Chimeric yellow fever virus 17D-Japanese encephalitis virus vaccine: Dose-response effectiveness and extended safety testing in rhesus monkeys

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 enc ephalitis virus (JE), SA14-14-2 (T. J. Chambers et at, J. Virol, 73:3095-31 01, 1999). Since the prM and E proteins contain antigens conferring protect ive humoral and cellular immunity, the immune response to vaccination is di rected principally at JE. The prM-E genome sequence of the ChimeriVax-JE in diploid fetal rhesus lung cells (FRhL, a substrate acceptable for human va ccines) was identical to that of JE SA14-14-2 vaccine and differed from seq uences of virulent wild-type strains (SA14 and Nakayama) at six amino acid residues in the envelope gene (E107, E138, E176, E279, E315, and E439). Chi meriVax-JE was fully attenuated for weaned mice inoculated by the intracere bral (i.c.) route, whereas commercial yellow fever 17D vaccine (YF-Vax) cau sed 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 lo w 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. Ne utralizing antibody titers to the homologous (vaccine) strain were higher t han to the heterologous wild-type JE strains. All immunized monkeys and sha m-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 a nd had mild residual brain lesions, whereas controls developed viremia, cli nical encephalitis, and severe histopathologic lesions. Immunized monkeys d eveloped significant (greater than or equal to 4-fold) increases in serum a nd cerebrospinal fluid neutralizing antibodies after i.c. challenge. In a s tandardized test for neurovirulence, ChimeriVax-JE and YF-Vax mere compared in groups of 10 monkeys inoculated i.c. and analyzed histopathologically o n 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 protecti ve efficacy.