Correlates of protection against SIV/SHIV challenge

该项目的主要目标是利用临床前动物模型阐明针对 HIV-1 感染的免疫介导保护的相关性。为此，项目 1 将确定对减毒 SIV 的体液和细胞介导的免疫反应，称为 SIVGY，它诱导对异源致病性 SIV 后续攻击的保护性免疫。项目 3 将使用 DNA 疫苗、E1 缺失腺病毒 (Ad) 载体和痘病毒载体的组合来确定不同初免-加强疫苗方案引起的免疫反应。项目2将使用中和抗体被动免疫来确定抗体介导的保护的基线参数，并长期开发诱导B和T细胞的疫苗。项目 3 将评估疫苗诱导的粘膜 T 细胞在限制 SIV 传播中的作用。该计划的第二个目标是确定疫苗诱导的免疫反应（包括 Ad 载体诱导的免疫反应）是否有害，以及 E1 删除的 Ad 载体的进一步修饰是否可以提高其安全性和免疫原性/功效。为此，项目 3 将测试以下假设：病毒载体疫苗针对转基因产物或载体成分诱导的 CD4 T 细胞反应促进非人灵长类动物 SIV 感染后疾病进展。项目1将尝试通过生成和测试第二代E1删除的Ad载体来提高Ad载体疫苗的功效和安全性，该载体将额外删除E2a以减少Ad载体的高免疫原性结构抗原的合成。该应用程序分为以下 3 个项目和 2 个核心。项目 1 (H. Ertl)：疫苗诱导的保护相关性 项目 2 (R. Ruprecht)：CTL 疫苗的中和抗体覆盖范围 项目 3 (G. Silvestri)：粘膜 T 细胞反应和猿猴艾滋病保护 核心 A (H. Ertl)：管理核心 核心 B (X. Zhou)：载体核心

It is the primary objective of this program to elucidate correlates of immune-mediated protection against HIV-1 infection using pre-clinical animal models. To this end, Project 1 will determine humoral and cell-mediated immune responses to an attenuated SIV, termed SIVGY that induces protective immunity to subsequent challenge with a heterologous pathogenic SIV. Project 3 will determine immune responses elicited by different prime-boost vaccine regimens using combinations of DNA vaccines, E1-deleted adenovirus (Ad) vectors and poxvirus vectors. Project 2 will use passive immunization with neutralizing antibodies to determine baseline parameters of antibody-mediated protection with the long-term to develop vaccines that induce B and T cells. Project 3 will assess the role of vaccine-induced mucosal T cells in limiting the spread of SIV. It is the secondary objective of this program to determine if vaccine-induced immune responses including those induced by Ad vectors can be detrimental and if further modifications of E1-deleted Ad vectors can improve both their safety and immunogenicity/efficacy. To this end, Project 3 will test the hypothesis that CD4+ T cell responses induced by viral vector vaccines against the transgene product or components of the vector facilitate disease progression upon SIV infection of nonhuman primates. Project 1 will attempt to improve the efficacy and safety profile of Ad vector vaccines by generating and testing 2nd generation E1-deleted Ad vectors that will have an additional deletion of E2a to reduce synthesis of the highly immunogenic structural antigens of Ad vectors. The application is subdivided into the following 3 Projects and 2 Cores. Project 1 (H. Ertl): Vaccine-Induced Correlates of Protection Project 2 (R. Ruprecht): Neutralizing Antibody Coverage for CTL Vaccines Project 3 (G. Silvestri): Mucosal T Cell Responses and Protection from Simian AIDS Core A (H. Ertl): Administrative Core Core B (X. Zhou): Vector Core