Development of a Novel Vaccine Against Herpes Simplex Type 2

描述（由申请人提供）：单纯疱疹病毒2型（HSV-2）是世界范围内重要的医学病原体，在美国的患病率超过20%。复发性疱疹性生殖器病变引起的身体疼痛和社会心理压力为开发有效的疫苗提供了强大的动力。然而，迄今为止在临床试验中测试的2型单纯疱疹病毒疫苗仅显示出有限的益处。确定有效疫苗的免疫相关性尤其具有挑战性，因为对2型单纯疱疹病毒的自然免疫不足以防止复发感染和病毒脱落。因此，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）的天然免疫的研究表明，CD8 T细胞对MCMV免疫优势抗原的特异性对限制病毒复制无效。这表明，疱疹病毒扭曲宿主T细胞的反应，以使优势的特异性，有利于病毒的持久性，而不是清除。我们假设，在疱疹病毒中高度保守的基本非结构蛋白可能代表了一类新的T细胞靶标，因为它们的表达和序列稳定性需要。特别重要的是，我们最近的结果表明，使用MCMV的两个保守的必需基因中的任何一个进行DNA免疫可以保护小鼠免受MCMV复制。在此资助申请中，我们计划实现以下目标：在Specific Aim 1中，我们将快速确定小鼠模型中哪些保守的HSV-2必需基因通过DNA接种具有保护作用，并确定保护基因和糖蛋白D2 (gD2) DNA的最佳组合。在特异性目标2中，我们将把我们的发现扩展到豚鼠模型中，以便可以测量对原发性和复发性HSV-2感染的保护作用。将保守的、必需的HSV-2基因和gD2 DNA的最佳组合所产生的免疫和保护作用与临床试验中部分保护的gD2/MPL/明矾蛋白亚单位疫苗进行比较。在特异性靶3中，我们将在豚鼠中测试DNA介导的保护是否可以通过随后用全灭活病毒和MPL/明矾佐剂的新型组合增强，这种增强可能会引发病毒特异性Th1和中和抗体反应。该提案的总体目标是证明“原理证明”，即2型单纯疱疹病毒的保守的基本基因在动物模型中也对2型单纯疱疹病毒具有保护作用，并为使用这类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。

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.