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.

Immunological Cross-Reactivity to Dengue Virus among Persons with Neuroinvasive West Nile Virus Infection

“…We demonstrated that the antibody response in three participants with neuroinvasive WNV infection has the capacity to cause ADE of DENV2 in K562 cells and likely other DENV serotypes not tested given antibody cross-reactivity by ELISA was observed to all four DENV serotypes. The WNV envelope protein is a potential antigen of interest in the development of WNV vaccines, therefore, antibodies generated following WNV vaccination could potentially cause antibody-dependent enhancement of DENV virus [11, 12]. We recommend that assessments for the development of cross-reactive antibodies to other flaviviruses, including DENV, should be investigated as a safety measure during WNV vaccine development.…”

Development of Vaccines against Emerging Mosquito-Vectored Arbovirus Infections

“…The DNA vaccine encodes the protein prM and the E glycoproteins of the NY99 strain of WNV under the transcriptional control of the CMV/R promoter [ 70 ]. More than 95% of recipients who used this vaccine developed neutralizing antibodies, but this result was obtained only after administration of three doses 4 weeks apart (NCT00300417).…”

Recent Insights Into the Molecular Mechanism of Toll-Like Receptor Response to Dengue Virus Infection

“…Therefore, mRNA vaccines may open a new window for an effective DENV vaccine. Based on this information, it is important to enhance vaccine efficacy by improving the design of safe, effective, and affordable vaccines against dengue, including the use of various adjuvants such as TLR agonist adjuvants ( Van Hoeven et al, 2018 ; Bidet et al, 2019 ).…”