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

• Published in: Virology (New York, N.Y.) N.Y.), 2010-09, Vol.405 (1), p.243-252
• Main Authors: Engel, Amber R, Rumyantsev, Alexander A, Maximova, Olga A, Speicher, James M, Heiss, Brian, Murphy, Brian R, Pletnev, Alexander G
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; 60 APPLIED LIFE SCIENCES; ANIMALS; Animals, Suckling; ARACHNIDS; ARTHROPODS; Brain; Cercopithecus aethiops; Dengue virus; Dengue Virus - genetics; Dengue Virus - pathogenicity; DISEASES; ENCEPHALITIS; Encephalitis Viruses, Tick-Borne - genetics; Encephalitis Viruses, Tick-Borne - pathogenicity; Flavivirus; Gene Expression Regulation, Viral - physiology; GENES; Genome, Viral; Infectious Disease; INVERTEBRATES; Live attenuated vaccine; MAMMALS; MICE; MICROORGANISMS; MONKEYS; Mutation; MUTATIONS; NERVOUS SYSTEM DISEASES; Neurovirulence; ORGANIC COMPOUNDS; PARASITES; PRIMATES; PROTEINS; RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; Reassortant Viruses - genetics; Reassortant Viruses - pathogenicity; RODENTS; Tick-borne encephalitis virus; TICKS; VACCINES; Vero Cells; VERTEBRATES; Viral Envelope Proteins - genetics; Viral Envelope Proteins - metabolism; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virulence; Virus Replication; VIRUSES
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2010.06.014

Abstract 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 (E315 ) and NS5 (NS5654,655 ) proteins, and into the 3′ non-coding region (Δ30) of TBEV/DEN4. The variant that contained all three mutations (vΔ30/E315 /NS5654,655 ) 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 vΔ30/E315 /NS5654,655 should be further evaluated as a TBEV vaccine.