Vaccination With a Single Consensus Envelope Protein Ectodomain Sequence Administered in a Heterologous Regimen Induces Tetravalent Immune Responses and Protection Against Dengue Viruses in Mice

Abstract

The development of a safe and effective tetravalent dengue vaccine that elicits protection against all dengue virus (DENV) serotypes is urgently needed. The consensus sequence of the ectodomain of envelope (E) protein of DENV (cE80) has been examined as an immunogen previously. In the current study, a cE80 DNA (D) vaccine was constructed and evaluated in conjunction with the cE80 protein (P) vaccine to examine whether both vaccines used together can further improve the immune responses. The cE80 DNA vaccine was administrated using either a homologous (DNA alone, DDD) or heterologous (DNA prime-protein boost: DDP or DPP) regimen, and evaluated for immunogenicity and protective efficacy in mice. Among the three DNA-based immunization regimens tested, DDP immunization is the optimal immunization regimen that elicited the greatest systemic immune response and conferred protection against all four DENV serotypes. This work provides innovative ideas for the development of consensus E-based dengue vaccines and the testing of optimal immunization regimens.

T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine

“…Three weeks after the final immunization, the cytokines IL-2, IL-4, and IFN-γ secreted by the splenocytes of C57BL/6 mice were determined using enzyme-linked immunospot (ELISPOT) kits (BD, USA) according to the manufacturer’s instructions and the previous protocol (Wang et al 2020 , 2019c ). In brief, mouse splenocytes were plated at 3 × 10 5 /well into 96-well filtration plates (Millipore, USA) pre-coated with capture antibodies and stimulated with 5 μg/well purified JEV or ZIKV particles for 60 h at 37 °C.…”

Dengue mouse models for evaluating pathogenesis and countermeasures

“…A more common use of immunocompetent mice has been to evaluate the immunogenicity of DENV vaccine candidates [33][34][35]. Challenge of immunized mice can assess vaccine efficacy against morbidity and mortality when DENV is administered directly into the brain via intracranial injection route [36,37] or through intraperitoneal injection of DENVinfected hematopoietic tumor (e.g., K562) cells [38,39] (Table 1). Survival from lethal intracranial DENV challenge was established for several vaccines platforms including adjuvanted DENV E ectodomain protein and DNA plasmids encoding DENV prM and E [36,37,40].…”

Defeat Dengue and Zika Viruses With a One-Two Punch of Vaccine and Vector Blockade

“…To this end, we obtained a consensus E80 sequence that contains epitopes conserved across all four serotype viruses through in silicon calculation with a dataset composed of 3,127 published sequences of dengue viruses, and found this single consensus E80 protein was immunogenic and capable of inducing neutralizing antibodies toward all four serotypes of DENV, with less bias than conventional tetravalent E80 vaccine (Sun et al, 2017). When administered in a DNA prime and protein boost regimen, this vaccine conferred protections against all four serotypes of viruses in a mouse model (Wang et al, 2019). This vaccine design strategy uniformly enriched all conserved epitopes on a single E80, further incorporation of consensus E80 monomers derived from both DENV and ZIKV to a stabilized dimer might help to present most cross-neutralizing epitopes on surface.…”