Chimeric West Nile/dengue virus vaccine candidate: preclinical evaluation in mice, geese and monkeys for safety and immunogenicity.
A live attenuated virus vaccine is being developed to protect against West Nile virus (WN) disease in humans. Previously, it was found that chimeric West Nile/dengue viruses (WN/DEN4 and WN/DEN4Delta30) bearing the membrane precursor and envelope protein genes of WN on a backbone of dengue type 4 virus (DEN4) with or without a deletion of 30 nucleotides (Delta30) in the 3' noncoding region of the DEN4 part of the chimeric genome were attenuated and efficacious in mice and monkeys against WN challenge. Here, we report the generation of a clinical lot of WN/DEN4Delta30 virus and its further preclinical evaluation for safety and immunogenicity in mice, geese and monkeys. The vaccine candidate had lost neuroinvasiveness in highly sensitive immunodeficient mice inoculated intraperitoneally and had greatly reduced neurovirulence in suckling mice inoculated intracerebrally (IC). Compared to the wild-type WN parent, the chimeric virus was highly restricted in replication in both murine and human neuroblastoma cells as well as in brains of suckling mice. The WN/DEN4Delta30 virus failed to infect geese, indicating that chimerization of WN with DEN4 completely attenuated WN for this avian host. This observation suggests that the WN/DEN4 chimeric viruses would be restricted in their ability to be transmitted from vaccinees to domestic or wild birds. In monkeys, the WN/DEN4Delta30 vaccine candidate was highly immunogenic despite its low level of replication with undetectable viremia. Furthermore, the WN/DEN4Delta30 vaccine virus was safe and readily induced neutralizing antibodies against WN in monkeys immune to each of the four serotypes of dengue virus. These studies confirm the attenuation of WN/DEN4Delta30 for non-human primates, including dengue-immune monkeys, and demonstrate both a highly restricted replication (>10(8)-fold decrease) in the brain of mice inoculated IC and an absence of infectivity for birds, findings that indicate this vaccine should be safe for both the recipient and the environment.
Pletnev
Alexander G
AG
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-8133, USA. apletnev@niaid.nih.gov
Swayne
David E
DE
Speicher
Jim
J
Rumyantsev
Alexander A
AA
Murphy
Brian R
BR
D000818:Animals; D001921:Brain / Q000821:virology; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D005777:Geese / Q000276:immunology* / Q000821:virology; D005818:Genetic Engineering; D006801:Humans; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology; D051379:Mice; D009474:Neurons / Q000821:virology; D014765:Viral Vaccines / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication; D014902:West Nile virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity
D014765:Viral Vaccines