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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们以前证明，复制能力的Ad-SIV重组初免/蛋白加强方案引起恒河猴对SIVmac 251的有效免疫原性和强，持久的保护。此外，天然达特疫苗已赋予食蟹猴针对SHIV 89.6 P攻击的强保护，而天然、灭活或载体化的达特疫苗未能在恒河猴中引发类似的保护功效。在这里，我们询问是否用复制的Ad-HIVtat引发恒河猴并用达特蛋白加强免疫会引起对SHIV 89.6 P的保护。我们还评估了达特/env方案，加入Ad-HIVenv重组体和包膜蛋白加强，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、-HIVVenv、-SIVgag和-SIVnef重组体以及达特、Env和Nef蛋白。所有方案均具有免疫原性。在ELISPOT应答（Env gt Gag gt Nef gt达特）和抗体滴度（Env gt达特gt Nef gt Gag）中观察到分级。在静脉注射SHIV 89.6P攻击后，所有猕猴都被感染。与对照组相比，在仅Tat组中没有观察到保护作用，证实了先前的报道。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），多基因组和达特/env组分别使慢性病毒血症减少3和4 log（多基因，p = 0.0003;达特/env，p lt 0.0001）。与多基因组相比，tat/env显著更大的降低（p = 0.014）与达特和Env结合抗体相关。由于攻击前抗Env抗体缺乏SHIV 89.6 P中和活性，因此正在研究其他功能性抗Env和抗达特活性，以及达特和Env免疫原之间可能的协同作用。 我们将继续监测剩余动物，以评估组间可能的生存差异。