A Novel Synthetic TLR-4 Agonist Adjuvant Increases the Protective Response to a Clinical-Stage West Nile Virus Vaccine Antigen in Multiple Formulations.

Neal Van Hoeven,Rhea N Coler,Angela Bosco-Lauth,David E Clements,Ghislain Ismael Nana,Steven G Reed,Sharvari Waghmare Joshi,Susan Baldwin,Richard A Bowen,Christopher Fox,D Elliot Parks,Timothy Martyak,Matthias Johannes Schnell

doi:10.1371/journal.pone.0149610

Neal Van Hoeven, Rhea N Coler + Show 11 more

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https://doi.org/10.1371/journal.pone.0149610

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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.

Highlights

West Nile virus (WNV) is a mosquito-borne member of the family Flaviviridae that has emerged in recent years to become a serious public health threat
We evaluated the ability of the TLR4 agonist adjuvant synthetic lipid A (SLA) formulated in a stable oil-in-water emulsion (SE) to enhance the immune response and enable antigen dose-sparing when combined with WN-80E
Following a single injection of WN-80E adjuvanted with alum, SE or synthetic lipid-A (SLA) agonist combined with SE (SLA-SE), we examined both cellular and humoral WN80E specific immune responses

Summary

Introduction

West Nile virus (WNV) is a mosquito-borne member of the family Flaviviridae that has emerged in recent years to become a serious public health threat. West Nile Virus was first identified in North America in the United States in 1999, and has since spread into Canada [1], Mexico [2], as well as central and South America [3]. Following introduction into North America, the number of WNV cases increased steadily as the virus spread geographically; in 2003, almost 10,000 cases were reported in the US, resulting in 264 deaths [4]. During the 2012 reporting season, the United States reported the second highest number of WNV infections since the outbreak began, with 5674 total cases reported, compared to only 712 cases in 2011 [6]. Serious complications from WNV infection, which result from spread of the virus into the central nervous system (CNS), include meningitis, paralysis, and eventually death (Reviewed in [7, 8]). The continued geographic spread and consistent seasonal outbreaks of WNV highlight the need for development of effective vaccines

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