VACCINE DEVELOPMENT FOR ALPHAVIRUSES

这个子项目是利用这些资源的众多研究子项目之一

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. Chikungunya (CHIK) is a vectorborne viral disease caused by chikungunya virus, a pathogenic alphavirus. Initially we recapitulated the viral disease in an experimental nonhuman primate model (M. fascicularis) (n=3). This morbidity model emulated the clinical syndrome and showed the hallmarks of natural disease noted in human infections. The model was established to provide an advanced monitoring system for testing the efficacy of candidate vaccines developed against CHIK. The CHIK vaccines under development are based upon constructs containing a picornavirus internal ribosomal entry site (IRES) to replace the subgenomic promoter for expression of the CHIK virus (CHIKV) structural proteins. This approach highly attenuates the virus and prevents mosquito infection, but preserves immunogenicity. The CHIK nonhuman primate model was used to test two versions of the vaccine (CHIK/IRESv1, v2) in separate experiments. Animals were implanted with remote radiotelemetry for continuous monitoring of clinical signs (core temperature, respiratory rate, heart rate, ECG) and samples were taken for viremia, antibody, and viremia assays following vaccination and after challenge. Groups of four animals (N=16) prime vaccinated with a single dose of 5.5^log by either the subcutaneous (SQ; CHIK/IRESv1) or intradermal (ID; CHIK/IRESv2) route, or sham vaccinated with saline. Approximately 45 days postvaccination, all animals were challenged SQ with 6.0log of wild-type CHIKV. The highest neutralizing antibody titers were generated by the CHIK/IRESv2 vaccine group, with slightly lower mean titers by CHIK/IRESv1 (ID) and CHIK/IRESv1 (SQ) groups. Little or no virema was noted after vaccination, and clinical response after vaccination as measured by implantable telemetry was unremarkable. Upon challenge with WT CHIKV, no vaccinated animals developed viremia, elevation in core temperature, or any other clinical hallmarks indicative of CHIK disease up to +45 days postinfection. In contrast, sham-vaccinated controls developed viremia acutely (+1-3d PI) and showed dramatic changes in core temperature, heart rate, and electrocardiogram measurements. The CHIK/IRES vaccine candidates are safe, highly immunogenic, and protect nonhuman primates from a robust experimental challenge model using WT CHIKV. Refinements in vaccine dose, as well as route of vaccination may be explored to evaluate the long term immunity associated with this vaccine product.