PROTECTIVE EFFICACY OF LIVE ATTENUATED SIV VACCINES

减毒活疫苗已显示出显著的保护效果 在各种实验条件下对抗强毒病毒的挑战 然而，在某些条件下，减毒活疫苗的安全性仍然 需要仔细研究。在之前的授权期内进行的实验 解决了活体减毒删除的安全性问题 恒河猴的突变疫苗(多次高剂量口服 新生儿感染、孕妇感染和直接感染 中枢神经系统接种)和对 静脉、粘膜和异源病毒挑战。的目标 目前的建议是：1)进一步界定相关的安全问题 用减毒活疫苗和SIV模式2)研制 加速保护的开始和增加 对异源SIV毒株的保护广度和各种途径 曝光。此外，一些动物从实验中开始 在之前的授权期内，将进行维护以确保安全 新生儿接种减毒活疫苗的长期效果数据。 为了进一步定义安全性，拟议的实验将调查 疫苗接种时免疫抑制对病毒载量的影响 急性和慢性免疫刺激(使用可溶性抗原、卡介苗和 慢性寄生虫感染)以及与SRV-1和一种新疱疹病毒的混合感染 病毒rHKSHV。动物对动物通道的安全(恢复到 毒力)和生殖器分泌物中的病毒数量(风险 非故意传播)也将被研究。在药效方面 将测试具有多个缺失突变菌株的多价方法 因为它能够扩大异源保护的范围。一个时间进程 SIVdelta4与阴道免疫起始时间关系的研究 SIVdelta3面临的挑战和评估保护的研究 还提出了细胞相关暴露的建议。

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.