IMMUNOGENICITY OF REPLICATION-DEFICIENT RABIES VIRUS VECTORS IN NHPS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 全世界每年约有40,000至70,000人死于狂犬病，超过1,000万人在接触潜在感染动物后接受暴露后预防(PEP)。目前的暴露前或暴露后疫苗方案需要三到六次接种，因此，成本和遵从性问题极大地阻碍了当前狂犬病病毒(RV)疫苗的有效性。因此，新的轮状病毒疫苗将有助于应对这一全球健康问题。我们正在开发复制缺陷的基于轮状病毒的疫苗载体，它缺乏其五个必需基因中的一个，这些基因已经在小鼠模型中被证明是免疫原性和有效的。在这项研究中，我们在非人类灵长类动物模型中测试了一种基质(M)蛋白缺失的RV载体(SPBN-Delta M)。用活的SPBN-Delta M或灭活的人类二倍体细胞疫苗(HDCV)免疫恒河猴，五天后用同样的疫苗加强免疫。免疫后不同时间点采集免疫动物血液，测定诱导的抗轮状病毒抗体反应动力学。对照HDCV免疫的动物表现出温和的抗体反应，在第60天保持稳定，而SPBN-Delta M免疫的动物表现出更快和更强大的RV特异性抗体反应。值得注意的是，在第14天至60天期间的所有时间点，接种SPBN-Delta M的猴子的抗RV抗体效价显著高于接种HDCV的猴子。这一数据表明SPBN-Delta M能够建立快速而强大的抗轮状病毒免疫，可能优于目前获得许可的疫苗。计划在免疫后第180天从动物身上收集更多的样本，其他免疫学分析将用于进一步表征抗RV免疫反应，如病毒中和抗体和CD4+T辅助细胞增殖分析。进一步开发一种只需一到两剂疫苗而不是最多六剂疫苗的疫苗，有可能在发达国家和发展中国家挽救生命和降低成本。基于在小鼠和非人类灵长类动物身上获得的有希望的结果，我们向美国国立卫生研究院提交了一份为期5年的R01拨款申请，建议进一步测试SPBN-Delta M和其他复制缺陷载体。

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. Rabies kills approximately 40,000 to 70,000 people per year worldwide and over 10 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Current pre- or post-exposure vaccine regimens require three to six inoculations and therefore, cost and compliance issues have greatly hampered the effectiveness of current rabies virus (RV) vaccines. Therefore, new RV vaccines would help to combat this global health issue. We are developing replication-deficient RV-based vaccine vectors that lack one of its five essential genes, which have been shown to be immunogenic and effective in a mouse model. In this study, we test a matrix (M) protein-deleted RV vector (SPBN-delta M) in a non-human primate model. Rhesus macaques were immunized with either live SPBN-delta M or a killed human diploid cell vaccine (HDCV), followed by a boost with the same vaccine five days later. Blood was collected from the immunized animals at various time points post-immunization and the kinetics of the induced anti-RV antibody response was determined. Control HDCV-immunized animals showed modest antibody responses, which remained stable through day 60, whereas SPBN-delta M-immunized animals showed a more rapid and robust RV-specific antibody response. Of note, the anti-RV antibody titers were significantly greater from monkeys immunized with SPBN-delta M compared with those immunized with the HDCV at all time points tested between days 14 and 60. This data indicates that SPBN-delta M is able to mount rapid and robust anti-RV immunity and might be superior to the currently licensed vaccine. Additional samples are scheduled to be collected from the animals through day 180 post-immunization and other immunological assays will be used to further characterize the anti-RV immune response, such as virus neutralizing antibody and CD4+ T-helper proliferation assays. The further development of a vaccine that relies on only one to two doses rather than up to six inoculations has the potential to save lives and reduce costs in both developed and developing countries. Based on the promising results obtained in both mice and non-human primates, we have submitted a 5-year R01 grant application to the NIH that proposes to test SPBN-delta M and other replication-deficient vectors further.