A tetravalent virus-like particle vaccine designed to display domain III of dengue envelope proteins induces multi-serotype neutralizing antibodies in mice and macaques which confer protection against antibody dependent enhancement in AG129 mice

Background Dengue is one of the fastest spreading vector-borne diseases, caused by four antigenically distinct dengue viruses (DENVs). Antibodies against DENVs are responsible for both protection as well as pathogenesis. A vaccine that is safe for and efficacious in all people irrespective of their age and domicile is still an unmet need. It is becoming increasingly apparent that vaccine design must eliminate epitopes implicated in the induction of infection-enhancing antibodies. Methodology/principal findings We report a Pichia pastoris-expressed dengue immunogen, DSV4, based on DENV envelope protein domain III (EDIII), which contains well-characterized serotype-specific and cross-reactive epitopes. In natural infection
Author summary Dengue is mosquito-borne viral disease which is currently a global public health problem. It is caused by four different types of dengue viruses. Nearly a 100 million people a year suffer from overt sickness, which may range from mild fever to potentially fatal disease. A virus-based dengue vaccine was launched for the first time in late 2015. Unexpectedly, this vaccine mimics the dengue viruses in that it appears to elicit disease-enhancing antibodies. To reduce such risk, safer vaccines that eliminate viral proteins responsible for undesirable antibodies are needed. We focused our attention on a small domain of the dengue virus surface protein known as envelope domain III (EDIII). Humans make only a small amount of antibodies against EDIII, but these antibodies are effective in blocking dengue virus from entering cells. We used a yeast expression system to display EDIIIs of all four types of dengue viruses on the surface of non-infectious virus-like particles (VLPs). These VLPs elicited antibodies, in mice and monkeys, which blocked all four dengue virus types and their variants from entering cells in culture. Importantly, these antibodies did not enhance dengue infection in a mouse model.