EFFICACY OF FLAGELLIN/F1/V MUCOSAL PLAGUE VACCINE IN C MACAQUES AND C AETHIOPS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 接触鼠疫耶尔森氏菌会导致严重的疾病，其中肺炎形式的疾病是最严重的。有许多候选疫苗正在开发中，以预防这种疾病。研究表明，一种含有F1和V的候选疫苗(肌肉注射)对食蟹猴(Macaca Fascularis)具有保护作用，但对非洲绿猴(ChlorOcean Bus Atheiops)的保护作用较差。这种差异的基础尚不清楚。这些发现提出了评估增强非洲绿猴反应的方法的必要性，特别是如果非洲绿猴可能更好地预测人类的反应。我们先前的研究已经证实，鞭毛蛋白在小鼠和食蟹猴身上是一种高效的粘膜佐剂。用鞭毛蛋白和鼠疫菌F1和/或V抗原经鼻腔免疫的动物会产生非常高水平的抗原特异性IgA和IgG。鞭毛蛋白和鼠疫耶尔森氏菌蛋白可以是分离的，也可以是单个融合蛋白的形式，其中F1和V序列已插入鞭毛蛋白的高变区。免疫的小鼠对致命的呼吸道攻击具有完全的保护作用，具有150LD50的鼠疫杆菌CO92。用鞭毛蛋白、F1和V免疫食蟹猴的血浆可以完全和完全地保护幼小鼠免受鼠疫杆菌的致命呼吸道攻击。鉴于1)鞭毛蛋白作为粘膜佐剂的非凡效力，2)含有鞭毛蛋白和F1和V抗原的疫苗产生的抗F1和V抗体效价比候选疫苗高得多，以及3)基于粘膜鞭毛蛋白的疫苗诱导保护性IgA的能力，而不是免疫接种的疫苗，我们建议评估粘膜鞭毛蛋白/F1/V疫苗在线虫和非洲绿猴体内诱导抗F1和V特异性IgA和IgG的相对有效性，并提供对鼠疫菌CO92的气雾剂攻击的保护作用。到目前为止，这项包括非洲绿猴的研究阶段正在进行中；这些动物已经接种了疫苗，并等待着鼠疫杆菌对气溶胶的挑战。

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. Exposure to Yersinia pestis causes severe disease, with the pneumonic form of the disease being the most severe. There are a number of vaccine candidates under development to protect against this disease. It has been shown that a candidate vaccine containing F1 and V (given intramuscularly) was protective in Cynomolgus monkeys (Macaca fascicularis), but was poorly protective in African green monkeys (Chlorocebus aethiops). The basis for this disparity is not known. These findings raise the need to evaluate ways to enhance the response in African green monkeysespecially if the African green monkey is a potentially better predictor of the response in humans. Our prior studies have established that flagellin is a highly efficacious mucosal adjuvant in mice and Cynomolgus monkeys. Animals immunized intra-nasally with flagellin and the F1 and/or V antigens of Yersinia pestis produce very high levels of antigen-specific IgA and IgG. The flagellin and Y. pestis proteins may be separate or in the form of a single fusion protein in which the F1 and V sequences have been inserted into the hypervariable region of flagellin. Immunized mice are fully protective against lethal respiratory challenge with 150 LD50 of Y. pestis CO92. Plasma from Cynomolgus monkeys immunized with flagellin and F1 and V provides full and complete protection against lethal respiratory challenge with Y. pestis in na¿ve mice. In view of 1) the extraordinary potency of flagellin as a mucosal adjuvant, 2) the finding that a vaccine containing flagellin and the F1 and V antigens generates much higher titers of anti-F1 and V antibodies than the candidate vaccine, and 3) the ability of a mucosal flagellin-based vaccine, as opposed to a vaccine given i.m., to induce protective IgA, we propose to evaluate the relative efficacy of a mucosal flagellin/F1/V vaccine in Cynomolgus and African green monkeys to induce anti-F1 and V specific IgA and IgG and to provide protection against an aerosol challenge with Y. pestis CO92. To date, the phase of this study that includes the African green monkeys is underway; the animals have been immunized and await aerosol challenge with Y. pestis.