Preclinical evaluation of novel sterically optimized VLP-based vaccines against all four DENV serotypes

Over the past few decades, dengue fever has become a significant threat to global health, mainly in tropical regions but more lately also in regions with moderate climates. Since the currently approved vaccines have significant practical limitations, there is a strong need for a dengue vaccine that is safer and more effective. In this study, we introduce novel vaccination candidates covering all four Dengue virus (DENV) Serotypes based on virus-like particles (VLPs). VLPs are traditional vaccine platforms which are already implemented on the market for several diseases. They are considered safe and efficient because they have a highly organized and repetitive surface and lack any replication-competent genetic material. Due to the high thermostability of VLPs used here, distribution and administration in DENV endemic zones would be simplified and facilitate vaccination programs. To design such vaccine candidates, the Dengue virus envelope protein domain III (DV) of the serotypes 1, 2, 3, or 4, which represents the major target of DENV-neutralizing antibodies, was selected to be either genetically fused or chemically coupled to bacteriophage-derived AP205-VLPs. To facilitate the incorporation of the relatively large EDIII domain, AP205 monomers were dimerized, resulting in a VLP with 90 rather than 180 N- and C-termini. The generated vaccines induced high antibody titers of high affinity/avidity in mice, indicating a protective potential of the vaccine candidates. This was confirmed by the ability to neutralize the different Dengue virus serotypes in an in vitro neutralization assay. The administration of a tetravalent vaccine simultaneously induced high neutralizing titers against all four serotypes. Importantly, no enhancing antibodies were induced, at least not against the tested DENV2. In conclusion, the vaccine candidates, especially when administered in a combined fashion, exhibit intriguing properties for potential use in the field, and exploring the possibility of conducting a clinical trial would be a logical next step.