Recombinant, chimaeric live, attenuated vaccine (ChimeriVax™) incorporating the envelope genes of Japanese encephalitis (SA14-14-2) virus and the capsid and nonstructural genes of yellow fever (17D) virus is safe, immunogenic and protective in non-human primates

• Published in: Vaccine Vol. 17; no. 15; pp. 1869 - 1882
• Main Authors: Monath, T.P, Soike, K, Levenbook, I, Zhang, Z.-X, Arroyo, J, Delagrave, S, Myers, G, Barrett, A.D.T, Shope, R.E, Ratterree, M, Chambers, T.J, Guirakhoo, F
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 09.04.1999; Elsevier
• Subjects: Animals; Biological and medical sciences; Capsid - genetics; Capsid - immunology; Cell Line; Central Nervous System - pathology; Central Nervous System - virology; Dose-Response Relationship, Immunologic; Drug Evaluation, Preclinical; Encephalitis Virus, Japanese - genetics; Encephalitis Virus, Japanese - growth & development; Encephalitis Virus, Japanese - immunology; Encephalitis, Japanese - pathology; Encephalitis, Japanese - prevention & control; Encephalitis, Japanese - virology; Fundamental and applied biological sciences. Psychology; Macaca mulatta; Microbiology; Neutralization Tests; Sequence Analysis, DNA; Vaccination; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - immunology; Viral Proteins - genetics; Viral Proteins - immunology; Viral Vaccines - administration & dosage; Viral Vaccines - genetics; Viral Vaccines - immunology; Viremia - virology; Virology; Yellow fever virus - genetics; Yellow fever virus - growth & development; Yellow fever virus - immunology; Immunoprotection; Toxicity; Recombinant virus; Monkey; Central nervous system; Macaca mulatta; Vaccine; Flavivirus; Protein; Virus; Vertebrata; Mammalia; Histopathology; Immunogenicity; Primates; Simioidea; Japanese encephalitis virus; Japanese encephalitis group virus; Flaviviridae; Attenuated strain; Yellow fever group virus; Virus envelope; Yellow fever virus
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/S0264-410X(98)00487-3

Yellow fever 17D virus, a safe and effective live, attenuated vaccine, was used as a vector for genes encoding the protective antigenic determinants of a heterologous member of the genus Flavivirus, Japanese encephalitis (JE) virus, the leading cause of acute viral central nervous system infection and death throughout Asia. The viral envelope (prM and E) genes of a full-length cDNA clone of YF 17D virus were replaced with the corresponding genes of JE SA14-14-2, a strain licensed as a live, attenuated vaccine in China. Full-length RNA transcripts of the YF/JE chimaera were used to transfect Vero cells. The progeny virus (named `ChimeriVax™-JE'), was used to define safety after intracerebral (IC) inoculation of rhesus monkeys. Monkeys ( N=3) inoculated with a high dose (6.6 log 10 pfu) developed a brief viremia, showed no signs of illness, developed high titers of anti-JE neutralizing antibody, and had minimal brain and spinal cord lesion scores according to criteria specified in the WHO monkey neurovirulence test. A control group of 3 monkeys that received a lower dose (4.2 log 10 pfu) of commercial YF 17D vaccine had slightly higher lesion scores. To develop a lethal monkey model of JE for vaccine protection tests, we inoculated groups of monkeys IC or intranasally (IN) with a JE virus strain found to be highly neurovirulent and neuroinvasive for mice. Monkeys inoculated IC, but not IN, developed severe encephalitis after an incubation period of 8–13 days. The ChimeriVax™-JE virus was passed in a cell line acceptable for human use (diploid fetal rhesus lung) and 4.3 or 5.3 log 10 pfu were inoculated into groups of 3 monkeys by the subcutaneous route. All 6 animals developed brief viremias (peak titer<2.0 log 10 pfu/ml) and subsequently had anti-JE but no yellow fever neutralizing antibodies. On day 64, the monkeys were challenged IC with 5.5 log 10 pfu of virulent JE virus. The immunized animals had no detectable viremia post-challenge, whereas 4 unimmunized controls became viremic. Only 1 of 6 (17%) vaccinated monkeys but 4 of 4 (100%) unvaccinated controls developed encephalitis. Histopathological examination 30 days after challenge confirmed that the protected, immunized animals had no or minimal evidence of encephalitis. These data demonstrated the ability of the ChimeriVax™-JE to induce a rapid humoral immune response and to protect against a very severe, direct intracerebral virus challenge. Target areas of neuronal damage and inflammation in monkeys infected IC with wild-type JE, the chimaeric virus and YF 17D were similar, indicating that the histopathological scoring system used for the WHO yellow fever monkey neurovirulence test will be applicable to control testing of chimaeric seed viruses and vaccines.