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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们之前报道过不同“初免-加强”免疫方案保护功效的比较研究，包括用表达 HIV-1 SF162 Env 或 SIVmac239 Gag/Pol 的重组痘苗或 DNA 载体初免，然后用 DNA、蛋白质加强；或表达相同抗原的异源病毒载体。结果显示，无论引发免疫原如何，用蛋白质疫苗加强免疫的动物具有显着更高的抗体滴度，包括同源中和抗体（NtAb）。 SHIVSF162P4 攻击后，所有免疫组中均观察到平均血浆病毒载量显着降低。攻击当天的 NtAb 滴度与攻击后血浆病毒载量峰值之间观察到负相关（Spearman's r = -0.819，p0.0001）。 12 只动物中，有 5 只接受蛋白质强化，在攻击后显示出高 NtAb 滴度且未检测到病毒血症，这与感染保护作用一致。我们还扩展了比较研究，包括蛋白质引发，然后用 DNA、蛋白质或病毒载体进行加强。使用蛋白质疫苗进行两次免疫后，产生了高水平的病毒特异性抗体反应，包括同源 NtAb。然而，用 DNA 或病毒载体进一步免疫显示很少或没有增强效果。直肠内 SHIV162 P4 攻击后，蛋白质-DNA 或蛋白质-蛋白质初免-加强组中除一只动物外，所有动物均被感染。这些结果进一步支持了初免-加强免疫中初免在产生针对灵长类慢病毒感染的保护性免疫中的重要作用。为了进一步确定这些动物中中和抗体反应的性质，将 PBMC 送到杜兰大学的 James Robinson 博士处，以分离针对 HIV-1 的中和单克隆抗体。 Robinson 博士的初步数据表明，其中一些抗体可能识别针对 HIV-1 包膜的构象依赖性表位。这些抗体的进一步表征正在进行中。