IN VIVO ANIMAL MODEL EVALUATION OF CANDIDATE VACCINES

在这个项目中所做的研究将仔细地将发现交错在一起 将项目1和项目2整合到适当的动物模型系统中以测试候选人 疫苗株。目标如下： 首先，来自项目1的基因工程突变将被测试 首先在小鼠身上，然后在豚鼠身上确定它们的 在中枢神经系统、外周组织中复制的能力，建立潜伏期， 在豚鼠身上造成复发的皮损，在移植后重新激活 为了保护这些动物物种免受挑战， 致命的病毒。这些研究将有助于样机的设计。 基于项目1和项目3的研究结果的疫苗株。 其次，一旦确定了候选疫苗毒株，就可以广泛使用 在小鼠和豚鼠身上的挑战研究将使用不同的 免疫和挑战的途径。成功的挑战将进一步 与全身和粘膜免疫反应相关。 第三，试图通过新的和 在可行性实验中谨慎使用Interleukins将是 已启动。这些实验将使用IL-4、IL-5和/或IL-6 免疫以确定其对免疫反应的影响。如果豁免权可以 在没有不良影响的情况下得到加强，将尝试 评价不同启动子作用下携带IL基因的重组病毒。 从这些研究中获得的知识将为更多的 详细的动物安全性和免疫原性研究 审判。

The studies done in this Project will carefully interdigitate the findings of Projects 1 and 2 into appropriate animal model systems to test candidate vaccine strains. The objectives are as follows: First, genetically engineered mutants from Project 1 will be tested initially in mice and subsequently in guinea pigs to determine their capacity to replicate in the CNS, peripheral tissue, to establish latency, to cause recurrent lesions in guinea pigs, to reactivate upon explantation from ganglia, and to protect these animal species from challenge with virulent viruses. These studies will aid in the design of prototype vaccines strains based on the results of studies in Projects 1 and 3. Second, once candidate vaccine strains become identified, extensive challenge studies in mice and guinea pigs will be done utilizing different routes of immunization and challenge. Successful challenge will be further correlated with systemic and mucosal immune responses. Third, attempts to enhance systemic and mucosal immunity by novel and careful employment of interleukins in feasibility experiments will be initiated. These experiments will utilize IL-4, IL-5, and/or IL-6 before immunization to determine its effects on immune response. If immunity can be enhanced without evidence of adverse effects, an attempt will be made to evaluate recombinant viruses carrying IL genes under various promoters. The knowledge gained from these studies will provide a basis for more detailed animal safety and immunogenicity studies in anticipation of human trials.