A chimeric dengue virus vaccine candidate delivered by high density microarray patches protects against infection in mice

Abstract

Dengue viruses (DENV) cause an estimated 390 million infections globally. With no dengue-specific therapeutic treatment currently available, vaccination is the most promising strategy for its control. A wide range of DENV vaccines are in development, with one having already been licensed, albeit with limited distribution. We investigated the immunogenicity and protective efficacy of a chimeric virus vaccine candidate based on the insect-specific flavivirus, Binjari virus (BinJV), displaying the structural prM/E proteins of DENV (BinJ/DENV2-prME). In this study, we immunized AG129 mice with BinJ/DENV2-prME via a needle-free, high-density microarray patch (HD-MAP) delivery system. Immunization with a single, 1 µg dose of BinJ/DENV2-prME delivered via the HD-MAPs resulted in enhanced kinetics of neutralizing antibody induction when compared to needle delivery and complete protection against mortality upon virus challenge in the AG129 DENV mouse model.

Implications of Dengue Virus Maturation on Vaccine Induced Humoral Immunity in Mice

“…To examine the immune responses of bDENV-2 particles of varying maturities, five AG129 mice per group were immunized twice, three weeks apart, with 1 μg of mature, partially mature, or immature bDENV-2 + 3 μg of QA adjuvant ( Figure 2 A). The effects of the saponin-based adjuvant QA, which has been used to enhance the neutralizing immune response generated by bDENV-2 [ 35 ] and other dengue vaccines [ 48 ], on the virion structure was not directly investigated. However, the inclusion of QA within all vaccination groups equalized the effects of QA to allow direct comparison.…”

“…The current study provides further validation of the BinJV chimeric vaccine platform for flaviviruses. Previous work by our group and collaborators have shown complete protection in WNV, YFV, ZIKV, and DENV-2 murine challenge models upon immunization with BinJV-based chimeric vaccines [ 35 , 37 , 59 , 60 ]. We add to this body of work by showing that independent of virion maturation, two 1 μg intradermal doses of bDENV-2 are 80–100% protective against challenge with DENV-2 in AG129 mice.…”

“…The effects of particle maturation status in DENV vaccine efficiency remains to be rationally explored. As such, we utilized a recently reported chimeric flavivirus vaccine candidate, bDENV-2 [ 35 ], based off the insect specific Binjari (BinJV) virus [ 36 ], to investigate the differential humoral immunity generated in AG129 mice to mature, immature, and partially mature DENV particles. More specifically, this will assist in further understanding the role of immature and partially mature virions in ADE and protection from DENV.…”

Chimeric Vaccines Based on Novel Insect-Specific Flaviviruses

“…These insect-specific flaviviruses (ISFs) have been detected globally, infecting multiple mosquito genera (Table 3). While the isolation and characterization of ISFs provide essential insights into the evolutionary history of the Flavivirus genus, more recent data suggest that some of these viruses can regulate the transmission of vertebrateinfecting flaviviruses (VIFs), such as WNV and ZIKV in co-infected mosquitoes [61][62][63][64][65][66], as well as act as a genetic backbone to produce hybrid viruses that can be used as safe vaccines and diagnostic reagents for flaviviral pathogens [67][68][69][70][71].…”

“…Using circular polymerase extension reaction (CPER), a novel system that allows for the construction and in vivo transcription of viral cDNA and rescue of infectious RNA viruses without the need for cloning, we generated a series of wild-type and recombinant flaviviruses. These included wild-type Lineage I (PCV) and Lineage II (BinJV) ISFs as well as chimeric viruses between these ISFs and a range of VIFs (e.g., WNV, ZIKV, YFV and DENV; Table 4) [67][68][69][70][71]81,107,108]. This new system provided the tools to investigate mechanisms of host restriction and platforms for rapidly generating recombinant and mutant RNA viruses [109].…”