VACCINE USING HIV/SIV ENV, GAG, NEF & TAT ADENOVIRUS WITH PROTEIN BOOSTING

使用 HIV/SIV ENV、GAG、NEF 进行疫苗

• 批准号: 7958842
• 负责人: Marjorie Robert-Guroff
• 金额: $ 49.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958842
• 关键词: Acute; Adenoviruses; Animals; Antibodies; Antigens; Binding; Cellular Immunity; Chronic; Computer Retrieval of Information on Scientific Projects Database; Funding; GAG Gene; Gagging; Grant; Institution; Intravenous; Investigation; Macaca; Macaca fascicularis; Macaca mulatta; Monitor; Phase; Primates; Proteins; Recombinants; Reporting; Research; Research Personnel; Resources; Source; Testing; Treatment Protocols; United States National Institutes of Health; Vaccines; Viremia; env Gene Products; enzyme linked immunospot assay; immunogenic; immunogenicity; nef Protein; protective efficacy; response; tat Protein

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We previously demonstrated that replication-competent Ad-SIV recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIVmac251. Additionally, native Tat vaccines have conferred strong protection against SHIV89.6P challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-HIVtat and boosting with Tat protein would elicit protection against SHIV89.6P. We also evaluated a tat/env regimen, adding an Ad-HIVenv recombinant and envelope protein boost to test whether envelope antibodies would augment acute phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIVtat, -HIVenv, -SIVgag and -SIVnef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in ELISPOT responses (Env gt Gag gt Nef gt Tat) and antibody titers (Env gt Tat gt Nef gt Gag). Following intravenous SHIV89.6P challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports. However, the multigenic group blunted acute viremia approximately 1 log (p = 0.017), and both the multigenic and tat/env groups reduced chronic viremia by 3 and 4 logs respectively compared to controls (multigenic, p = 0.0003; tat/env, p lt 0.0001). The strikingly greater reduction in the tat/env compared to the multigenic group (p = 0.014) was correlated with Tat and Env binding antibodies. As pre-challenge anti-Env antibodies lacked SHIV89.6P neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between Tat and Env immunogens. We are continuing to monitor the remaining animals to assess possible survival differences between the groups.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们之前证明，具有复制能力的 Ad-SIV 重组初免/蛋白加强方案可引发有效的免疫原性，并对恒河猴提供针对 SIVmac251 的强大、持久的保护。此外，天然 Tat 疫苗对食蟹猴的 SHIV89.6P 攻击具有强大的保护作用，而天然、灭活或载体 Tat 疫苗未能在恒河猴中产生类似的保护功效。在这里，我们询问用复制型 Ad-HIVtat 启动恒河猴并用 Tat 蛋白加强是否会引起针对 SHIV89.6P 的保护。我们还评估了 tat/env 方案，添加 Ad-HIVenv 重组体和包膜蛋白增强剂，以测试包膜抗体是否会增强急性期保护。此外，期望细胞免疫增强慢性病毒血症控制，我们测试了多基因组：Ad-HIVtat、-HIVenv、-SIVgag 和 -SIVnef 重组体以及 Tat、Env 和 Nef 蛋白。所有方案均具有免疫原性。在 ELISPOT 反应 (Env gt Gag gt Nef gt Tat) 和抗体滴度 (Env gt Tat gt Nef gt Gag) 中观察到层次结构。静脉注射 SHIV89.6P 攻击后，所有猕猴都被感染。与对照组相比，仅使用 Tat 的组没有看到任何保护作用，这证实了之前的报告。然而，与对照组相比，多基因组使急性病毒血症减弱约 1 log (p = 0.017)，多基因组和 tat/env 组分别使慢性病毒血症降低 3 和 4 log (多基因组，p = 0.0003；tat/env，p < 0.0001)。与多基因组相比，tat/env 显着降低（p = 0.014），这与 Tat 和 Env 结合抗体相关。由于攻击前的抗 Env 抗体缺乏 SHIV89.6P 中和活性，因此正在研究其他功能性抗 Env 和抗 Tat 活性，以及​​ Tat 和 Env 免疫原之间可能的协同作用。 我们正在继续监测剩余的动物，以评估各组之间可能存在的生存差异。