IMMUNOGENICITY OF REPLICATION-DEFICIENT RABIES VIRUS VECTORS IN NHPS

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。 狂犬病每年在全世界造成约40，000至70，000人死亡，超过1000万人在接触可能受感染的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，成本和合规性问题极大地阻碍了目前狂犬病病毒（RV）疫苗的有效性。 因此，新的RV疫苗将有助于应对这一全球健康问题。 我们正在开发基于复制缺陷RV的疫苗载体，该载体缺乏其五个必需基因之一，这些基因已被证明在小鼠模型中具有免疫原性和有效性。 在本研究中，我们在非人灵长类动物模型中测试了基质（M）蛋白缺失的RV载体（SPBN-delta M）。 用活SPBN-δ M或杀死的人二倍体细胞疫苗（HDCV）免疫恒河猴，然后在5天后用相同的疫苗加强免疫。 在免疫后的不同时间点从免疫的动物收集血液，并测定诱导的抗RV抗体应答的动力学。 对照HDCV免疫的动物显示出适度的抗体应答，其在第60天保持稳定，而SPBN-δ M免疫的动物显示出更快速和稳健的RV特异性抗体应答。 值得注意的是，在第14天至第60天之间的所有测试时间点，用SPBN-δ M免疫的猴的抗RV抗体滴度显著高于用HDCV免疫的猴。该数据表明SPBN-δ M能够产生快速和强大的抗RV免疫，并且可能上级目前许可的疫苗。计划在免疫后第180天从动物中采集额外样本，并将使用其他免疫学试验进一步表征抗RV免疫应答，如病毒中和抗体和CD 4+辅助性T细胞增殖试验。进一步开发一种只需要一到两剂而不是多达六次接种的疫苗，有可能在发达国家和发展中国家挽救生命并降低成本。基于在小鼠和非人灵长类动物中获得的有希望的结果，我们已经向NIH提交了一份为期5年的R 01资助申请，该申请建议进一步测试SPBN-δ 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.