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J Virol 2008 Jun;82(11):5255-68

Comparative neuropathogenesis and neurovirulence of attenuated flaviviruses in nonhuman primates.

Maximova OA, Ward JM, Asher DM, St Claire M, Finneyfrock BW, Speicher JM, Murphy BR, Pletnev AG

Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, 33 N Dr,Room 3W10A,MSC 3203, Bethesda, MD 20892 USA NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA Bioqual Inc, Rockville, MD 20850 USA


Based on previous preclinical evaluation in mice and monkeys, the chimeric TBEV/DEN4Delta30 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/DEN4Delta30 virus, Langat virus (LGTV), a former live TBEV vaccine, and yellow fever 17D virus vaccine (YF 17D) in rhesus monkeys inoculated intracerebrally. TBEV/DEN4Delta30 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/DEN4Delta30 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.

Category: Journal Article
PubMed ID: #18353947
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29