Immunization to Reduce Genital and Neonatal Herpes

描述(申请人提供)：生殖器疱疹的控制将需要广泛使用有效的疫苗。然而，如果单纯疱疹病毒(HSV)疫苗不能实现灭菌免疫(防止病毒在入口点复制)，病毒将建立潜伏期，使宿主在重新激活期间具有潜在的传染性，并允许继续传播。虽然各种疫苗的动物研究表明，免疫并不能阻止病毒在高滴度攻击后在生殖器粘膜中复制，但在最近的一项临床试验中，HSV 2型糖蛋白D疫苗保护了39%-46%的血清阴性妇女免受感染。由于生殖器疱疹的大部分传播发生在病毒相对较少的无症状脱落期，我们认为这种保护作用是因为免疫增加了感染生殖器粘膜所需的病毒接种量。在目标1中，我们将通过在小鼠模型中确定临床研究疫苗对感染生殖器粘膜所需的病毒接种量的影响来探索这一假设。在目标2中，我们将再次使用感染阈值来衡量疗效，并确定与DNA或仅使用糖蛋白的免疫相比，DNA主要糖蛋白Boost是否提高了保护作用。这些研究是相关的，因为有效的疫苗除了抗体外还需要诱导T辅助类型1(Th1)反应，而与仅使用蛋白质免疫相比，蛋白质增强的DNA疫苗免疫被证明可以增加Th1反应。虽然提高感染门槛的疫苗将减少传播的发生率，但它不会提供普遍的保护。在目标3中，我们将使用克服感染保护的条件来检查免疫接种对潜伏感染和复发疾病(临床复发和病毒进入生殖道)的影响。这些研究将提供有关受感染的免疫宿主传播风险的新信息。综上所述，这项提案中的研究将提供有关HSV疫苗减少生殖器疱疹传播的能力的新信息。这些研究设计可能成为HSV疫苗临床前评估的标准。

DESCRIPTION (provided by applicant): The control of genital herpes will require widespread use of effective vaccines. However, if herpes simplex virus (HSV) vaccines do not achieve sterilizing immunity (prevent virus replication at the entry site) the virus will establish latency, rendering the host potentially contagious during reactivation, and allowing continued transmission. While animal studies with a variety of vaccines show that immunization does not prevent virus replication in the genital mucosa following high titer challenge, a HSV type 2 glycoprotein D vaccine protected 39-46% of seronegative women against infection in a recent clinical Trial. Since much of the spread of genital herpes occurs during periods of asymptomatic shedding when relatively little virus is present, we believe that the protection resulted because immunization increased the virus inoculum required to infect the genital mucosa. In Aim 1 we will explore this hypothesis by determining the effect of immunization with the clinical study vaccine on the virus inoculum required to infect the genital mucosa in a mouse model. In Aim 2 we will again use the threshold of infection to measure efficacy and determine whether DNA prime glycoprotein boost improves protection compared to DNA or glycoprotein only immunization. These studies are relevant because an effective vaccine will need to induce T helper type 1 (Th1) responses in addition to antibody and DNA vaccine priming with protein boosting has been shown to increase Th1 responses compared to protein only immunization. While a vaccine that increases the threshold of infection will reduce the incidence of transmission, it will not provide universal protection. In Aim 3 we will use conditions that overcome protection from infection to examine the impact of immunization on the magnitude of latent infection and recurrent disease (both clinical recurrences and virus shedding into the genital tract). These studies will provide new information about the risks of transmission from immunized hosts who become infected. Taken together, the studies in this proposal will yield new information about the capacity of HSV vaccines to reduce the spread of genital herpes. These study designs may become standard for preclinical evaluation of HSV vaccines.