Monath TP, Levenbook I, Soike K, Zhang ZX, Ratterree M, Draper K,
           Barrett AD, Nichols R, Weltzin R, Arroyo J, Guirakhoo F
           OraVax Inc., Cambridge, Massachusetts 02139, USA. [email protected]
           J Virol 2000 Feb;74(4):1742-51

        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.