Integrase Defective Lentiviral Vector (IDLV)-ENV Immunogen Strategy for an HIV Vaccine

HIV 疫苗的整合酶缺陷型慢病毒载体 (IDLV)-ENV 免疫原策略

• 批准号: 8899045
• 负责人: Mary E. Klotman
• 金额: $ 184.87万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899045
• 关键词: Address; Affinity; Animal Model; Antibodies; Antibody Response; Antigens; Attenuated; B-Lymphocytes; Back; Binding; Binding Sites; Biodistribution; Biological Assay; Biopsy; Blood; CCR5 gene; CD8B1 gene; Cells; Characteristics; Cytomegalovirus; Data; Development; Engineering; Epitope Mapping; Epitopes; Evaluation; Evolution; Exposure to; Gagging; Generations; Genetic Recombination; Genetic Transcription; Goals; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV/SIV vaccine; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin-Secreting Cells; In Vitro; Individual; Injection of therapeutic agent; Integrase; Intramuscular; Kinetics; Lead; Lentivirus Vector; Life; Mediating; Modeling; Monoclonal Antibodies; Mucosal Immune Responses; Mus; Mutate; Petit mal status; Plasma; Preparation; Production; Program Research Project Grants; Proteins; Protocols documentation; Reporting; SIV; Safety; Sampling; Series; Site; Somatic Mutation; Spleen; Staging; Subfamily lentivirinae; System; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Transgenes; Vaccination; Vaccines; Variant; Viral Antigens; Virion; Virus; Work; adaptive immunity; anti-IgA; arm; base; design; efficacy trial; env Gene Products; expression vector; improved; in vivo; lymph nodes; neutralizing antibody; nonhuman primate; novel; prevent; protein expression; public health relevance; research study; response; simian human immunodeficiency virus; vaccine efficacy; vaccine response; vector; vector vaccine; vector-induced

 DESCRIPTION (provided by applicant): While results from the RV144 vaccine efficacy trial were encouraging, protection was modest and not sustained. An emerging picture of desirable characteristics of candidate HIV vaccines include one that induces a sustained response that includes broadly neutralizing antibodies (bnAbs), non- neutralizing antibodies including those that mediate ADCC as well as strong virus-specific memory T cells. Results from attenuated virus studies, CMV-vectored SIV/HIV vaccines and analysis of antibody maturation over time all suggest that ongoing viral antigen expression may be an essential component to drive a mature and broad response. Integrase defective lentiviral vectors (IDLV) engineered with safety features that prevent integration and replication result in prolonged antigen expression with robust and sustained T and B cell responses in mice and non-human primates (NHP). This Program Project Grant combines the unique features of IDLV with recent immunogen design strategies aimed at promoting maturation of an effective immune response over time and will be studied in the NHP model. IDLV will be engineered to express a series of Envelope immunogens based on the recently described CH505 transmitted/founder envelope and a series of subsequent variants derived from an individual that developed CD4-binding site bnAbs. An administrative core (Core A) will assure that the proposed scientific plan is effectively carried ot and an NHP core (Core B) which will oversee two NHP protocols and perform quantitative and qualitative T cell assays in support of two projects. Project 1 will develop and validate IDLV engineered to express the Env immunogens and will define the mechanisms that uniquely sustain antigen expression. In vitro and in vivo testing will determine vector and expression durability, integration state and ability to mobilize vector-based virus. Project 2 will determine he systemic and mucosal B cell responses including neutralization and ADCC (against bnAb-associated epitopes) and isolate and characterize monoclonal antibodies over time two vaccine arms. These studies will test the hypothesis that persistent expression of strategically chosen envelopes will lead to maturation and broadening to an effective immune response.

 描述（由申请人提供）：虽然RV 144疫苗效力试验的结果令人鼓舞，但保护作用有限，且不持久。候选HIV疫苗的期望特征的新图像包括诱导持续应答的疫苗，所述持续应答包括广泛中和抗体（bnAb）、非中和抗体（包括介导ADCC的那些抗体）以及强病毒特异性记忆T细胞。来自减毒病毒研究、CMV载体SIV/HIV疫苗和抗体随时间成熟的分析的结果都表明，持续的病毒抗原表达可能是驱动成熟和广泛应答的重要组成部分。整合酶缺陷型慢病毒载体（IDLV）经工程改造具有防止整合和复制的安全特征，导致小鼠和非人灵长类动物（NHP）中延长的抗原表达以及稳健和持续的T和B细胞应答。该计划项目资助将IDLV的独特功能与最近的免疫原设计策略相结合，旨在随着时间的推移促进有效免疫应答的成熟，并将在NHP模型中进行研究。将对IDLV进行工程改造，以表达基于最近描述的CH 505传播/创始者包膜的一系列包膜免疫原和衍生自产生CD 4结合位点bnAb的个体的一系列后续变体。一个行政核心（核心A）将确保拟议的科学计划得到有效实施，一个NHP核心（核心B）将监督两个NHP方案，并进行定量和定性T细胞测定，以支持两个项目。项目1将开发和验证经工程改造以表达Env免疫原的IDLV，并将定义独特维持抗原表达的机制。体外和体内测试将确定载体和表达持久性、整合状态和动员基于载体的病毒的能力。项目2将确定全身和粘膜B细胞应答，包括中和和ADCC（针对bnAb相关表位），并分离和表征两个疫苗组随时间推移的单克隆抗体。这些研究将检验以下假设：策略性选择的包膜的持续表达将导致成熟并扩大到有效的免疫应答。