DEVELOPMENT OF AN OPTIMAL LIVE ATTENUATED SIV VACCINE

最佳 SIV 减毒活疫苗的开发

• 批准号: 6268022
• 负责人: Michael A Murphey-Corb
• 金额: $ 32.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-15 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6268022
• 关键词: AIDS vaccines; Macaca mulatta; T lymphocyte; active immunization; antigen presenting cell; attenuated microorganism; cellular immunity; cytokine; drug administration routes; genetic strain; humoral immunity; immunomodulators; intravenous administration; live vaccine; macrophage; mucosal immunity; nonhuman therapy evaluation; rectum /anus; simian immunodeficiency virus; vaccine development; vector vaccine; viral vaccines; virulence; virus infection mechanism; virus replication

An attenuated monocyte-tropic clone of SIV (SIV/17E-C1) has properties which are unique to a live attenuated SIV vaccine. Infection with SIV/17E-C1 induces an early vigorous type-specific neutralizing antibody response which broadens during the first 7 months postinfection to include activity against SIV/DeltaB670, a heterologous primary isolate. The induction of protective immune responses coincides with the switch from type-specific to group-specific neutralizing antibody, and, at least in part, appears mediated by antibody since sera from protected monkeys passively protected 2 of 4 recipients. A nef-deleted variant of this monocyte-tropic clone, but not the lymphocyte-tropic parent SIVmac239deltanef, also induced detectable class I restricted CTL during the first 6 months postinfection. These unique properties are likely due to a unique gp120 conformation imposed by sequences which enable it to replicate in macrophages, and/or selective presentation to the immune system by the infected macrophage. We propose to further characterize the protective responses induced by SIV/17E-C1 infection, and to utilize this information to design a subunit vaccine that can induce the protective responses observed with the attenuated virus. The protection observed by intravenous challenge with cell-free virus of SIV/e-C1- infected monkeys will be extended to protection against infected cells, delivered both intravenously and at the intestinal mucosal surface. The role of antibody in passive protection will be confirmed by passive transfer of purified immunoglobulin. Antibodies binding to native versus denatured gp120 will be affinity purified, characterized in vitro and similarly analyzed to define the specificity of protective responses. Passive transfer studies will also be performed with monoclonal antibodies derived from SIV/17E-C1-infected monkeys to identify the specific epitope(s) required for protection. The contribution of cellular immunity will be determined by determining the kinetics of class I restricted CTL induction in infected monkeys, and correlating these responses to protection. The efficacy of a purified recombinant gp120 vaccine comprised of SIV/17E-C1 sequences will be evaluated to determine whether these sequences per se uniquely induce protective immunity. The ability of DNA vaccines comprised of SIV/17E sequences, alone or in combination with cytokine expression vectors, to elicit protective responses will be assessed using both direct injection of DNA and the particle delivery system developed by Agracetus. The optimal HIV vaccine strategy is one which is efficacious in both SIV (disease) and HIV (infection) model systems. Thus, the ability of SIV/HIV recombinant viruses to serve as live attenuated vaccines will be determined to extend the observations gained from SIV to HIV glycoproteins. A model for assessing effective SIV subunit vaccines, as well as heterologous (inter- clade) protection, will be established using SHIV constructs.

SIV的减毒单核细胞嗜性克隆（SIV/17 E-C1）具有以下特性： 其是减毒SIV活疫苗所特有的。 感染 SIV/17 E-C1诱导早期强型特异性中和抗体 在感染后的前7个月， 包括抗SIV/DeltaB 670（一种异源原代分离物）活性。 保护性免疫反应的诱导与转换相一致 从类型特异性中和抗体到组特异性中和抗体，并且，至少 部分是由抗体介导，因为来自受保护猴的血清 被动保护4个收件人中的2个。 一个非缺失的变体 亲单核细胞克隆，而不是亲淋巴细胞的亲本 SIVmac 239 deltanef也诱导可检测的I类限制性CTL， 感染后的前6个月。 这些独特的属性可能是由于 一种独特的gp 120构象，它由一种序列所施加， 在巨噬细胞中复制，和/或选择性呈递给免疫细胞 感染的巨噬细胞。 我们建议进一步描述 SIV/17 E-C1感染诱导的保护性反应，并利用 利用这些信息来设计亚单位疫苗， 用减毒病毒观察到保护性应答。 保护 通过用SIV/e-C1的无细胞病毒静脉内攻击观察到， 受感染的猴子将被扩展到保护免受受感染的细胞， 静脉内和肠粘膜表面递送。 的 抗体在被动保护中的作用将通过被动 纯化免疫球蛋白的转移。 抗体结合天然与 变性的gp 120将被亲和纯化、体外表征并 类似地分析以定义保护性反应的特异性。 还将使用单克隆抗体进行被动转移研究。 来自SIV/17 E-C1感染猴的抗体， 保护所需的特定表位。 的贡献 细胞免疫将通过确定类免疫的动力学来确定。 我在受感染的猴子中限制了CTL诱导， 对保护的回应。 纯化的重组gp 120的功效 将对由SIV/17 E-C1序列组成的疫苗进行评价，以确定 这些序列本身是否独特地诱导保护性免疫。 的 由SIV/17 E序列组成的DNA疫苗，单独或与 与细胞因子表达载体组合，以引发保护性 将使用直接注射DNA和 由Agracetus开发的颗粒输送系统。 最佳HIV疫苗 一种对SIV（疾病）和HIV都有效的策略 （感染）模型系统。 因此，SIV/HIV重组体 作为减毒活疫苗的病毒将被确定为 从SIV到HIV糖蛋白的观察。 的典范 评估有效的SIV亚单位疫苗，以及异源（间- 进化枝）保护，将使用SHIV构建体建立。