PROTECTIVE EFFICACY OF GLYCAN-MODIFIED ENV VACCINE

聚糖修饰的 ENV 疫苗的保护作用

• 批准号: 8357597
• 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/8357597
• 关键词: Adjuvant; Amino Acids; Animals; Antibody Formation; CCR5 gene; Control Animal; Effectiveness; Family suidae; Follow-Up Studies; Funding; Gagging; Grant; HIV-1; Health; Immunity; Immunization; Link; Macaca; National Center for Research Resources; Polysaccharides; Primates; Principal Investigator; Recombinant Proteins; Regimen; Research; Research Infrastructure; Resources; SIV; Secondary Immunization; Source; Subfamily lentivirinae; Tail; United States National Institutes of Health; Vaccines; Vaccinia virus; Viral Load result; Virus; cost; mutant; neutralizing antibody; protective efficacy; research study; response

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 showed that immunization of pig-tailed macaques with the N7 Env, which had a N-linked glycan at amino acid residue 197 removed, resulted in enhanced neutralizing antibody (NAb) response not only against the homologous virus, 89.6, but also HIV-1 SF162 and a standard panel of subtype B primary isolates. In this study, we aimed to extend these studies to evaluate the protective efficacy of N7 Env vaccines against a heterologous CCR5 virus challenge. We immunized three groups of pig-tailed macaques (N=6/group) with a "prime-boost" regimen, consisting of priming with recombinant vaccinia virus and boosting with recombinant proteins. Two of these groups were immunized with either wild-type or mutant N7 Env vaccines. An additional group of animals received both N7 Env and SIV Gag-Pol vaccines. Control animals received parental vaccinia virus and adjuvant only. All animals generated lentivirus-specific antibody responses, including NAb against the heterologous virus SF162, albeit at 5- to10-fold less than what we observed in the first study described above. This prompted us to administer an additional booster immunization. However, no increase in NAb titer was observed, consistent with the notion that the magnitude of response was determined largely by the effectiveness of the primary immunization. After challenge with an intrarectal inoculation of SHIV162P4, all control and immunized animals were infected, consistent with the low titer of Nab titer at the day of challenge. However, animals immunized with the N7 Env showed significant reduction of peak viral load and those received both N7 Env and SIV Gag-Pol vaccines showed reduction of setpoint viral loads. These results indicate that protective immunity against a heterologous virus can be generated by the prime boost immunization regimen. This experiment was concluded in July, 2010 and the remaining animals transferred to Colony Health for follow up studies.

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。 我们先前表明，使用N7 Env进行了猪尾猕猴的免疫，该猕猴在197中的氨基酸残基处具有N连接的聚糖，导致中和抗体（NAB）的反应增强，不仅针对同源病毒，89.6，还增加了HIV-1 SF162，还可以增强。在这项研究中，我们旨在扩展这些研究，以评估N7 Env疫苗针对异源CCR5病毒挑战的保护作用。我们通过“素促进剂”方案对三组猪尾猕猴（n = 6/组）进行了免疫，包括用重组式牛ac病毒启动，并用重组蛋白促进。这些组中的两个用野生型或突变的N7 ENV疫苗免疫。另外一组动物接受了N7 Env和SIV GAG-POL疫苗。对照动物仅接受亲本疫苗病毒和佐剂。所有动物都会产生慢病毒特异性抗体反应，包括针对异源性病毒SF162的NAB，尽管比上述第一项研究中观察到的5至10倍。这促使我们进行了额外的助推器免疫。但是，未观察到NAB滴度的增加，这与响应幅度的概念一致，即反应的大小主要取决于原发免疫的有效性。在对SHIV162P4进行直肠内接种的挑战之后，所有对照和免疫动物都被感染，这与挑战当天的NAB滴度的低滴度一致。然而，用N7 Env免疫的动物显示出峰值病毒载量的显着降低，而接受N7 Env和SIV GAG-POL疫苗的动物显示了设定点病毒负荷的降低。这些结果表明，针对异源病毒的保护性免疫可以由Prime Boost免疫方案产生。该实验于2010年7月结束，其余动物转移到殖民地健康进行后续研究。