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。 我们之前表明，用 N7 Env（去除了氨基酸残基 197 处的 N 连接聚糖）对猪尾猕猴进行免疫，不仅可以增强针对同源病毒 89.6 的中和抗体（NAb）反应，还可以增强针对 HIV 的中和抗体（NAb）反应。 -1 SF162 和 B 亚型初级分离株的标准组。在本研究中，我们旨在扩展这些研究，以评估 N7 Env 疫苗针对异源 CCR5 病毒攻击的保护功效。我们用“初免-加强”方案对三组猪尾猕猴（N=6/组）进行了免疫，其中包括用重组牛痘病毒初免和用重组蛋白加强。其中两组使用野生型或突变型 N7 Env 疫苗进行免疫。另外一组动物接种了 N7 Env 和 SIV Gag-Pol 疫苗。对照动物仅接受亲本痘苗病毒和佐剂。所有动物均产生慢病毒特异性抗体反应，包括针对异源病毒 SF162 的 NAb，尽管比我们在上述第一项研究中观察到的低 5 至 10 倍。这促使我们进行额外的加强免疫接种。然而，没有观察到 NAb 滴度增加，这与反应程度主要由初次免疫的有效性决定的观点一致。在直肠内接种 SHIV162P4 攻击后，所有对照和免疫动物均被感染，这与攻击当天的低滴度 Nab 滴度一致。然而，用 N7 Env 免疫的动物表现出峰值病毒载量显着降低，而同时接受 N7 Env 和 SIV Gag-Pol 疫苗的动物则表现出设定点病毒载量降低。这些结果表明针对异源病毒的保护性免疫可以通过初免加强免疫方案产生。该实验于 2010 年 7 月结束，其余动物转移至 Colony Health 进行后续研究。