COMBINED APPROACH TO BROADLY PROTECTIVE AIDS VACCINES: PROJECT 4

广泛保护性艾滋病疫苗的综合方法：项目 4

• 批准号: 8357598
• 负责人: Shiu-Lok Hu
• 金额: $ 37.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357598
• 关键词: AIDS Vaccines; Animals; Antibodies; Antibody Formation; Antigens; Comparative Study; DNA; Data; Epitopes; Funding; Gagging; Generations; Grant; HIV-1; Immunity; Immunization; Infection; Lentivirus Infections; Molecular Conformation; National Center for Research Resources; Nature; Peripheral Blood Mononuclear Cell; Plasma; Primate Lentiviruses; Primates; Principal Investigator; Proteins; Recombinants; Regimen; Reporting; Research; Research Infrastructure; Resources; Role; Source; United States National Institutes of Health; Universities; Vaccines; Vaccinia; Vaccinium; Viral Load result; Viral Vector; Viremia; Virus; cost; neutralizing antibody; neutralizing monoclonal antibodies; protective efficacy; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We previously reported comparative studies of the protective efficacy of different "prime-boost" immunization regimens consisted of priming with recombinant vaccinia or DNA vectors expressing HIV-1 SF162 Env or SIVmac239 Gag/Pol, followed by boosting with DNA, protein; or heterologous viral vector expressing the same antigens. Results showed that, regardless of the priming immunogen, animals boosted with protein vaccines had significantly higher antibody titers, including homologous neutralization antibodies (NtAb). After SHIVSF162P4 challenge, significant reduction of mean plasma viral load was observed in all immunization groups. An inverse correlation (Spearman's r = -0.819, p0.0001) was observed between NtAb titer on the day of challenge and peak plasma viral load after challenge. Five of 12 animals boosted with proteins showed high NtAb titer and no detectable viremia after challenge, consistent with protection from infection. We have also extended the comparative study to include protein priming, followed by boosting with DNA, protein or viral vector. After two immunizations with protein vaccines, high level of virus-specific antibody responses, including homologous NtAb, were generated. However, further immunizations with DNA or viral vectors showed little or no boosting effects. Following intrarectal SHIV162 P4 challenge, all but one animal in each of the protein-DNA or protein-protein prime-boost groups were infected. These results further support the important role of priming in the prime-boost immunization in the generation of protective immunity against primate lentivirus infection. To further define the nature of neutralizing antibody responses in these animals, PBMC were sent to Dr. James Robinson at Tulane University to isolate neutralizing monoclonal antibodies against HIV-1. Preliminary data from Dr. Robinson indicate that some of these antibodies may recognize conformation-dependent epitopes against HIV-1 envelope. Further characterization of these antibodies is in progress.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们先前报道了对不同“原始促进”免疫方案的保护疗效的比较研究，包括用表达HIV-1 SF162 ENV或SIVMAC239 GAG/POL的重组疫苗或DNA载体的启动，然后再用DNA，蛋白质增强；或表达相同抗原的异源病毒载体。结果表明，不管免疫原理如何，用蛋白质疫苗增强的动物具有明显更高的抗体滴度，包括同源中和抗体（NTAB）。在SHIVSF162P4挑战之后，在所有免疫组中观察到平均血浆病毒载量的显着降低。在挑战当天，在NTAB滴度与挑战之后的峰血浆病毒载荷之间观察到了反相关性（Spearman的R = -0.819，P0.0001）。蛋白质增强的12只动物中有5只在挑战后显示出高NTAB滴度，没有可检测的病毒血症，这与免受感染的保护一致。我们还将比较研究扩展到包括蛋白质启动，然后用DNA，蛋白质或病毒载体增强。两次用蛋白质疫苗进行免疫接种后，产生了包括同源NTAB在内的高水平的病毒特异性抗体反应。但是，用DNA或病毒载体进行进一步的免疫接种显示几乎没有或没有增强作用。在直肠内SHIV162 P4挑战之后，每个蛋白-DNA或蛋白质蛋白质促进基团中除一只动物外，所有动物都被感染。这些结果进一步支持了启动在促进免疫中的重要作用在针对灵长类动病毒感染的保护性免疫中的重要作用。为了进一步定义这些动物中和抗体反应的性质，将PBMC发送给杜兰大学的詹姆斯·罗宾逊博士，以隔离中和对HIV-1的单克隆抗体。罗宾逊博士的初步数据表明，其中一些抗体可能识别依赖于HIV-1包膜的构象的表位。这些抗体的进一步表征正在进行中。