METHODS: We produced two NiV vaccine candidates using the licensed VSV-EBOV vaccine as a backbone and tested its efficacy against lethal homologous and heterologous NiV challenge with Nipah virus Bangladesh and Nipah virus Malaysia, respectively, in the African green monkey model.
FINDINGS: The VSV-EBOV vaccine expressing NiV glycoprotein G (VSV-NiVG) induced high neutralising antibody titers and afforded complete protection from homologous and heterologous challenge. The VSV-EBOV vaccine expressing NiV fusion protein F (VSV-NiVF) induced a lower humoral response and afforded complete homologous protection, but only partial heterologous protection. Both vaccines reduced virus shedding from the upper respiratory tract, and virus replication in the lungs and central nervous system. None of the protected animals vaccinated with VSV-NiVG or VSV-NiVF showed histological lesions in the CNS, but one VSV-NiVF-vaccinated animal that was not protected developed severe meningoencephalitis.
INTERPRETATION: The VSV-NiVG vaccine offers broad protection against NiV disease.
FUNDING: This study was supported by the Intramural Research Program, NIAID, NIH.
RESULTS: Mosquitoes were collected from a total of 15 sites using gravid traps and a backpack aspirator around Kampong Puruh Karu, Sarawak, Malaysian Borneo, where sylvatic DENV spillover has been documented. A total of 2447 mosquitoes comprising 10 genera and 4 species of Aedes, were collected over the three years, 2013, 2014 and 2016, in the three major land cover types in the area, homestead, agriculture and forest. Mosquitoes were identified morphologically, pooled by species and gender, homogenized, and subject to DNA barcoding of each Aedes species and to arbovirus screening. As predicted, Ae. niveus was found almost exclusively in forests whereas Ae. albopictus was collected in all land cover types. Aedes albopictus was significantly (P = 0.04) more abundant in agricultural fields than forests. Sylvatic DENV was not detected in any Aedes mosquito pools, however genomes of 14 viruses were detected using next generation sequencing.
CONCLUSIONS: Land cover type affects the abundance and distribution of the most likely bridge vectors of sylvatic DENV in Malaysia Borneo. Conversion of forests to agriculture will likely decrease the range and abundance of Ae. niveus but enhance the abundance of Ae. albopictus.
RESULTS: Cluster-wide C19MC miRNA expression profiling by microarray analysis showed wholesome C19MC activation in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, in multipotent adipose-derived mesenchymal stem cells (MSCs) and a unipotent human white pre-adipocyte cell line, only selected C19MC miRNAs were expressed. MiRNA copy number analysis also showed selective C19MC expression in cancer cells with expression patterns highly similar to those in MSCs, suggesting similar miRNA regulatory mechanisms in these cells. Selective miRNA expression also suggests complex transcriptional mechanism(s) regulating C19MC expression under specific cellular and pathological conditions. Bioinformatics analysis showed that sixteen of the C19MC miRNAs share the same "AAGUGC" seed sequence with members of the miR-302/-372 family, which are known cellular reprogramming factors. In particular, C19MC-AAGUGC-miRNAs with the nucleotides 2-7 canonical seed position as in miR-302/-372 miRNAs, may play similar roles as miR-302/-372 in induced pluripotency. A biased 3p-arm selection of the C19MC-AAGUGC-miRNAs was observed indicating that targets of the 3p species of these miRNAs may be biologically significant in regulating stemness. Furthermore, bioinformatics analysis of the putative targets of the C19MC-AAGUGC-miRNAs predicted significant involvement of signaling pathways in reprogramming, many of which contribute to promoting apoptosis by indirect activation of the pro-apoptotic proteins BAK/BAX via suppression of genes of the cell survival pathways, or by enhancing caspase-8 activation through targeting inhibitors of TRAIL-inducing apoptosis.
CONCLUSIONS: This work demonstrated selective C19MC expression in MSCs and cancer cells, and, through miRNA profiling and bioinformatics analysis, predicted C19MC modulation of apoptosis in induced pluripotency and tumorigenesis.