Development of Bacteriophage Virus-Like Particle Vaccines Displaying Conserved Epitopes of Dengue Virus Non-Structural Protein 1.

Nikole L Warner,Kathryn M Frietze

doi:10.3390/vaccines9070726

Abstract

Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.

Highlights

Dengue virus (DENV) is an arthropod-borne flavivirus with four serotypes (DENV-1–4) that is transmitted by Aedes mosquitos
If that individual is infected with a heterologous serotype, the individual is at higher risk for developing severe dengue (SD); dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) [5,6]
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Summary

Introduction

Dengue virus (DENV) is an arthropod-borne flavivirus with four serotypes (DENV-1–4) that is transmitted by Aedes mosquitos. The current DENV vaccine, Dengvaxia by Sanofi-Pasteur has been criticized for its safety efficacy in population-based vaccination campaigns [4] This is in part a result of the unique immune response that follows DENV infection. If that individual is infected with a heterologous serotype, the individual is at higher risk for developing severe dengue (SD); dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) [5,6]. This is likely due to a phenomenon called Antibody-Dependent Enhancement of infection (ADE), whereby non-neutralizing antibodies to structural proteins present on the DENV virion are able to facilitate infection of Fcγ receptor-expressing cells, leading to increased infection and disease. This unique antibody response is why protection against all four DENV serotypes must be addressed in a successful vaccine, while avoiding antibodies that can cause ADE

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