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

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.

West Nile Virus: adjuvant combinations boost vaccine efficacy

There is currently no approved human vaccine for West Nile Virus (WNV); however, it is known that protective immune responses are generally directed to the viral E protein. Neal Van Hoeven and colleagues at the Infectious Disease Research Institute in Seattle use recombinant WNV E-protein antigen adjuvanted with different combinations of a synthetic Toll-like receptor 4 agonist (SLA) and the saponin QS21 to determine optimal vaccination strategies in preclinical mouse and hamster models. SLA plus QS21 synergize in the production of neutralizing antibodies and when used together generate higher antibody diversity—a property that directly correlates with their protective capacity in vivo. Uniquely, the combination of QS21 plus SLA was also able to elicit robust T helper 1 responses. These findings highlight a promising adjuvant combination that might form the basis of an effective human WNV vaccine.