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: 7958867
• 负责人: Shiu-Lok Hu
• 金额: $ 33.14万
• 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/7958867
• 关键词: AIDS Vaccines; Adjuvant; Animals; Antibodies; Antibody Formation; Antigens; Cellular Immunity; Computer Retrieval of Information on Scientific Projects Database; Control Animal; DNA; Dose; Funding; Gagging; Generations; Grant; HIV-1; Immunity; Immunization; Infection; Infection Control; Institution; Macaca; Modeling; Plasma; Play; Primate Lentiviruses; Primates; Proteins; Recombinants; Research; Research Personnel; Resources; Rest; Role; SIV; Source; United States National Institutes of Health; Vaccinia; Viral Load result; Viral Vaccines; Viral Vector; Viremia; cohort; comparative efficacy; protective efficacy; vector

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. Since early 1990's, heterologous "prime-boost" immunization has been shown to protect against primate lentiviruses in multiple macaque models. However, few studies have compared the efficacy of different prime-boost strategies. In this study, we compared the protective efficacy of DNA, protein, or viral vaccines in different prime-boost combinations. Two cohorts of 24 macaques were primed with recombinant vaccinia or DNA vectors expressing HIV-1 SF162 Env or SIVmac239 Gag/Pol. Animals in each cohort were divided into three groups (N=6/group) and were boosted with DNA, protein; or heterologous viral vector expressing the same antigens. Six control animals in each cohort received empty vectors and adjuvant only. Protective efficacy was evaluated following a high-dose intrarectal challenge of SHIV-SF162P4. After the last immunization, all experimental animals generated SIV- and HIV-specific antibodies. Regardless of the priming, animals boosted with proteins had significantly higher antibody titers, including homologous neutralization antibodies (NtAb). After SHIV-SF162P4 challenge, significant reduction of mean plasma viral load was observed in all immunization groups. An inverse correlation (Spearman's r = -0.819, p lt 0.0001) 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. Although the rest of the immunized animals were all infected, two animals primed with vaccinia and boosted with DNA showed low ( lt 2x10^3 copies/ml) and transient plasma viremia, indicating the potential role of cellular immunity in controlling infection. Together, these results indicate that protective immunity against mucosal infection with a CCR5-using primate lentivirus can be achieved by systemic prime-boost immunization. NtAb played an important role in protection against mucosal infection by SHIVSF162P4. Boosting with protein immunogens appears to be superior to DNA or viral vectors in the generation of antigen-specific antibody responses, including NtAb.

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。 自20世纪90年代初以来，异源“初免-加强”免疫已显示在多种猕猴模型中保护免受灵长类慢病毒。然而，很少有研究比较不同的prime-boost策略的有效性。在这项研究中，我们比较了DNA，蛋白质或病毒疫苗在不同的初免-加强组合中的保护效果。 用表达HIV-1 SF 162 Env或SIVmac 239 Gag/Pol的重组牛痘或DNA载体致敏两组24只猕猴。每组动物分为三组（N=6/组），并用DNA、蛋白质或表达相同抗原的异源病毒载体加强免疫。每组中的六只对照动物仅接受空载体和佐剂。在SHIV-SF 162 P4的高剂量直肠内攻击后评价保护功效。 在最后一次免疫后，所有实验动物都产生了SIV和HIV特异性抗体。无论引发如何，用蛋白质加强的动物具有显著更高的抗体滴度，包括同源中和抗体（NtAb）。在SHIV-SF 162 P4攻击后，在所有免疫组中观察到平均血浆病毒载量显著降低。攻毒当天的NtAb滴度与攻毒后血浆病毒载量峰值之间存在负相关（斯皮尔曼r =-0.819，p lt 0.0001）。用蛋白质加强免疫的12只动物中有5只在攻击后显示高NtAb滴度和不可检测的病毒血症，与感染保护一致。尽管其余免疫动物均被感染，但两只用牛痘初免并用DNA加强的动物表现出低水平（lt 2x10^3拷贝/ml）和短暂的血浆病毒血症，表明细胞免疫在控制感染中的潜在作用。 总之，这些结果表明，针对使用CCR 5的灵长类慢病毒的粘膜感染的保护性免疫可以通过系统性初免-加强免疫来实现。NtAb在抗SHIVSF 162 P4粘膜感染中起重要作用。用蛋白质免疫原加强似乎在产生抗原特异性抗体应答（包括NtAb）方面上级DNA或病毒载体。