Novel vaccine to CMV based on a disc virus

描述（由申请方提供）：巨细胞病毒（CMV）是一种普遍存在的病原体，可导致免疫功能低下人群的显著发病率和死亡率。目前，还没有针对CMV的有效疫苗。由于存在胎儿先天性感染的风险，开发疫苗，特别是针对育龄妇女的疫苗，被认为是一项重大的公共卫生优先事项。本申请提出了缺乏必需基因的复制受损活CMV疫苗的用途。突变病毒将能够在病毒复制的失败的单循环中感染非互补细胞，但不能产生感染性病毒。我们假设，无论使用的病毒剂量如何，针对CMV的失能感染性单循环（DISC）疫苗都是非致病性的，但对一系列病毒抗原具有高度免疫原性诱导抗体和T细胞应答。此外，我们建议，这种DISC疫苗对CMV的有效性将进一步增强引入第二个拷贝的主要中和抗原，糖蛋白gB，到病毒基因组。我们还假设，疫苗株与促炎细胞因子（IL-12）佐剂的共同给药将抑制针对病毒的1型辅助T细胞（Th 1）免疫应答，从而产生细胞介导的免疫应答偏倚。人CMV与所有CMV一样，是种属特异性病毒，因此必须研究动物CMV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。拟议的研究将确定对一系列疫苗候选CMV DISC株的抗体和细胞免疫应答。此外，该研究将确定候选DISC疫苗与先前在该模型中测试的重组gB亚单位疫苗策略相比保护免受先天性CMV感染的能力。 公共卫生相关性：HCMV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。免疫活性个体的原发性HCMV感染通常是良性的，但会导致终身潜伏感染。实体器官移植受者或艾滋病患者特别容易受到病毒重新激活的影响，这可能导致危及生命的终末器官疾病。新生儿先天性感染HCMV（约占美国活产婴儿的1%）可导致严重的症状性疾病，包括智力迟钝和听力损失。事实上，据估计，先天性HCMV相关的感音神经性听力损失（SNHL）的发生频率高于前HIB疫苗时代流感嗜血杆菌感染相关的SNHL。此外，先天性HCMV感染是新生儿中仅次于唐氏综合征的第二大最常见的智力迟钝原因。虽然抗病毒药物可用于治疗艾滋病和移植患者，但由于对胎儿有毒副作用的风险，这些药物不能用于预防先天性感染。此外，抗病毒药物在病毒感染的晚期发挥作用，并可能导致长期治疗产生耐药菌株。因此，针对HCMV的疫苗可能是预防或降低疾病发生率的最有效方法。此外，疫苗将大大节省目前用于患有严重听力损失和智力迟钝的先天性感染新生儿的长期治疗/护理的资源。

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.