Current requirements for control of live
viral vaccines, including
yellow fever 17D, produced from potentially neurotropic wild-type viruses include tests for neurovirulence in nonhuman primates. We have used
yellow fever 17D virus as a live vector for novel flavivirus
vaccines (designated
ChimeriVax) against
dengue,
Japanese encephalitis (JE), and West Nile (WN) viruses. For control of these
vaccines, it would be preferable to substitute a test in mice for the test in a higher species (monkeys). In this study, we compare the neurovirulence of
ChimeriVax vaccine candidates in suckling mice inoculated by the intracerebral (IC) route with graded doses of the test article or
yellow fever 17D
vaccine as a reference control. Mortality ratio and survival distribution are the outcome measures. The monkey safety test is performed as described for control of
yellow fever vaccines. In both mice and monkeys, all chimeric
vaccines were significantly less neurovirulent than
yellow fever 17D
vaccine. The test in suckling mice discriminated between strains of two different
vaccines (ChimeriVax-JE and ChimeriVax-DEN1) differing by a single
amino acid change, and was more sensitive for detecting virulence differences than the test in monkeys. The results indicate that the suckling mouse test is simple to perform, highly sensitive and, with appropriate validation, could
complement or possibly even replace the neurovirulence component of the monkey safety test. The test in infant mice is particularly useful as a means of demonstrating
biological consistency across seed virus and
vaccine lots.