title: Assurance of neuroattenuation of a live vaccine against West Nile virus: a comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4Δ30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine.
abstract: The upsurge of West Nile virus (WNV) human infections in 2012 suggests that the US can expect periodic WNV outbreaks in the future. Availability of safe and effective vaccines against WNV in endemic areas, particularly for aging populations that are at high risk of West Nile neuroinvasive disease (WNND), could be beneficial. WN/DEN4Δ30 is a live, attenuated chimeric vaccine against WNV produced by replacement of the genes encoding the pre-membrane and envelope protein genes of the vaccine virus against dengue virus type 4 (DEN4Δ30) with corresponding sequences derived from a wild type WNV. Following intrathalamic inoculation of nonhuman primates (NHPs), a comprehensive neuropathogenesis study was performed and neurovirulence of WN/DEN4Δ30 vaccine candidate was compared to that of two parental viruses (i.e., WNV and DEN4Δ30), as well as to that of an attenuated flavivirus surrogate reference (i.e., yellow fever YF 17D). Clinical and virological data, as well as results of a semi-quantitative histopathological analysis, demonstrated that WN/DEN4Δ30 vaccine is highly attenuated for the central nervous system (CNS) of NHPs in comparison to a wild type WNV. Importantly, based on the virus replicative ability in the CNS of NHPs and the degree of induced histopathological changes, the level of neuroattenuation of WN/DEN4Δ30 vaccine was similar to that of YF 17D, and therefore within an acceptable range. In addition, we show that the DEN4Δ30 vaccine tested in this study also has a low neurovirulence profile. In summary, our results demonstrate a high level of neuroattenuation of two vaccine candidates, WN/DEN4Δ30 and DEN4Δ30. We also show here a remarkable sensitivity of our WNV-NY99 NHP model, as well as striking resemblance of the observed neuropathology to that seen in human WNND. These results support the use of this NHP model for translational studies of WNV neuropathogenesis and/or testing the effectiveness of vaccines and therapeutic approaches.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: maximovao@niaid.nih.gov.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Maximova
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: James M
authors.initials: JM
authors.lastname: Speicher
authors.affiliation: Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Skinner
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Murphy
authors.affiliation: Office of the Chief Scientist, Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Marisa C
authors.initials: MC
authors.lastname: St Claire
authors.affiliation: Office of the Chief Scientist, Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Danny R
authors.initials: DR
authors.lastname: Ragland
authors.affiliation: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Herbert
authors.affiliation: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Pare
authors.affiliation: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Rashida M
authors.initials: RM
authors.lastname: Moore
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: apletnev@niaid.nih.gov.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Pletnev
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D002490:Central Nervous System / Q000473:pathology / Q000821:virology*; D008253:Macaca mulatta; D014613:Vaccines, Attenuated / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D014766:Viremia / Q000473:pathology; D014779:Virus Replication; D014901:West Nile Fever / Q000473:pathology* / Q000517:prevention & control; D014902:West Nile virus / Q000472:pathogenicity / Q000502:physiology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines
keywords: Live attenuated WNV vaccine; Neuropathogenesis; Neurovirulence; Nonhuman primates; West Nile virus (WNV)
references.citation: Science. 2012 Aug 31;337(6098):1030
references.pmid: 22936749
references.citation: Virology. 2006 Nov 10;355(1):44-51
references.pmid: 16904151
references.citation: Antiviral Res. 2013 Jul;99(1):1-5
references.pmid: 23624155
references.citation: Science. 1999 Dec 17;286(5448):2333-7
references.pmid: 10600742
references.citation: Hum Pathol. 2004 Aug;35(8):983-90
references.pmid: 15297965
references.citation: J Infect Dis. 2011 May 15;203(10):1396-404
references.pmid: 21398392
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6694-9
references.pmid: 16617103
references.citation: Curr Infect Dis Rep. 2011 Aug;13(4):350-9
references.pmid: 21544522
references.citation: Nat Clin Pract Neurol. 2006 May;2(5):264-75
references.pmid: 16932563
references.citation: Epidemiol Infect. 2013 Mar;141(3):591-5
references.pmid: 22640592
references.citation: Arch Virol. 1983;75(1-2):71-86
references.pmid: 6299247
references.citation: Emerg Infect Dis. 2006 Mar;12(3):375-80
references.pmid: 16704772
references.citation: Proc Soc Exp Biol Med. 1951 Aug;77(4):661-5
references.pmid: 14891830
references.citation: Vaccine. 2013 Nov 19;31(48):5772-7
references.pmid: 23968769
references.citation: MMWR Morb Mortal Wkly Rep. 2012 Jul 13;61(27):510-4
references.pmid: 22785342
references.citation: Clin Microbiol Rev. 2012 Oct;25(4):635-48
references.pmid: 23034323
references.citation: Am J Epidemiol. 1967 May;85(3):503-17
references.pmid: 4290525
references.citation: Curr Opin Investig Drugs. 2010 Feb;11(2):139-46
references.pmid: 20112163
references.citation: J Infect Dis. 2011 Jan 1;203(1):75-84
references.pmid: 21148499
references.citation: J Neuropathol Exp Neurol. 1956 Oct;15(4):448-60
references.pmid: 13367865
references.citation: Emerg Infect Dis. 2003 Nov;9(11):1388-94
references.pmid: 14718080
references.citation: Immunotherapy. 2011 Feb;3(2):269-85
references.pmid: 21322763
references.citation: J Virol. 2008 Jun;82(11):5255-68
references.pmid: 18353947
references.citation: Vet Pathol. 2010 Sep;47(5):806-18
references.pmid: 20551474
references.citation: J Virol. 2004 Nov;78(22):12497-507
references.pmid: 15507637
references.citation: Clin Vaccine Immunol. 2009 Sep;16(9):1332-7
references.pmid: 19641099
references.citation: J Histochem Cytochem. 2009 Oct;57(10):973-89
references.pmid: 19581627
references.citation: Ann Neurol. 2006 Sep;60(3):286-300
references.pmid: 16983682
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3036-41
references.pmid: 11880643
references.citation: Virology. 2003 Sep 15;314(1):190-5
references.pmid: 14517072
references.citation: Am J Trop Med Hyg. 2001 Nov;65(5):405-13
references.pmid: 11716091
references.citation: Antioxid Redox Signal. 2011 Jan 15;14(2):261-73
references.pmid: 20524846
references.citation: Vaccine. 2006 Sep 29;24(40-41):6392-404
references.pmid: 16831498
references.citation: ILAR J. 2008;49(2):220-55
references.pmid: 18323583
references.citation: J Neuropathol Exp Neurol. 2009 Oct;68(10):1053-60
references.pmid: 19918117
references.citation: MMWR Surveill Summ. 2010 Apr 2;59(2):1-17
references.pmid: 20360671
references.citation: J Infect Dis. 2004 Feb 15;189(4):669-76
references.pmid: 14767821
references.citation: PLoS One. 2010 Dec 02;5(12):e15514
references.pmid: 21151986
references.citation: Vet Res. 2012 Mar 01;43:16
references.pmid: 22380523
references.citation: Vaccine. 2012 Oct 19;30(47):6656-64
references.pmid: 22959989
references.citation: Vector Borne Zoonotic Dis. 2005 Spring;5(1):1-10
references.pmid: 15815144
references.citation: N Engl J Med. 2012 Oct 4;367(14):1281-4
references.pmid: 23013055
references.citation: J Infect Dis. 2007 Dec 15;196(12):1732-40
references.pmid: 18190252