ChimeriVax-JE is a live, attenuated recombinant virus prepared by replacing the genes encoding two structural
proteins (prM and E) of
yellow fever 17D virus with the corresponding genes of an attenuated strain of Japanese encephalitis virus (JE), SA14-14-2 (T. J. Chambers et al., J. Virol. 73:3095-3101, 1999). Since the prM and E
proteins contain
antigens conferring protective humoral and cellular immunity, the immune response to vaccination is directed principally at JE. The prM-E genome sequence of the
ChimeriVax-JE in diploid fetal rhesus lung cells (FRhL, a substrate acceptable for human
vaccines) was identical to that of JE SA14-14-2
vaccine and differed from sequences of virulent wild-type strains (SA14 and Nakayama) at six
amino acid residues in the envelope gene (E107, E138, E176, E279, E315, and E439).
ChimeriVax-JE was fully attenuated for weaned mice inoculated by the intracerebral (i.c.) route, whereas commercial
yellow fever 17D
vaccine (YF-Vax) caused lethal
encephalitis with a 50% lethal dose of 1.67 log(10) PFU. Groups of four rhesus monkeys were inoculated by the subcutaneous route with 2.0, 3.0, 4.0, and 5. 0 log(10) PFU of
ChimeriVax-JE. All 16 monkeys developed low
viremias (mean peak
viremia, 1.7 to 2.1 log(10) PFU/ml; mean duration, 1.8 to 2.3 days).
Neutralizing antibodies appeared between days 6 and 10; by day 30,
neutralizing antibody responses were similar across dose groups.
Neutralizing antibody titers to the homologous (
vaccine) strain were higher than to the heterologous wild-type JE strains. All immunized monkeys and
sham-immunized controls were challenged i.c. on day 54 with 5.2 log(10) PFU of wild-type JE. None of the immunized monkeys developed
viremia or illness and had mild residual brain lesions, whereas controls developed
viremia, clinical
encephalitis, and severe histopathologic lesions. Immunized monkeys developed significant (>/=4-fold) increases in serum and cerebrospinal fluid
neutralizing antibodies after i.c. challenge. In a standardized test for neurovirulence,
ChimeriVax-JE and YF-Vax were compared in groups of 10 monkeys inoculated i.c. and analyzed histopathologically on day 30. Lesion scores in brains and spinal cord were significantly higher for monkeys inoculated with YF-Vax.
ChimeriVax-JE meets preclinical safety and efficacy requirements for a human
vaccine; it appears safer than
yellow fever 17D
vaccine but has a similar profile of immunogenicity and protective efficacy.