The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3' non-coding region of the genome.
Tick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia. Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV). The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E(315)) and NS5 (NS5(654,655)) proteins, and into the 3' non-coding region (Delta30) of TBEV/DEN4. The variant that contained all three mutations (vDelta30/E(315)/NS5(654,655)) was significantly attenuated for neuroinvasiveness and neurovirulence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice. The high level of safety in the central nervous system indicates that vDelta30/E(315)/NS5(654,655) should be further evaluated as a TBEV vaccine.
Engel
Amber R
AR
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. engelam@mail.nih.gov
Rumyantsev
Alexander A
AA
Maximova
Olga A
OA
Speicher
James M
JM
Heiss
Brian
B
Murphy
Brian R
BR
Pletnev
Alexander G
AG
D020413:3' Untranslated Regions; D000818:Animals; D000833:Animals, Suckling; D001921:Brain; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000235:genetics* / Q000472:pathogenicity; D004669:Encephalitis Viruses, Tick-Borne / Q000235:genetics* / Q000472:pathogenicity; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D016679:Genome, Viral; D051379:Mice; D009154:Mutation; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity*; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication
D020413:3' Untranslated Regions; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins