VACCINATION AGAINST HERPES SIMPLEX VIRUS

本提案的目的是评估新的疫苗接种方法对抗单纯疱疹病毒（HSV）。我们假设，用DNA疫苗对呼吸道进行免疫或用复制能力不足的重组HSV载体进行肠内免疫，可以在阴道中产生不同形式的免疫。如果诱导足够的适当类型的抗hsv抗体，这可以防止病毒入侵，从而提供屏障免疫。然而，从入侵的阴道粘膜清除病毒可能需要最佳的CD4+ T细胞功能和CD8+ T细胞反应。疫苗将由编码主要糖蛋白gB的质粒DNA与编码一种或多种免疫调节分子的DNA的组合组成，或通过鼻内给药，或通过肠内给药表达免疫调节蛋白的重组HSV载体。疫苗在诱导T细胞和体液免疫的各种参数方面的功效将被评估。动物将通过阴道途径感染单纯疱疹病毒，以衡量保护作用，并建立免疫与一种或多种免疫成分活性的关系。此外，还将测试疫苗是否有能力改变动物的免疫反应模式，以表达CD4+ Th2介导的反应，缺乏CD8+ T细胞反应性。为了实现模式转换，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疫苗的设计，并可能应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.