Immunization to Reduce Genital and Neonatal Herpes

描述（由申请人提供）：控制生殖器疱疹需要广泛使用有效的疫苗。然而，如果单纯疱疹病毒（HSV）疫苗不能达到绝育免疫（防止病毒在进入部位复制），病毒将建立潜伏期，使宿主在重新激活时具有潜在传染性，并允许继续传播。尽管使用多种疫苗进行的动物研究表明，免疫接种不能阻止高滴度攻击后生殖器粘膜中的病毒复制，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间，我们认为免疫接种增加了感染生殖器粘膜所需的病毒接种量，从而产生了保护作用。在目的1中，我们将通过确定临床研究疫苗免疫对小鼠模型中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测量有效性，并确定与DNA或糖蛋白单独免疫相比，DNA启动糖蛋白增强是否能提高保护作用。这些研究是相关的，因为除了抗体和DNA疫苗外，有效的疫苗还需要诱导辅助性T型1 （Th1）反应，与仅免疫蛋白质相比，蛋白质增强的DNA疫苗启动已被证明可以增加Th1反应。虽然提高感染阈值的疫苗将降低传播发生率，但它不会提供普遍保护。在目标3中，我们将使用克服感染保护的条件来检查免疫对潜伏感染和复发性疾病（临床复发和病毒进入生殖器轨迹）的程度的影响。这些研究将提供关于被感染的免疫宿主传播风险的新信息。在目标4中，我们将评估母体免疫提高新生儿疱疹感染阈值的能力，从而减少生殖器疱疹感染最具破坏性后果的发生率。这些研究将提供关于单纯疱疹病毒疫苗减少生殖器疱疹传播和新生儿疾病发生率的能力的新信息。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 clincal 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 trac). These studies will provide new information about the risks of transmission from immunized hosts who become infected. In Aim 4 we will evaluate the ability of maternal immunization to raise the threshold of infection for neonatal herpes and so reduce the incidence of the most devastating consequence of genital herpes infection. These studies will yield new information about the capacity of HSV vaccines to reduce the spread of genital herpes and incidence of neonatal disease. These study designs may become standard for preclinical evaluation of HSV vaccines.