Impact of Dengue Virus Serotype 2 Strain Diversity on Serological Immune Responses to Dengue

Dengue is a mosquito-borne disease caused by four dengue virus serotypes (DENV1–4) that are loosely categorized by sequence commonalities and antibody recognition profiles. The highly variable envelope protein (E) that is prominently displayed on the surface of DENV is an essential component of vaccines currently under development, yet the impact of using single strains to represent each serotype in tetravalent vaccines has not been adequately studied. We synthesized chimeric E by replacing highly variable residues from a dengue virus serotype 2 vaccine strain (PUO-218) with those from 16 DENV2 lineages spanning 60 years of antigen evolution. Examining sera from human and rhesus macaques challenged with single strains of DENV2, antibody–E interactions were markedly inhibited or enhanced by residues mainly focused within a 480 Å2 footprint displayed on the E backbone. The striking impact of E diversity on polyclonal immune responses suggests that frequent antigen updates may be necessary for vaccines to counter shifts in circulating strains