A combination of TLR-4 agonist and saponin adjuvants increases antibody diversity and protective efficacy of a recombinant West Nile Virus antigen

Scott Winram,Sean Gray,David E Clements,Steven G Reed,Rhea N Coler,D Elliot Parks,Neal Van Hoeven,Andrew Fiore-Gartland,Brian Granger,Christopher Fox,Dan T Stinchcomb,Steven Wiley,Emily Gage

doi:10.1038/s41541-018-0077-1

Abstract

Members of the Flaviviridae family are the leading causes of mosquito-borne viral disease worldwide. While dengue virus is the most prevalent, the recent Zika virus outbreak in the Americas triggered a WHO public health emergency, and yellow fever and West Nile viruses (WNV) continue to cause regional epidemics. Given the sporadic nature of flaviviral epidemics both temporally and geographically, there is an urgent need for vaccines that can rapidly provide effective immunity. Protection from flaviviral infection is correlated with antibodies to the viral envelope (E) protein, which encodes receptor binding and fusion functions. TLR agonist adjuvants represent a promising tool to enhance the protective capacity of flavivirus vaccines through dose and dosage reduction and broadening of antiviral antibody responses. This study investigates the ability to improve the immunogenicity and protective capacity of a promising clinical-stage WNV recombinant E-protein vaccine (WN-80E) using a novel combination adjuvant, which contains a potent TLR-4 agonist and the saponin QS21 in a liposomal formulation (SLA-LSQ). Here, we show that, in combination with WN-80E, optimized SLA-LSQ is capable of inducing long-lasting immune responses in preclinical models that provide sterilizing protection from WNV challenge, reducing viral titers following WNV challenge to undetectable levels in Syrian hamsters. We have investigated potential mechanisms of action by examining the antibody repertoire generated post-immunization. SLA-LSQ induced a more diverse antibody response to WNV recombinant E-protein antigen than less protective adjuvants. Collectively, these studies identify an adjuvant formulation that enhances the protective capacity of recombinant flavivirus vaccines.

Highlights

Members of the Flaviviridae family of arboviruses cause significant morbidity and mortality throughout the world
We investigated the ability of the synthetic Toll-Like receptors (TLR)-4 agonist synthetic lipid A (SLA) to enhance immunogenicity of a recombinant West Nile Virus (WNV) E protein antigen (WN-80E), and found that SLA induced potent antiviral immunity when formulated with aluminum-oxyhydroxcapsid (C) protein and the premembrane protein, which is cleaved during virus maturation to yield the membrane (M)
WN-80E was combined with SLA formulated in Alum (SLA-Alum), in a stable oil-in-water emulsion (SLA-SE), in a liposome (SLA-Lipo) and in liposomes containing QS21 (SLA-LSQ) a

Summary

Introduction

Members of the Flaviviridae family of arboviruses cause significant morbidity and mortality throughout the world. Licensed vaccines for flaviviruses include live attenuated viruses (YF17D for yellow fever, SA14.14.2 for Japanese encephalitis virus (JEV)), recombinant chimeric viruses (DengVaxia, for DENV, ChimeriVax-JE for JEV), and inactivated whole virus vaccines (e.g. Ixiaro for JEV, FSME-IMMUN and Encepur for tickborne encephalitis virus). While effective, these approaches have long development cycles and have manufacturing challenges which can restrict available vaccine supply.[2] In addition to these traditional approaches, recombinant subunit vaccines targeting the envelope (E) protein have been tested in preclinical studies and in Phase 1 clinical trials.

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Results

Conclusion