Immune correlates of protection during gamma-herpesvirus vaccination

描述(申请人提供)：持续性病毒感染是世界范围内的一个主要健康问题。免疫系统无法清除感染是人类免疫缺陷病毒(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)终身持续的特征。其中，3-疱疹病毒是非常成功的病原体。EBV感染了95%的人类人口。在非洲流行地区，KSHV血清阳性率超过60%。由于它们与许多疾病有关，3-疱疹病毒疫苗是一项健康优先事项。然而，事实证明，针对持久性病毒，特别是3-疱疹病毒的疫苗接种是一项挑战。小鼠感染小鼠伽玛-疱疹病毒68(MHV-68)提供了一种宝贵的动物模型来表征自然宿主的免疫反应，该模型可用于开发针对3-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所诱导的保护的免疫相关性，该策略可改善MHV-68攻击后小鼠的急性感染并防止潜伏期。我们的初步数据显示，在接种DCS11疫苗后，在急性感染期间，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DCS11疫苗免疫应答的功能特征。在目标2中，我们将通过分析DCS11免疫小鼠对病毒攻击的召回反应来确定疫苗保护的机制(S)。这些研究产生的信息将对我们理解针对3-疱疹病毒的疫苗如何产生保护至关重要，并可能有助于开发针对持续病毒感染的免疫疗法。 公共卫生相关性：持续的病毒感染是世界范围内的一个主要健康问题。本应用的目的是确定我们的新疫苗策略所诱导的保护的免疫相关性，该策略可改善小鼠的急性感染并防止小鼠在小鼠3-疱疹病毒攻击后的潜伏期。这些研究产生的信息将对我们理解针对3-疱疹病毒的疫苗如何产生保护至关重要，并可能有助于开发针对持续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.