体和细胞免疫反应。此外，该研究将确定候选DISC疫苗预防先天性巨细胞病毒感染的能力，并与先前在该模型中测试的重组gB亚单位疫苗策略进行比较。

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant morbidity and mortality in immunocompromised populations. Currently, there is no effective vaccine against CMV. Development of a vaccine, particularly for women of child-bearing age, is considered to be a major public health priority because of the risk of congenital infection to the fetus. This application proposes the use of a replication-impaired live CMV vaccine lacking an essential gene. The mutant viruses will be capable of infecting non-complementing cells in an abortive single cycle of virus replication but incapable of producing infectious virus. We hypothesize that a disabled infectious single cycle (DISC) vaccine against CMV would be non-pathogenic, regardless of virus dosage used, but highly immunogenic inducing antibody and T-cell responses to an array of viral antigens. Additionally, we propose that the effectiveness of such a DISC vaccine against CMV will be further augmented by introducing a second copy of the major neutralizing antigen, glycoprotein gB, into the viral genome. We also hypothesize that the co-administration of the vaccine strain with a pro-inflammatory cytokine (IL-12) adjuvant will polarize the T cell helper type 1 (Th1) immune response against the virus creating a bias towards a cell mediated immune response. Human CMV, as with all CMV, is a species specific virus and consequently animal CMVs in their respective hosts must be studied to test any proposed vaccine or antiviral strategy. Among the small animal models of CMV only the guinea pig model allows the study of congenital infection. Our long-term goal is the continued development of this model to test intervention strategies against congenital infection in particular pre-conception vaccines. As proof of principle for the CMV DISC vaccine strategy these studies will be carried out in the guinea pig model. The proposed research will define the antibody and cellular immune responses to a series of vaccine candidate CMV DISC strains. Additionally, the research will determine the ability of candidate DISC vaccines to protect against congenital CMV infection in comparison to a recombinant gB subunit vaccine strategy that has previously been tested in this model. PUBLIC HEALTH RELEVANCE: HCMV is a ubiquitous pathogen that causes significant morbidity and mortality in immunocompromised populations. Primary HCMV infection in immunocompetent individuals is usually benign but establishes a lifelong latent infection. Solid organ transplant recipients or AIDS patients are particularly susceptible to reactivation of the virus, which can lead to life-threatening end-organ disease. Congenital infection of newborns by HCMV (approximately 1% of live births in the US) can lead to serious symptomatic disease including mental retardation and hearing loss. Indeed it is estimated that congenital HCMV related sensorineural hearing loss (SNHL) occurs at a greater frequency than SNHL related to Hemophilus influenza infection in the pre-HIB vaccine era. Furthermore, congenital HCMV infection is the second most common cause of mental retardation next to Down's syndrome in newborns. Although antivirals are available for treatment of AIDS and transplant patients these drugs cannot be used to prevent congenital infection because of the risk of toxic side effects on the fetus. Additionally, antivirals act at late stages of virus infection and can result in the development of resistant strains with prolonged therapy. Consequently, a vaccine against HCMV is probably the most effective method of preventing or lowering the incidence of disease. Additionally, a vaccine would save considerably in the resources currently employed for the long term treatment/ care of congenitally infected newborns with severe hearing loss and mental retardation.