VACCINATION AGAINST HERPES SIMPLEX VIRUS

这项建议的目的是评估针对单纯疱疹病毒(HSV)的疫苗接种的新方法。我们假设，用DNA疫苗对呼吸道进行免疫，或用复制能力不强的重组HSV载体进行肠道免疫，都可以在阴道产生不同形式的免疫。如果诱导出足够的适当类型的抗单纯疱疹病毒抗体，这可能会防止病毒入侵，从而提供屏障免疫。然而，清除侵入的阴道粘膜中的病毒可能需要最佳的CD4+T细胞功能，也许还需要CD8+T细胞的反应。疫苗将包括编码主要糖蛋白gB的质粒DNA和编码一个或多个免疫调节分子的DNA的组合，或者由肠道给予表达免疫调节蛋白的重组HSV载体。将评估疫苗在诱导T细胞和体液免疫各参数方面的效果。动物将通过阴道途径接受HSV的挑战，以测量保护措施，并建立免疫与一个或多个免疫成分的活性的关系。此外，还将测试疫苗在表达CD4+Th2介导的反应和缺乏CD8+T细胞反应性的动物中转换免疫应答模式的能力。为了实现模式转变，将使用编码病毒蛋白的DNA疫苗以及含有未甲基化CpG二核苷酸的寡核苷酸。我们的结果应该适用于未来针对HSV的疫苗设计，并可能适用于其他需要免疫调节的情况。

This proposal's aim is to evaluate novel approaches for vaccination against herpes simplex virus (HSV). We hypothesize that immunization for the respiratory tract with DNA based vaccines or immunization enterically with replication incompetent recombinant HSV vectors can be tailored to produce different forms of immunity in the vaginal tract. If sufficient anti-HSV antibody of the appropriate type is induced, this may protect against viral invasion and so provide barrier immunity. However, clearance of virus from the invaded vaginal mucosa likely requires optimal CD4+ T cell function and perhaps CD8+ T cell responses. Vaccines will consist of combinations of plasmid DNA encoding the major glycoprotein gB along with DNA encoding one or more immunomodulatory molecules administered intranasally, or recombinant HSV vectors expressing immunomodulating proteins given enterically. The efficacy of vaccines at inducing various parameters of T cell and humoral immunity will be assessed. Animals will be challenged via the vaginal route HSV to measure protection and to establish the relationship of immunity to the activity of one or more immune components. In addition, vaccines will be tested for their ability to switch the pattern of immune responsiveness in animals primed to express CD4+ Th2 mediated responses and lacking CD8+ T cell reactivity. To achieve pattern shifting, DNA vaccines encoding viral protein along with oligonucleotides containing unmethylated CpG dinucleotides will be used. Our results should be applicable to the future design of vaccines against HSV and may have application to other situations that require immunomodulation.