Effect of immunization route and prior immunity for a live attenuated varicella AIDS vaccine

 描述(申请人提供)：需要一种安全有效的疫苗来控制由人类免疫缺陷病毒(HIV)引起的全球艾滋病流行。水痘带状疱疹减毒活疫苗(VZVOka)是一种有吸引力的疫苗载体，可表达其他病原体的外源抗原。它已被证明是安全的，目前已获得儿童和成人的许可。猴水痘病毒(SVV)与水痘病毒(VZV)关系密切，在非人类灵长类动物中引起一种自然的水痘样疾病。我们的长期目标是建立一种新型的儿科、活的、减毒的重组水痘-艾滋病疫苗方案，在婴幼儿免疫系统极其活跃的时候，在他们的性成熟之前，产生病毒特异性免疫，以保护他们免受粘膜艾滋病毒的感染。我们的假设是，鼻腔和皮下双重rSVV-SIV原发和电穿孔SIV DNA增强，并在SIV攻击之前延长休息时间将1)是安全的，2)最大限度地促进病毒特异性免疫反应，3)在不增加SIV易感性的情况下提供对黏膜SIV攻击的保护，4)预先存在的SVV免疫不会减弱疫苗诱导的免疫反应。这一假说建立在我们对rSVV-SIV免疫和SIV静脉攻击后特异性免疫反应和显著降低血浆SIV负荷的发现的基础上。在体内，SIV DNA的电穿孔被证明能够刺激免疫反应，包括粘膜免疫，并显著减少SIV攻击后的SIV病毒血症。这项建议将利用猴水痘和儿童艾滋病恒河猴模型来测试rSVV-SIV Prime、SIV DNA Boost免疫策略和黏膜SIV攻击在SVV幼稚和SVV血清阳性的婴儿恒河猴中的作用，以确定免疫路线、病毒特异性免疫反应、靶向表位、先前存在的SVV免疫的效果以及对SIV粘膜攻击的保护。我们的80%预防感染的目标可能更好地预测了人类试验的结果。这样的结果将加速开发对应的rVZV-HIV疫苗，简化审批程序，并随后进行临床人体试验。一种安全有效的儿童rVZV-HIV疫苗将是一项具有里程碑意义的艾滋病预防战略，特别是对世界上艾滋病毒流行地区的儿童来说。

 DESCRIPTION (provided by applicant): A safe and effective vaccine is needed to control the worldwide AIDS epidemic caused by the human immunodeficiency virus (HIV). The live, attenuated varicella zoster virus (VZVOka) vaccine is an attractive vaccine vector to express foreign antigens of other pathogens. It is proven safe and currently licensed for children and adults. The simian varicella virus (SVV), closely related to VZV, causes a natural, varicella-like disease in nonhuman primates. Our long term goal is to establish a novel pediatric, live, attenuated recombinant varicella-AIDS vaccine protocol to produce virus specific immunity in infants and young children, at a time when their immune systems are extremely active and well before sexual maturity to protect them against mucosal HIV infection. Our hypothesis is that a dual intranasal and subcutaneous rSVV-SIV Prime and electroporated SIV DNA Boost, with extended rest prior to SIV challenge will 1) be safe, 2) promote maximum virus specific immune responses 3) provide protection against mucosal SIV challenge without increasing SIV susceptibility and 4) preexisting SVV immunity will not diminish the vaccine induced immune responses. This hypothesis builds on our findings of specific immune responses and significantly reduced plasma SIV load following rSVV-SIV immunization and SIV intravenous challenge. In vivo electroporation of SIV DNA has been shown to stimulate immune responses, including mucosal immunity and significantly reduce SIV viremia following SIV challenge. This proposal will utilize the simian varicella and pediatric AIDS rhesus models to test the rSVV-SIV Prime, SIV DNA Boost immunization strategy and mucosal SIV challenge in SVV naïve and SVV seropositive infant rhesus to define immunization route, virus specific immune responses, targeted epitopes, effects of preexisting SVV immunity, and protection against an SIV mucosal challenge. Our goal of >80% protection from infection may be better predictive of human trial outcomes. Such outcomes would hasten development of a counterpart rVZV-HIV vaccine, streamlined approvals and subsequent clinical human trials. A safe and effective pediatric rVZV-HIV vaccine would be a monumental AIDS prevention strategy, especially for children in areas of the world with endemic HIV infection.