Immune correlates of protection during gamma-herpesvirus vaccination

描述（由申请人提供）：持续性病毒感染是世界范围内的主要健康问题。免疫系统不能清除感染的特征是人免疫缺陷病毒（HIV-1）、爱泼斯坦-巴尔病毒（EBV）、卡波西肉瘤病毒（KSHV）、巨细胞病毒（CMV）和丙型肝炎病毒（HCV）的终身持续性。其中，3-疱疹病毒是非常成功的病原体。EBV感染了95%的人类。KSHV血清阳性率在非洲流行地区超过60%。由于3-疱疹病毒与许多疾病有关，因此其疫苗是卫生方面的优先事项。然而，针对一般持久性病毒，特别是3-疱疹病毒的疫苗接种已被证明是一个挑战。用鼠γ-疱疹病毒68（MHV-68）感染小鼠提供了一种宝贵的动物模型来表征天然宿主中的免疫应答，其可用于开发针对β-疱疹病毒的疫苗。在目前的提案中，我们将确定一种新的疫苗接种策略诱导的保护的免疫相关性，该策略可改善急性感染并预防MHV-68攻击后小鼠的潜伏期。我们的初步数据显示，在接种DCS 11疫苗后，急性感染期间病毒载量减少了50，000倍，并且无法检测到病毒潜伏期。在目标1中，我们将确定对DCS 11疫苗接种的免疫应答的功能特征。在目标2中，我们将通过分析DCS 11疫苗接种小鼠对病毒攻击的回忆反应来确定疫苗保护的机制。这些研究所产生的信息对于我们理解针对3-疱疹病毒的疫苗如何引起保护至关重要，并且可能有助于开发针对持续性病毒感染的免疫疗法。 公共卫生相关性：持续性病毒感染是世界范围内的主要健康问题。本申请的目的是确定由我们的新型疫苗接种策略诱导的保护的免疫相关性，所述疫苗接种策略在鼠3-疱疹病毒攻击后改善小鼠中的急性感染并防止潜伏期。这些研究所产生的信息对于我们理解针对3-疱疹病毒的疫苗如何引起保护至关重要，并且可能有助于开发针对持续性病毒感染的免疫疗法。

DESCRIPTION (provided by applicant): Persistent viral infections are a major health problem worldwide. The inability of the immune system to clear infection characterizes life-long persistence by human immunodeficiency virus (HIV-1), Epstein- Barr virus (EBV), Kaposi's sarcoma virus (KSHV), cytomegalovirus (CMV) and hepatitis C virus (HCV). Among them, the 3-herpesviruses are very successful pathogens. EBV infects 95% of the human population. KSHV seroprevalence exceeds 60% in endemic African regions. Due to their association with a large number of diseases a vaccine for 3-herpesviruses is a health priority. Nevertheless, vaccination against persistent viruses in general, and 3-herpesviruses in particular, has proven a challenge. Infection of mice with murine gamma-herpesvirus 68 (MHV-68) provides an invaluable animal model to characterize immune responses in a natural host that may be used to develop vaccines against 3-herpesvirues. In the current proposal, we will identify the immune correlates of protection induced by a novel vaccination strategy that ameliorate acute infection and prevent latency in mice after MHV-68 challenge. Our preliminary data show that after DCS11 vaccination there is a reduction in virus load by a 50,000-fold during acute infection and that viral latency cannot be detected. In Aim 1, we will determine the functional characteristics of the immune response to DCS11 vaccination. In Aim 2, we will identify the mechanism(s) of vaccine protection by analyzing the recall response to a virus challenge in DCS11-vaccinated mice. The information generated by these studies will be critical for our understanding of how vaccines against 3-herpesviruses can elicit protection, and it will likely aid in the development of immune therapies against persistent viral infections. PUBLIC HEALTH RELEVANCE: Persistent viral infections are a major health problem worldwide. The goal of the present application is to determine the immune correlates of protection induced by our novel vaccination strategy that ameliorate acute infection and prevent latency in mice after murine 3-herpesvirus challenge. The information generated by these studies will be critical for our understanding of how vaccines against 3-herpesviruses can elicit protection, and it will likely aid in the development of immune therapies against persistent viral infections.