Immunogenicity, Genetic Stability, and Protective Efficacy of a Recombinant, Chimeric Yellow Fever-Japanese Encephalitis Virus (ChimeriVax-JE) as a Live, Attenuated Vaccine Candidate against Japanese Encephalitis

Abstract

Yellow fever (YF) 17D vaccine virus, having a 60-year history of safe and effective use, is an ideal vector to deliver heterologous genes from other medically important flaviviruses. A chimeric YF/Japanese encephalitis (JE) virus (ChimeriVax-JE virus) was constructed by insertion of the premembrane and envelope (prME) genes of an attenuated human vaccine strain (SA14-14-2) of Japanese encephalitis (JE) virus between core and nonstructural (NS) genes of a YF 17D infectious clone. The virus grew to high titers in cell cultures and was not neurovirulent for 3- to 4-week-old mice at doses </=6 log10 plaque forming units (pfu) inoculated by the intracerebral (IC) route. In contrast, commercial YF 17D vaccine was highly neurovirulent for weanling mice by the same route. Mice inoculated subcutaneously with one dose of >/=10(3) pfu of ChimeriVax-JE virus were solidly protected against intraperitoneal challenge with a virulent JE virus. Genetic stability of the chimera was assessed by sequential passages in cell cultures or in mouse brain. All attenuating residues and the avirulent phenotype were preserved after 18 passages in cell cultures or 6 passages in mouse brains.

Recombinant Chimeric Yellow Fever-Dengue Type 2 Virus Is Immunogenic and Protective in Nonhuman Primates

“…The PUO-218 virus differs from NGC virus in two amino acids in prM (residues 55 and 125, respectively L and I in PUO-218 instead of F and T in NGC) and six amino acids in the E protein (amino acid 71 is E in PUO-218 and D in NGC [71 E3D], 126 E3K, 141 V3I, 164 V3I, 402 F3I and 484 I3V) ( Table 2). In Table 3 nucleotide and amino acid differences within the nonstructural (NS) genes of ChimeriVax-D2, ChimeriVax-JE (9), and the parent YF 17D virus (22) are shown. There were six nucleotide differences between ChimeriVax-D2 and YF 17D.…”

Japanese Encephalitis Virus: Innate and Adaptive Immunity

“…Studies in mice and monkey models have shown that this chimeric vaccine was highly immunogenic and protects the animals against lethal JEV i.c. challenge (Monath et al, 2000;Guirakhoo et al, 1999;Monath et al, 1999). Phase I and II clinical trials of the vaccine have been carried out and it was found to be well tolerated and induced neutralizing antibodies in 100% of naïve and yellow fever virus immune participants.…”

When Japanese Encephalitis Virus Invaded Eastern Hemisphere – The History of the Spread of Virus Genotypes

“…Currently, three JEV vaccines are in use (Guirakhoo et al, 1999 ;Chang et al, 2000): (i) a formalin-inactivated, mouse brain-derived vaccine, based on the wild-type Nakayama or Beijing-1 strains, has been used internationally since the 1960s; (ii) a cell culture-derived inactivated vaccine; (iii) a cell culture-derived live attenuated vaccine, in China only. All vaccine types were developed from GIII JEV strains.…”