Development of a Novel Vaccine Against Herpes Simplex Type 2

描述（由申请方提供）：2型单纯疱疹病毒（HSV-2）是一种全球重要的医学病原体，在美国的患病率超过20%。由于生殖器疱疹性病变的复发而引起的生理疼痛和心理压力为有效疫苗的开发提供了强大的动力。然而，迄今为止在临床试验中测试的HSV-2疫苗仅显示出有限的益处。定义有效疫苗的免疫相关性是特别具有挑战性的，因为对HSV-2的天然免疫不足以防止复发性感染和病毒脱落。因此，成功的疫苗产生的免疫反应必须比天然免疫更有效。最近对另一种疱疹病毒，鼠巨细胞病毒（MCMV）的天然免疫的研究表明，对免疫显性MCMV抗原特异性的CD 8 T细胞在限制病毒复制方面无效。这表明疱疹病毒扭曲宿主T细胞反应，以使有利于病毒持续而不是清除的特异性占主导地位。我们假设，疱疹病毒之间高度保守的基本的非结构蛋白可能代表一类新的T细胞靶点，由于其表达和序列稳定性的要求。特别重要的是，我们最近的研究结果表明，使用MCMV的两个保守的，必需的基因之一的DNA免疫保护小鼠免受MCMV复制。在这项授权申请中，我们建议实现以下目标：在具体目标1中，我们将快速确定HSV-2的哪些保守的必需基因在小鼠模型中通过DNA疫苗接种具有保护性，并确定保护性基因和糖蛋白D2（gD 2）DNA的最佳组合。在具体目标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。将比较由保守的、必需的HSV-2基因和gD 2 DNA的最佳组合产生的免疫力和保护力与在临床试验中具有部分保护力的gD 2/MPL/明矾蛋白亚单位疫苗。在特定目标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加MPL/明矾佐剂的新组合进行加强来增强，这种加强可能会引发病毒特异性Th 1和中和抗体应答。本提案的总体目标是证明HSV-2的保守的必需基因在动物模型中也对HSV-2具有保护性的“原理证明”，并为使用这类新型抗原进行更全面的免疫和保护临床前研究提供理由。 单纯疱疹病毒2型（HSV-2）引起终身持续感染，导致生殖器复发性病变，可引起身体疼痛和情绪压力。此外，出生时的病毒传播可导致新生儿的毁灭性疾病，生殖器HSV-2感染已被发现是感染艾滋病毒的重要风险因素。美国人口中的高感染率以及该疾病的医学和心理影响使HSV-2成为开发可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.