Abstract
Vaccines against dengue virus (DV) are commercially nonexistent. A subunit vaccination strategy may be of value, especially if a safe viral vector acts as biologically active adjuvant. In this paper, we focus on an immunoglobulin-like, independently folded domain III (DIII) from DV 2 envelope protein (E), which contains epitopes that elicits highly specific neutralizing antibodies. We modified the hepatitis B small surface antigen (HBsAg, S) in order to display DV 2 DIII on a virus-like particle (VLP), thus generating the hybrid antigen DIII-S. Two varieties of measles virus (MV) vectors were developed to express DIII-S. The first expresses the hybrid antigen from an additional transcription unit (ATU) and the second additionally expresses HBsAg from a separate ATU. We found that this second MV vectoring the hybrid VLPs displaying DIII-S on an unmodified HBsAg scaffold were immunogenic in MV-susceptible mice (HuCD46Ge-IFNarko), eliciting robust neutralizing responses (averages) against MV (1:1280 NT90), hepatitis B virus (787 mIU/mL), and DV2 (1:160 NT50) in all of the tested animals. Conversely, the MV vector expressing only DIII-S induced immunity against MV alone. In summary, DV2 neutralizing responses can be generated by displaying E DIII on a scaffold of HBsAg-based VLPs, vectored by MV.
Highlights
Dengue virus (DV) is the most prevalent arthropod-borne viral disease in the world and its importance both in terms of number of people infected and economic impact for endemic countries is unrivaled among arboviruses [1]
Antigen), composed of an artificial ORF lead by the light immunoglobulin chain signal sequence fused in frame with amino acids 292 to 393 from the DV2 E glycoprotein protein linked to the amino terminus of the HBsAg
To promote independent folding by the DV2 E domain III (DIII) and HBsAg modules we separated them by a 14 amino acid bridge with a predicted -helical structure
Summary
Dengue virus (DV) is the most prevalent arthropod-borne viral disease in the world and its importance both in terms of number of people infected and economic impact for endemic countries is unrivaled among arboviruses [1]. A vaccine to prevent infection by any of the four described DV serotypes has been an elusive goal for more than six decades. Three extensive clinical trials of a tetravalent formulation of this vaccine have been conducted in areas of high dengue endemicity far, finding an unbalanced protection among DV serotypes [3,4,5]. After three doses of the vaccine cocktail, the protection against febrile diseases caused by DV2 goes from only approximately 35% to 50%, which suggest the need to reformulate the vaccine or the immunization approach
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