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 N55 (NS5(654 655)) proteins, and into the 3' non-coding region (Delta 30) of TBEV/DEN4. The variant that contained all three mutations (v Delta 30/E-315/N5(654.655)) was significantly attenuated for neuroinvasiveness and neurovirtilence 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 v Delta 30/E-315/NS5(654 655) should be further evaluated as a TBEV vaccine Published by Elsevier Inc