Correlates of protection against SIV/SHIV challenge

本项目的主要目的是使用临床前动物模型阐明免疫介导的抗HIV-1感染保护的相关性。为此，项目1将确定体液和细胞介导的免疫反应，以减毒SIV，称为SIVGY，诱导保护性免疫，随后的挑战与异源致病性SIV。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，确定不同初免-加强疫苗方案引起的免疫应答。项目2将使用中和抗体的被动免疫来确定抗体介导的保护的基线参数，以长期开发诱导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。本计划的第二个目的是确定疫苗诱导的免疫应答（包括Ad载体诱导的免疫应答）是否有害，以及E1缺失的Ad载体的进一步修饰是否可以改善其安全性和免疫原性/有效性。为此，项目3将检验以下假设：针对转基因产物或载体组分的病毒载体疫苗诱导的CD 4 + T细胞应答促进非人灵长类动物SIV感染后的疾病进展。项目1将尝试通过生成和测试第二代E1缺失的Ad载体来改善Ad载体疫苗的有效性和安全性，第二代E1缺失的Ad载体将具有额外的E2 a缺失，以减少Ad载体的高免疫原性结构抗原的合成。该应用程序被细分为以下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疫苗项目3的中和抗体覆盖率（G。Silvestri）：粘液T细胞反应和保护猿猴艾滋病核心A（H。Ertl）：管理核心核心B（X. Zhou）：Vector Core

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