title: A Novel Synthetic TLR-4 Agonist Adjuvant Increases the Protective Response to a Clinical-Stage West Nile Virus Vaccine Antigen in Multiple Formulations.
abstract: West Nile virus (WNV) is a mosquito-transmitted member of the Flaviviridae family that has emerged in recent years to become a serious public health threat. Given the sporadic nature of WNV epidemics both temporally and geographically, there is an urgent need for a vaccine that can rapidly provide effective immunity. Protection from WNV infection is correlated with antibodies to the viral envelope (E) protein, which encodes receptor binding and fusion functions. Despite many promising E-protein vaccine candidates, there are currently none licensed for use in humans. This study investigates the ability to improve the immunogenicity and protective capacity of a promising clinical-stage WNV recombinant E-protein vaccine (WN-80E) by combining it with a novel synthetic TLR-4 agonist adjuvant. Using the murine model of WNV disease, we find that inclusion of a TLR-4 agonist in either a stable oil-in-water emulsion (SE) or aluminum hydroxide (Alum) formulation provides both dose and dosage sparing functions, whereby protection can be induced after a single immunization containing only 100 ng of WN-80E. Additionally, we find that inclusion of adjuvant with a single immunization reduced viral titers in sera to levels undetectable by viral plaque assay. The enhanced protection provided by adjuvanted immunization correlated with induction of a Th1 T-cell response and the resultant shaping of the IgG response. These findings suggest that inclusion of a next generation adjuvant may greatly enhance the protective capacity of WNV recombinant subunit vaccines, and establish a baseline for future development.
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Neal
authors.initials: N
authors.lastname: Van Hoeven
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Sharvari Waghmare
authors.initials: SW
authors.lastname: Joshi
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Ghislain Ismael
authors.initials: GI
authors.lastname: Nana
authors.affiliation: Colorado State University Department of Biomedical Sciences, Foothills Campus, Fort Collins, CO 80523, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Bosco-Lauth
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fox
authors.affiliation: Colorado State University Department of Biomedical Sciences, Foothills Campus, Fort Collins, CO 80523, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bowen
authors.affiliation: Hawaii Biotech Inc. 99-193 Aiea Heights Drive, Aiea, Hawaii 96701, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Clements
authors.affiliation: Hawaii Biotech Inc. 99-193 Aiea Heights Drive, Aiea, Hawaii 96701, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Martyak
authors.affiliation: Hawaii Biotech Inc. 99-193 Aiea Heights Drive, Aiea, Hawaii 96701, United States of America.
authors.forename: D Elliot
authors.initials: DE
authors.lastname: Parks
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Baldwin
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Ave E., Seattle, WA 98103, United States of America.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D051379:Mice; D018417:Th1 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology / Q000494:pharmacology*; D014901:West Nile Fever / Q000276:immunology / Q000517:prevention & control*; D053060:West Nile Virus Vaccines / Q000276:immunology / Q000494:pharmacology*; D014902:West Nile virus / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000956:Antigens, Viral; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014759:Viral Envelope Proteins; D053060:West Nile Virus Vaccines; C065696:glycoprotein E, Flavivirus