Dendritic Cell Targeting Using a DNA Vaccine Induces Specific Antibodies and CD4+ T Cells to the Dengue Virus Envelope Protein Domain III

Abstract

Dengue fever has become a global threat, causing millions of infections every year. An effective vaccine against all four serotypes of dengue virus (DENV) has not been developed yet. Among the different vaccination strategies available today, DNA vaccines are safe and practical, but currently induce relatively weak immune responses in humans. In order to improve immunogenicity, antigens may be targeted to dendritic cells (DCs), the main antigen presenting cells and orchestrators of the adaptive immune response, inducing T and B cell activation. It was previously shown that a DNA vaccine encoding a fusion protein comprised of an antigen and a single-chain Fv antibody (scFv) specific for the DC endocytic receptor DEC205 induced strong immune responses to the targeted antigen. In this work, we evaluate this strategy to improve the immunogenicity of dengue virus (DENV) proteins. Plasmids encoding the scFv αDEC205, or an isotype control (scFv ISO), fused to the DENV2 envelope protein domain III (EDIII) were generated, and EDIII specific immune responses were evaluated in immunized mice. BALB/c mice were intramuscularly (i.m.) immunized three times with plasmid DNAs encoding either scDEC-EDIII or scISO-EDIII followed by electroporation. Analyses of the antibody responses indicated that EDIII fusion with scFv targeting the DEC205 receptor significantly enhanced serum anti-EDIII IgG titers that inhibited DENV2 infection. Similarly, mice immunized with the scDEC-EDIII plasmid developed a robust CD4+ T cell response to the targeted antigen, allowing the identification of two linear epitopes recognized by the BALB/c haplotype. Taken together, these results indicate that targeting DENV2 EDIII protein to DCs using a DNA vaccine encoding the scFv αDEC205 improves both antibody and CD4+ T cell responses. This strategy opens perspectives for the use of DNA vaccines that encode antigens targeted to DCs as a strategy to increase immunogenicity.

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

“…The uniqueness of the B cell-based vaccine approach is that antigens targeted to B cells elicit exaggerated Ag-specific Ab responses, although targeting antigens to dendritic cells (DCs) via lectins such as DEC205 has been shown to indirectly promote B cell humoral responses. 33 When DCs capture antigens to induce Ab responses, antigens are digested and dominant epitopes are presented on the surface as MHC class I or class II molecules. 34,35 The generation of blocking antibodies requires the presentation of intact Ag to B cells.…”

Molecular characterization of the viral structural protein genes of 2018 dengue virus serotype 1 epidemic in Yunnan, Southwest China

“…The E protein has three domains(I-III). Domain III contains serotype-specific epitopes that can elicit neutralizing antibodies and the host cell receptor recognition site that subserve viral attach and entry into host cell [40][41][42], EDIII is widely used in vaccine development for it can induce antibodies against DENV infection [42][43][44]. Kawano et al study found that the amino acid residue located in E155(DI region) of DENV-4 converted from T to I change virulence of the virus [45], our previous study also find the E155 amino acid of DENV-1 change from I to T may cause a weak in viral virulence [25].…”

“…Among these, 21 possible protein binding sites (including 87, 93, 97, 120, 157, 184, 198, 199, 200, 357, 376, 377, 503, 505, 507, 508, 509, 595, 622, 623, 642) were all found in MN123849, MN123854 and DEN-1SS. However, there are 9 and 10 sites were lost in MN123849 (5,7,158,195,197,365,366,429,621) and MN123854 (5,7,40,41,123,195 Approximately 8 and 5 distinct changes were found in the helical, respectively, and few changes observed in disordered region. Some difference observed in helical transmembrane regions between DEN-1SS and MN123849, MN123854 strains (Fig.4).…”

A Review on Dengue Vaccine Development

“…For example, integrating antigen sequence into lysosomal membrane protein increases the expression of MHC class II antigens, thereby enhancing the production of CD4 T cells and anti-CD4 antigens and ultimately improving the immunogenicity of the DENV2 prM/E DNA vaccine [98]. A DNA vaccine expressing an antigen fused with a single-chain Fv antibody (scFv) specific for the DC endocytic receptor DEC205 could induce a strong immune response to the target antigen [99].…”