Development of a Novel Vaccine Against Herpes Simplex Type 2

描述(申请人提供)：单纯疱疹病毒2型(HSV-2)是世界范围内一种重要的医学病原体，在美国的流行率超过20%。反复发生的疱疹生殖器病变造成的身体疼痛和心理社会压力为开发有效的疫苗提供了强大的推动力。然而，到目前为止，在临床试验中测试的HSV-2疫苗只显示出有限的好处。确定有效疫苗的免疫相关性尤其具有挑战性，因为对HSV-2的自然免疫力不足以预防复发感染和病毒脱落。因此，一种成功的疫苗产生的免疫反应必须比自然免疫更有效。最近对另一种疱疹病毒--小鼠巨细胞病毒(MCMV)的天然免疫研究表明，针对免疫优势的MCMV抗原的CD8T细胞在限制病毒复制方面无效。这表明疱疹病毒扭曲了宿主T细胞的反应，以便使有利于病毒持续而不是清除的特异性占优势。我们推测，由于对其表达和序列稳定性的要求，在疱疹病毒中高度保守的必需非结构蛋白可能代表了一类新的T细胞靶标。尤其重要的是，我们最近的结果表明，使用MCMV的两个保守的基本基因之一的DNA免疫可以保护小鼠免受MCMV的复制。在这项拨款申请中，我们建议实现以下目标：在特定目标1中，我们将在小鼠模型中快速鉴定哪些保守的HSV-2必需基因是DNA疫苗的保护性基因，并确定保护性基因和糖蛋白D2(GD2)DNA的最佳组合。在具体目标2中，我们将把我们的发现推广到豚鼠模型中，以便可以测量对初次和复发HSV-2感染的保护措施。由保守的、基本的HSV-2基因和GD2 DNA的最佳组合产生的免疫和保护将与在临床测试中具有部分保护作用的GD2/MPL/明矾蛋白亚单位疫苗进行比较。在具体目标3中，我们将在豚鼠身上测试DNA介导的保护是否可以通过随后使用完整、灭活病毒和MPL/明矾佐剂的新组合来增强，这种增强可能会引发病毒特异性Th1和中和抗体反应。这项建议的总体目标是在动物模型中证明HSV-2保守的基本基因也对HSV-2具有保护作用，并为使用这种新型抗原进行更全面的免疫和保护的临床前研究提供理由。 单纯疱疹病毒2型(HSV-2)会导致终生、持续的感染，导致反复发生的生殖器损伤，这可能会导致身体疼痛和精神压力。此外，病毒在出生期间的传播可能会在新生儿中造成毁灭性的疾病，而生殖器HSV-2感染已被发现是感染艾滋病毒的一个重要风险因素。美国人口的高感染率以及这种疾病的医疗和心理影响使HSV-2成为开发能够预防感染或疾病的有效疫苗的重要候选者。

DESCRIPTION (provided by applicant): Herpes simplex virus type 2 (HSV-2) is a medically important pathogen worldwide, with a prevalence rate of over 20% in the US. The physical pain and psychosocial stress due to recurrent herpetic genital lesions have provided a strong impetus for the development of an efficacious vaccine. However, the HSV-2 vaccines tested in clinical trials to date have shown only limited benefits. Defining the immune correlates of an effective vaccine is particularly challenging since the natural immunity to HSV-2 is not sufficient to protect against recurrent infection and viral shedding. Thus, immune responses generated by a successful vaccine must be more effective than natural immunity. Recent studies of the natural immunity to another herpesvirus, murine cytomegalovirus (MCMV), have demonstrated that CD8 T cells specific for an immunodominant MCMV antigen are ineffective at limiting viral replication. This suggests that the herpesviruses skew the host T cell response in order to make dominant the specificities that favor viral persistence rather than clearance. We hypothesize that the essential, nonstructural proteins that are highly conserved among the herpesviruses may represent a novel class of T cell targets due to the requirements for their expression and sequence stability. Of particular importance, our recent results show that DNA immunization using either of two conserved, essential genes of MCMV protects mice against MCMV replication. In this grant application, we propose to accomplish the following aims: In Specific Aim 1, we will quickly identify which of the conserved, essential genes of HSV-2 are protective by DNA vaccination in a mouse model, and the optimal combination of protective genes and glycoprotein D2 (gD2) DNA will be determined. In Specific Aim 2, we will extend our findings into the guinea pig model so that protection can be measured against both primary and recurrent HSV-2 infection. The immunity and protection generated by the optimal combination of conserved, essential HSV-2 genes and gD2 DNA will be compared to the gD2/MPL/alum protein subunit vaccine that was partially protective in clinical testing. In Specific Aim 3, we will test in guinea pigs whether the DNA mediated protection can be augmented by subsequent boosting with a novel combination of whole, killed virus plus the MPL/alum adjuvants, a boost that will likely elicit virus specific Th1 and neutralizing antibody responses. The overall goal of this proposal is to demonstrate "proof-of-principle" that the conserved, essential genes of HSV-2 are also protective against HSV-2 in animal models and to provide the justification for pursuing more comprehensive preclinical studies of immunity and protection using this novel class of antigens. Herpes simplex virus type 2 (HSV-2) causes a lifelong, persistent infection that results in the development of recurrent genital lesions that can cause both physical pain and emotional stress. In addition, transmission of the virus during birth can cause a devastating disease in the newborn, and genital HSV-2 infection has been found to be a significant risk factor for infection with HIV. The high prevalence of infection in the U.S. population together with the medical and psychological impacts of the disease make HSV-2 an important candidate for the development of an effective vaccine that can prevent infection or disease.