SMALLPOX VACCINATION ON ENDOTHELIAL FUNCTION AND HUMAN GENE EXPRESSION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。该方案旨在研究天花疫苗接种对参与Aventis Pasteur天花疫苗（APSV）研究的受试者的内皮抵抗力和基因表达的影响。 使用牛痘病毒感染的天花免疫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免疫大部分人群以对抗天花的生物恐怖主义威胁，将导致大量处于冠状动脉疾病风险中的人感染和相当大的全身性炎症。先前的研究发现，接种灭活疫苗导致动脉内皮对物理和药理学扩张刺激的阻力和导管血管暂时但严重的功能障碍。这些发现说明，即使是轻微的全身炎症反应也与内皮功能的显著改变相关，内皮功能的显著改变与心血管事件风险的增加相关。由于牛痘感染与强烈和更持久的炎症反应有关，这些研究人员假设，目前的天花免疫策略对内皮抵抗力、C反应蛋白和细胞因子表达的影响比之前对疫苗接种影响的研究更显著和持久。因此，接种疫苗诱发心血管疾病的风险将是显著的。该方案的第二个方面是在天花疫苗接受者中进行微阵列分析。近年来，微阵列已被用于检测感染或暴露于HIV-1、CMV、柯萨奇病毒、B型肝炎和C型肝炎病毒的细胞中基因表达的宿主变化。虽然已经进行了几项体内动物研究来评估感染病原体的宿主动物中基因表达的变化，但很少有关于感染痘病毒的人类的数据报道。在这项研究中，我们将检查正痘病毒感染（牛痘）作为人类正痘病毒感染（天花）的替代标志物的影响。因此，这些研究人员提出了一项初步研究，以测量参与APSV研究的24名志愿者在接种牛痘前、第4次和第5次访视（炎症最严重的日子：第6-8天和第9-11天）以及第8次访视（第51-61天）牛痘病变愈合后的内皮阻力、C反应蛋白。在随后的两次访视（炎症高峰前）和两个月接种疫苗前，将评估细胞因子和其他基因表达。

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.