IMMUNOGENICITY OF REPLICATION-DEFICIENT RABIES VIRUS VECTORS IN NHPS

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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.