SMALLPOX VACCINATION ON ENDOTHELIAL FUNCTION AND HUMAN GENE EXPRESSION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。该方案旨在研究天花疫苗接种对参与安万特巴斯德天花疫苗(APSV)研究的受试者内皮细胞抵抗力和基因表达的影响。天花免疫使用牛痘病毒感染，与相当程度的活动性全身炎症有关。流行病学和观察性研究表明，炎症和感染与发生心血管疾病的风险之间存在关联。广泛使用牛痘病毒感染来为大部分人口接种疫苗，以抵御天花的生物恐怖威胁，将导致大量面临冠状动脉疾病风险的人感染和相当程度的全身炎症。以前的研究发现，接种灭活疫苗会导致动脉内皮细胞对物理和药物扩张器刺激的抵抗力和管道血管的暂时性但严重的功能障碍。这些发现表明，即使是轻微的全身性炎症反应也与内皮功能的显著改变有关，与心血管事件的风险增加相关。由于痘苗感染与更强烈和更持久的炎症反应有关，这些研究人员假设，与之前关于疫苗接种效果的研究相比，目前的天花免疫策略将对内皮抵抗、C反应蛋白和细胞因子表达产生更显著和持久的影响。因此，接种疫苗引发心血管疾病的风险将是巨大的。该方案的第二个方面是对天花疫苗的接受者进行微阵列分析。近年来，基因芯片被用来检测感染或暴露于HIV-1、CMV、柯萨奇病毒、乙肝和丙型肝炎病毒的细胞中宿主基因表达的变化。虽然已经进行了几项活体动物研究，以评估感染病原体的宿主动物基因表达的变化，但在感染痘病毒的人类中，报告的数据很少。在这项研究中，我们将检验正肢感染(牛痘)作为人类正足感染(天花)的替代标记物的效果。因此，这些研究人员提议进行一项先导性研究，在接种牛痘之前、第4天和第5天(炎症最严重的日子：第6-8天和第9-11天)以及在第8次访问时(第51-61天)牛痘病变愈合后，对24名参与APSV研究的志愿者进行内皮阻力和C反应蛋白的测定。细胞因子和其他基因的表达将在接种疫苗之前、随后的两次就诊(在炎症高峰期之前)和两个月内进行评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This protocol is designed to study the effects of smallpox vaccination on endothelial resistance and gene expression in subjects participating in the Aventis Pasteur smallpox vaccine (APSV) study. Smallpox immunization, using infection with vaccinia virus, is associated with a considerable degree of active, systemic inflammation. Epidemiological and observational studies suggest an association between both inflammation and infection and the risk of develping cardiovascular disease. Widespread use of vaccinia virus infection to immunize large segments of the population against the bioterrorist threat of smallpox will result in infection and considerable systemic inflammation in large numbers of people at risk for coronary artery disease. Previous studies found that vaccination with a killed, inactivated vaccine resulted in temporary, but profound dysfunction of arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. These findings illustrate that even mild systemic inflammatory response is associated with significant alteration in endothelial function associated with an increased risk of cardiovascular events. Since vaccinia infection is associated with an intense and more long-lasting inflammatory response, these investigators hypothesize that current strategies of smallpox immunization will have more pronounced and durable effects on endothelial resistance, C-reactive protein, and cytokine expression than did the prior study on the effects of vaccination. Thus the risk of inducing cardiovascular disease with vaccination would be significant. The second aspect of this protocol is to perform microarray analysis in recipients of smallpox vaccine. In recent years, microarrays have been used to examine host changes in gene expression in cells infected or exposed to HIV-1, CMV, coxsackievirus, hepatitis B and hepatitis C viruses. While several in vivo animal studies have been conducted to evaluate changes in gene expression in a host animal infected with a pathogen, there are few data reported in humans infected with pox viruses. In this study, we will examine the effects of orthopox infection (vaccinia) as a surrogate marker of human orthopox infection (smallpox). Therefore, these investigators propose a pilot study to measure endothelial resistance, C-reactive protein in 24 volunteers participating in the APSV study prior to vaccinia innoculation, at visit 4 and 5 (the days of most intense inflammation: days 6-8 and 9-11), and following the healing of the vaccinia lesion on visit 8 (days 51-61). Cytokine and other gene expression will be assessed prior to vaccination at the two subsequent visits (prior to peak inflammation), and two months.