The upsurge of West Nile virus (WNV) human infections in 2012 suggests that the US
can expect periodic WNV outbreaks in the future. Availability of safe and effective
vaccines against WNV in endemic areas, particularly for aging populations that are
at high risk of West Nile neuroinvasive disease (WNND), could be beneficial. WN/DEN4Δ30
is a live, attenuated chimeric vaccine against WNV produced by replacement of the
genes encoding the pre-membrane and envelope protein genes of the vaccine virus against
dengue virus type 4 (DEN4Δ30) with corresponding sequences derived from a wild type
WNV. Following intrathalamic inoculation of nonhuman primates (NHPs), a comprehensive
neuropathogenesis study was performed and neurovirulence of WN/DEN4Δ30 vaccine candidate
was compared to that of two parental viruses (i.e., WNV and DEN4Δ30), as well as to
that of an attenuated flavivirus surrogate reference (i.e., yellow fever YF 17D).
Clinical and virological data, as well as results of a semi-quantitative histopathological
analysis, demonstrated that WN/DEN4Δ30 vaccine is highly attenuated for the central
nervous system (CNS) of NHPs in comparison to a wild type WNV. Importantly, based
on the virus replicative ability in the CNS of NHPs and the degree of induced histopathological
changes, the level of neuroattenuation of WN/DEN4Δ30 vaccine was similar to that of
YF 17D, and therefore within an acceptable range. In addition, we show that the DEN4Δ30
vaccine tested in this study also has a low neurovirulence profile. In summary, our
results demonstrate a high level of neuroattenuation of two vaccine candidates, WN/DEN4Δ30
and DEN4Δ30. We also show here a remarkable sensitivity of our WNV-NY99 NHP model,
as well as striking resemblance of the observed neuropathology to that seen in human
WNND. These results support the use of this NHP model for translational studies of
WNV neuropathogenesis and/or testing the effectiveness of vaccines and therapeutic
approaches.