The Immunodominance Change and Protection of CD4+ T-Cell Responses Elicited by an Envelope Protein Domain III-Based Tetravalent Dengue Vaccine in Mice

Abstract

Dengue is the leading cause of mosquito-borne viral infections and no vaccine is available now. Envelope protein domain III (ED3) is the major target for the binding of dengue virus neutralizing antibodies; however, the ED3-specifc T-cell response is less well understood. To investigate the T-cell responses to four serotypes of dengue virus (DENV-1 to 4), we immunized mice using either a tetravalent ED3-based DNA or protein vaccine, or combined both as a DNA prime-protein boost strategy (prime-boost). A significant serotype-dependent IFN-γ or IL-4 response was observed in mice immunized with either the DNA or protein vaccine. The IFN-γ response was dominant to DENV-1 to 3, whereas the IL-4 response was dominant to DENV-4. Although the similar IgG titers for the four serotypes were observed in mice immunized with the tetravalent vaccines, the neutralizing antibody titers varied and followed the order of 2 = 3>1>4. Interestingly, the lower IFN-γ response to DENV-4 is attributable to the immunodominance change between two CD4+ T-cell epitopes; one T-cell epitope located at E349-363 of DENV-1 to 3 was more immunogenic than the DENV-4 epitope E313-327. Despite DENV-4 specific IFN-γ responses were suppressed by immunodominance change, either DENV-4-specific IFN-γ or neutralizing antibody responses were still recalled after DENV-4 challenge and contributed to virus clearance. Immunization with the prime-boost elicited both IFN-γ and neutralizing antibody responses and provided better protection than either DNA or protein immunization. Our findings shed light on how ED3-based tetravalent dengue vaccines sharpen host CD4 T-cell responses and contribute to protection against dengue virus.

Immunogenicity of a novel tetravalent vaccine formulation with four recombinant lipidated dengue envelope protein domain IIIs in mice

“…The other two are on envelope protein residues 295 to 309 (D1-1, D2-1, and D3-1) and 349-363 (D1-10, D2-10, and D3-10) and are both recognized by CD4 + T cells ( Fig. 5C ), consistent with previous reports 52 53 54 . CD4 + T cells reacted to peptides derived from 4 serotypes of dengue virus in vaccinated mice.…”

“…Another region is on envelope protein residues 313 to 327 (D4-4) and is recognized by CD4 + T cells ( Fig. 5C ), which has been reported in our previous study 52 . The other two are on envelope protein residues 295 to 309 (D1-1, D2-1, and D3-1) and 349-363 (D1-10, D2-10, and D3-10) and are both recognized by CD4 + T cells ( Fig.…”

“…The plates were washed twice and blocked with RPMI medium supplemented with feta bovine serum (10%) for 1 hour to prevent nonspecific binding in later steps. The splenocytes were seeded at a concentration of 5 × 10 5 cells/well with a panel of 16 15-mer peptides with 9 overlapping amino acids derived from each serotype of ED III (2 μg/mL) 52 . Triplicate wells were set up for each stimulation.…”

Immunodomination of Serotype-Specific CD4+ T-Cell Epitopes Contributed to the Biased Immune Responses Induced by a Tetravalent Measles-Vectored Dengue Vaccine

“…ED3, with a length of ∼100 amino acids, has been reported to contain serotype-specific neutralizing antibody epitopes (52) and has been used as the target antigen of dengue vaccine (53)(54)(55)(56)(57)(58). In previous studies of ED3-based tetravalent DNA or MV vector vaccines, we identified serotype-specific and crossreactive CD4 + T-cell epitopes within ED3 in BALB/c (H-2 d ) and C57BL/6 (H-2 b ) mice and observed immunodominance changes among these T-cell epitopes (47,59). For example, in BALB/c mice, the tetravalent dengue ED3-based DNA vaccine induced one cross-reactive CD4 + T-cell epitope shared by DENV-1,−2, and−3 and one serotype-specific CD4 + T-cell epitope to DENV-4.…”

Discovery of T-cell Driven Subunit Vaccines from Zika Virus Genome: An Immunoinformatics Approach

“…T-cell subunit vaccines are safer, as they elicit immune responses based on the minimal pathogen-specific antigenic elements, conserved across multiple pathogenic strains and exclude self (host) antigens [16]. Indeed, T-cell epitopes have been shown as potential vaccine candidates in flaviviruses such as Dengue and Yellow fever [20][21][22][23][24][25][26][27]. Therefore, an immunoinformatics approach was implemented in the present study to detect minimal T-cell epitopes from the translated ssRNA (+) genome of Zika virus, capable of inducing cell-mediated immunity in humans.…”