NHP Core for Development of an Integrase Defective Lentiviral Vector HIV Vaccine

用于开发整合酶缺陷型慢病毒载体 HIV 疫苗的 NHP 核心

• 批准号: 9251738
• 负责人: SAMPA SANTRA
• 金额: $ 45.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9251738
• 关键词: Acute; Affinity; Animals; Antibodies; Antibody Response; Antigen Presentation; Antigens; Antiviral Agents; B cell repertoire; B-Lymphocytes; Biological Assay; Blood specimen; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Lineage; Cell Maturation; Cells; Clinical; Clinical Trials; Clinical assessments; Cytomegalovirus; Cytotoxic T-Lymphocytes; Development; Dose; Engineering; Evolution; Exposure to; Flow Cytometry; Generations; Genetic Recombination; Goals; HIV; HIV vaccine; HIV-1; HIV-1 vaccine; HIV/SIV vaccine; Immune response; Immune system; Immunity; Immunization; Immunize; Individual; Infection; Integrase; Interferon Type II; Intramuscular; Intravenous; Investigation; Kinetics; Lentivirus Vector; Macaca mulatta; Memory; Monkeys; Mus; Mutate; Program Research Project Grants; Proteins; Protocols documentation; Recombinant Vaccines; Regimen; Risk; SIV; SIV Vaccines; Safety; Sampling; Series; Site; Somatic Mutation; Surface; T cell response; T memory cell; T-Lymphocyte; Tissue Sample; Vaccinated; Vaccination; Vaccines; Variant; Virion; Virus; Virus Diseases; Work; base; immunogenic; immunogenicity; killings; neutralizing antibody; nonhuman primate; novel strategies; pre-clinical; programs; response; safety study; simian human immunodeficiency virus; success; transmission process; vaccine candidate; vector; vector vaccine

An effective HIV-1 vaccine is likely to require elicitation of broadly neutralizing antibodies to block virus infection at mucosal surfaces, as well as strong T cell responses to provide help to for the antibody responses and to kill virus-infected cells at the site of transmission. The most robust cellular immune responses induced to date have been generated employing live, recombinant vaccine vectors however they are limited by anti- vector immunity and raise significant safety issues. While the pivotal RV144 trial was encouraging with 31.2% protection, the humoral correlates of protection were not sustained. Integrase-defective lentiviral vectors (IDLV) engineered to enhance antigen expression with safe guards against integration, recombination, replication or vector mobilization are a novel approach to developing an effective HIV-1 vaccine which has the distinct advantage of providing long term antigen exposure with a single immunization. In preliminary studies, this vaccine approach has elicited persistent T cell responses as well as durable Envelope-specific antibody responses in both mice and nonhuman primates (NHP). Thus, we now aim to determine the ability of the persistent antigen expression provided by this vaccine regimen to elicit highly somatically-mutated antibody responses that are likely to result in broad neutralization capacity and develop functional CD4+ and CD8+ T cell responses in NHP that are desirable in an efficacious HIV-1 vaccine candidate. IDLV engineered to express the CH505 transmitted/founder envelope and a series of subsequent variants derived from an individual that was found to be associated with broadly neutralizing antibodies will be sequentially delivered to NHP with and without protein boost with the same immunogen. The NHP core of this program project grant, will perform the NHP immunization protocols and SHIV challenge and provide samples to Projects 1 and 2 of this program to assess the safety, immunogenicity and efficacy of the IDLV Env immunogen strategy. The core will also perform in-depth analyses of the vaccine-elicited, antigen specific functional CD4+ and CD8+ T . This work will determine whether the use of IDLV vector is a viable and effective strategy for HIV-1 vaccination that should be forwarded to clinical trials.

有效的HIV-1疫苗可能需要激发广泛中和抗体来阻断病毒 粘膜表面的感染，以及强烈的T细胞反应，为抗体反应提供帮助 并在传播部位杀死病毒感染的细胞。最强大的细胞免疫反应诱导 迄今为止，已经使用活的重组疫苗载体产生，但是它们受到抗- 病媒免疫力并引起重大的安全问题。而关键的RV 144试验令人鼓舞，31.2% 保护，保护的体液相关性没有持续。整合酶缺陷型慢病毒载体 （IDLV）工程化以增强抗原表达，同时安全地防止整合，重组， 复制或载体动员是开发有效的HIV-1疫苗的新方法， 这是用单次免疫提供长期抗原暴露的明显优点。在初步研究中， 这种疫苗方法已经引发了持久的T细胞应答以及持久的包膜特异性抗体 小鼠和非人灵长类动物（NHP）的反应。因此，我们现在的目标是确定 由该疫苗方案提供的持续抗原表达以引发高度体细胞突变的抗体 可能导致广泛中和能力并产生功能性CD 4+和CD 8 + T细胞的应答 NHP中的细胞应答，这在有效的HIV-1候选疫苗中是理想的。IDLV设计为 表达CH 505传输/创始人信封和一系列后续变体， 将发现与广泛中和抗体相关的个体依次递送至 用相同的免疫原进行有和没有蛋白质加强的NHP。NHP的核心项目赠款， 将执行NHP免疫方案和SHIV攻毒，并为项目1和2提供样本， 本项目旨在评估IDLV Env免疫原策略的安全性、免疫原性和有效性。的 核心还将对疫苗诱导的抗原特异性功能性CD 4+和CD 8 + T进行深入分析。 这项工作将确定使用IDLV载体是否是一种可行和有效的HIV-1疫苗接种策略 应该进行临床试验