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: 9251729
• 负责人: Mary E. Klotman
• 金额: $ 192.45万
• 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/9251729
• 关键词: Address; Affinity; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Attenuated; B-Lymphocytes; Back; Binding; Binding Sites; Biodistribution; Biological Assay; Biopsy; Blood; CCR5 gene; CD8-Positive T-Lymphocytes; Cells; Characteristics; Cytomegalovirus; Data; Development; Engineering; Epitope Mapping; Epitopes; Evaluation; Evolution; Exposure to; Generations; Genetic Recombination; Genetic Transcription; Goals; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; HIV/SIV vaccine; Immune response; Immunization; Immunize; Immunoglobulin A; Immunoglobulin G; Immunoglobulin-Secreting Cells; In Vitro; Individual; Injection of therapeutic agent; Integrase; Intramuscular; Kinetics; Lentivirus Vector; Mediating; Modeling; Monoclonal Antibodies; Mucosal Immune Responses; Mus; Mutate; Plasma; Preparation; Production; Program Research Project Grants; Proteins; Protocols documentation; Reporting; SIV; Safety; Sampling; Series; Site; Somatic Mutation; Spleen; Subfamily lentivirinae; System; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Transgenes; Vaccination; Vaccines; Variant; Viral Antigens; Virion; Virus; Work; adaptive immune response; anti-IgA; arm; base; design; efficacy trial; env Gene Products; experimental study; improved; in vivo; lymph nodes; neutralizing antibody; nonhuman primate; novel; overexpression; prevent; protein expression; public health relevance; 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（由适用提供）：虽然RV144疫苗效率试验的结果令人鼓舞，但保护是适度的且不持续的。候选HIV疫苗的理想特征的新兴图片包括一种诱导持续反应的疫苗，其中包括广泛中和抗体（BNAB），非中和抗体，包括介导ADCC以及强烈的病毒特异性记忆T细胞的抗体。病毒研究，CMV载体的SIV/HIV疫苗的结果以及随着时间的推移抗体成熟的分析，所有抗体成熟都表明，持续的病毒抗原表达可能是推动成熟和广泛反应的重要组成部分。整合酶有缺陷的慢病毒载体（IDLV）具有安全特征，可防止整合和复制，从而在小鼠和非人类隐私（NHP）中以稳健和持续的T和B细胞反应长时间抗原表达。该计划项目Grant将IDLV的独特功能与旨在促进随着时间的推移成熟的成熟的免疫原设计策略结合在一起，并将在NHP模型中进行研究。 IDLV将经过设计，以根据最近描述的CH505传输/创建者包络以及一系列随后的变体来表达一系列包膜免疫原，并从开发CD4结合位点BNAB的个体中得出。行政核心（核心A）将假设拟议的科学计划有效地携带了OT和NHP核心（核心B），该计划将监督两个NHP协议，并执行定量和定性的T细胞分析以支持两个项目。项目1将开发和验证设计以表达ENV免疫原的IDLV，并将定义独特的抗原表达的机制。体外和体内测试将确定载体和表达持续时间，整合状态以及动员基于向量的病毒的能力。项目2将确定他的系统性和粘膜B细胞反应，包括神经化和ADCC（反对BNAB相关的表位）和分离株，并在两个疫苗臂中表征单克隆抗体。这些研究将检验以下假设：持续的战略选择信封的持续表达将导致成熟并扩大到有效的免疫响应。