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.