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Comparative neuropathogenesis and neurovirulence of attenuated flaviviruses in nonhuman primates

Olga A Maximova1, Jerrold M Ward, David M Asher

  • 1Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland 20852, USA.

Journal of Virology
|March 21, 2008
PubMed

Insights

The chimeric tick-borne encephalitis virus/dengue type 4 virus (TBEV/DEN4Delta30) showed higher neurovirulence in monkeys than other vaccines, suggesting it may not be sufficiently attenuated for human use. Further research is needed for safe flavivirus vaccine development.

Area of Science:

  • Virology
  • Vaccinology
  • Neuroscience

Background:

  • Live attenuated virus vaccines are crucial for preventing tick-borne encephalitis virus (TBEV) infections.
  • A chimeric TBEV/DEN4Delta30 virus showed promise as a TBEV vaccine candidate based on preclinical studies.
  • Evaluating neurovirulence in nonhuman primates is essential before human trials.

Purpose of the Study:

  • To compare the neuropathogenesis and neurovirulence of the chimeric TBEV/DEN4Delta30 virus, Langat virus (LGTV), and yellow fever 17D virus (YF 17D) in rhesus monkeys.
  • To assess the safety and attenuation of the TBEV/DEN4Delta30 vaccine candidate.

Main Methods:

  • Rhesus monkeys were inoculated intracerebrally with TBEV/DEN4Delta30, LGTV, or YF 17D.
  • Central nervous system (CNS) tissues were analyzed for virus replication, histopathology, and viral antigen distribution.
  • Spatiotemporal profiles of neuropathogenesis were compared among the three viruses.

Main Results:

  • TBEV/DEN4Delta30 and YF 17D exhibited similar CNS replication and histopathology patterns, concentrated in cerebral hemispheres.
  • LGTV showed a reverse neurovirulence profile, progressing from inoculation site towards the cerebellum and spinal cord.
  • All three viruses demonstrated neurotropism, but TBEV/DEN4Delta30 displayed higher neurovirulence in monkeys than LGTV or YF 17D.

Conclusions:

  • The chimeric TBEV/DEN4Delta30 virus exhibited higher neurovirulence in nonhuman primates than LGTV or YF 17D, indicating potentially insufficient attenuation.
  • Understanding the neuropathogenesis of attenuated flaviviruses is critical for designing safer vaccines.
  • Further modifications may be necessary to ensure the safety of the TBEV/DEN4Delta30 vaccine candidate for human use.

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