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Comparative Neuropathogenesis and Neurovirulence of Attenuated Flaviviruses in Nonhuman Primates ^,

Olga A. Maximova,^1, Jerrold M. Ward,² David M. Asher,¹ Marisa St. Claire,^3, Brad W. Finneyfrock,³ James M. Speicher,⁴ Brian R. Murphy,⁴ and Alexander G. Pletnev^4*

Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland 20852,¹ Comparative Medicine Branch,² Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,⁴ Bioqual, Inc., Rockville, Maryland 20850³

Received 24 January 2008/ Accepted 11 March 2008

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 nonneuroinvasive 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 nonhuman primates needed to be evaluated. In the present study, we compared the neuropathogeneses 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 central nervous system (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 than 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.

Published ahead of print on 19 March 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

Present address: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Room 3W10A, MSC 3203, Bethesda, MD 20892-3203.

Present address: Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Room 2E19A, MSC 3201, Bethesda, MD 20892-3201.