Immunogenetics of Smallpox Vaccination

这个项目的目标是识别与抗病和易感有关的基因。 人类牛痘感染，以及因此，在接种天花疫苗时出现的一些不良反应。 我们(R.B.B.)最近领导了一项关于牛痘免疫临床反应的多中心前瞻性研究 680个纳尔瓦人。在665名对疫苗有反应的人中，84人(13%)出现发烧， 肌肉酸痛和淋巴结病引起我们所说的急性痘苗综合征(AVS) 大约30%的疫苗。这些症状出现的时间与 病毒脱落率最高，表明发烧和AVS的其他成分似乎是 仅次于病毒。我们假设患有动静脉曲张(尤其是发烧)的人有 与异常的先天免疫或延迟的适应性免疫相关的致病等位基因 对牛痘的反应。一般来说，这些人可能更容易感染痘病毒，而且可能 如果暴露在天花中，构成死亡风险增加的群体。我们建议找出那些 是对接种部位的牛痘病毒感染的反应，并系统地使用 转录分析。我们将比较患有AVS的人和那些 对免疫接种无不良反应的个人。这些研究将为我们提供一个 宿主对牛痘感染反应的转录图谱，识别宿主反应中的关键分子， 并且，建立保护性免疫反应的参数，可以用来测试新的 疫苗。我们还将确定与牛痘免疫不良反应相关的等位基因和 基于单倍型分析的病毒异常先天免疫应答 候选基因的核苷酸多态。这些等位基因的识别可能会为关键的 宿主对痘病毒的反应元件，并可提供一种方法来识别增加的个体 疫苗有不良反应的风险，或有痘病毒感染的更严重的疾病。这款车的设计 研究，包括接受牛痘疫苗免疫的个体的转录概况 具有详细的病毒学和免疫学特征，确保我们将获得关于宿主的宝贵信息 对牛痘免疫的反应。

The goal of this project is to identify genes that are involved in susceptibility and resistance to human vaccinia infection, and, consequently, in some of the adverse effects seen with smallpox vaccination. We (R.B.B.) recently led a multi-center prospective study on the clinical response to vaccinia immunization in 680 na'l've individuals. Among the 665 individuals responding to the vaccine, 84 (13%) developed fever, muscle aches and lymphadenopathy giving rise to what we have called Acute Vaccinia Syndrome (AVS) in approximately 30% of vaccines. The timing of the onset of these symptoms matched the timing of the highest levels of viral shedding, indicating that fever, and the other components of AVS appear to be secondary to the virus. We hypothesize that individuals developing AVS (and especially fever) have disease-predisposing alleles that are associated with abnormal innate immune or delayed adaptive immune responses to vaccinia. These individuals may be more susceptible to poxviruses in general, and could constitute a group at increased risk for mortality if exposed to smallpox. We propose to identify genes that are expressed in response to vaccinia infection at the site of inoculation and systemically using a transcriptional analysis. We will compare responses between individuals that develop AVS, and those individuals who develop no adverse reactions to immunization. These studies will provide us with a transcriptional profile of the host response to vaccinia infection, identify key molecules in the host response, and, establish parameters for protective immune responses that could be used to test the efficacy of new vaccines. We will also identify alleles associated with adverse effects to vaccinia immunization and abnormal innate immune responses to the virus through the analysis of haplotypes based on single nucleotide polymorphisms in candidate genes. The identify of these alleles may provide clues to the critical elements of the host response to poxvirus, and could provide a method to identify individuals at increased risk for adverse effects to the vaccine, or more severe disease with poxvirus infection. The design of the study, with the inclusion of transcriptional profiling of individuals receiving vaccinia immunization coupled with a detailed virologic and immunologic profile, ensures that we will obtain valuable information on the host response to vaccinia immunization.