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J. Virol. doi:10.1128/JVI.00172-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Comparative neuropathogenesis and neurovirulence of attenuated flaviviruses in non-human primates

Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland 20852; Comparative Medicine Branch, and Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; Bioqual, Inc., Rockville, Maryland 20850

^* To whom correspondence should be addressed. Email: apletnev{at}niaid.nih.gov.

	Abstract

Based on previous preclinical evaluation in mice and monkeys, the chimeric TBEV/DEN430 virus, carrying the prM and E protein genes from a highly virulent Far Eastern strain of tick-borne encephalitis virus (TBEV) on the backbone of a non-neuroinvasive dengue type 4 virus (DEN4), has been identified as a promising live attenuated virus vaccine candidate against disease caused by TBEV. However, prior to use of this vaccine candidate in humans, its neurovirulence in non-human primates needed to be evaluated. In the present study, we compared the neuropathogenesis of the chimeric TBEV/DEN430 virus, Langat virus (LGTV), a former live TBEV vaccine, and yellow fever 17D virus vaccine (YF 17D) in rhesus monkeys inoculated intracerebrally. TBEV/DEN430 and YF 17D demonstrated remarkably similar spatiotemporal profiles of virus replication and virus-associated histopathology in the CNS that were high in cerebral hemispheres but progressively decreased toward the spinal cord. In contrast, the neurovirulence of LGTV exhibited the reverse profile progressing from the site of inoculation toward the cerebellum and spinal cord. Analysis of the spatiotemporal distribution of viral antigens in the CNS of monkeys revealed a prominent neurotropism associated with all three attenuated viruses. Nevertheless, TBEV/DEN430 virus exhibited higher neurovirulence in monkeys compared to either LGTV or YF 17D, suggesting insufficient attenuation. These results provide insight into the neuropathogenesis associated with attenuated flaviviruses that may guide the design of safe vaccines.