PROTECTIVE EFFICACY OF LIVE ATTENUATED SIV VACCINES

SIV减毒活疫苗已显示出显著的保护效果， 在各种实验条件下， 然而，在某些条件下，减毒活疫苗的安全性仍然存在。 需要仔细研究在上一个授权期内， 进行了研究，以解决减毒活基因缺失的安全性 恒河猴突变疫苗（暴露于多次高剂量，口服 新生儿感染、孕妇感染和直接 接种到中枢神经系统）和针对 静脉内、粘膜和异源病毒攻击。的目标 目前的建议是：1）进一步界定有关的安全问题 与减毒活艾滋病疫苗使用SIV模型和2）开发 加速保护的开始并增加 对异源SIV毒株的保护范围以及 exposure.此外，一些动物从实验开始， 在前一个授予期间将保持收集安全 减毒活疫苗对新生儿的长期影响数据。 为了进一步确定安全性，拟议的实验将研究 接种时免疫抑制对病毒载量的影响， 急性和慢性免疫刺激（用可溶性抗原、BCG和 慢性寄生虫感染）以及与SRV-1和一种新的疱疹病毒合并感染 病毒rhKSHV。动物间通过的安全性（恢复至 毒力）和生殖器分泌物中的病毒量（ 非故意传播）也将进行研究。在功效方面， 将测试使用多个缺失突变株的多价方法 因为它能够扩大异源保护。的时间过程 研究确定SIVdelta 4和阴道免疫的开始 挑战和一项研究，以评估保护SIVdelta 3在面对 还提出了与细胞相关的暴露。

Live-attenuated SIV vaccines have shown marked efficacy in protecting against virulent viral challenge under a variety of experimental conditions, however, the safety of a live-attenuated vaccine still requires careful study. During the previous granting period experiments were performed that addressed the safety of live-attenuated deletion mutant vaccines in rhesus monkeys (exposure to multiple high doses, oral infection of neonates, infection of pregnant mothers and direct inoculation into the central nervous system) and the efficacy against intravenous, mucosal and heterologous virus challenge. The objectives of the current proposal are 1) to further define safety issues associated with a live-attenuated AIDS vaccines using the SIV model and 2) to develop strategies that accelerate the onset of protection and increase the breadth of protection to heterologous SIV strains and various routes of exposure. In addition, a number of animals from experiments initiated during the previous granting period will be maintained to gather safety data on the long term effects of the live-attenuated vaccines in neonates. To further define safety the proposed experiments will investigate the effect on virus load of immunosuppression at the time of vaccination, of acute and chronic immune stimulation (with soluble antigens, BCG and chronic parasitic infections) and co-infection with SRV-1 and a new herpes virus rhKSHV. The safety of animal to animal passage (reversion to virulence) and the amount of virus in genital secretions (risk of unintended transmission) will also be studied. In the area of efficacy a polyvalent approach with multiple deletion mutant strains will be tested for its ability to broaden the heterologous protection. A time course study to determine the onset of immunity with SIVdelta4 and vaginal challenge and a study to assess protection of SIVdelta3 in the face of cell associated exposure are also proposed.