A two-component cocktail of engineered DIII nanoparticles elicits broadly neutralizing antibody responses against...

Dengue virus (DENV) is a mosquito-transmitted flavivirus; there are four serotypes (DENV1-4) that co-circulate globally. Primary infection causes self-limiting febrile illness, but secondary infection by a heterologous serotype can predispose to severe dengue. Neutralizing antibodies are key mediators of long-term protection; however, cross-reactive, non-neutralizing antibodies can cause antibody-dependent enhancement (ADE) of infection, which contributes to severe dengue. Therefore, elicitation of a potent, broadly neutralizing antibody response against all four DENV serotypes is desired for vaccine design. Here, we developed nanoparticle immunogens bearing engineered variants of the E glycoprotein DIII domain (DIII) in which epitopes targeted by non-neutralizing antibodies were mutated via structure-guided design and phage display. A two-component cocktail of these DIII variants elicited a broadly neutralizing response against all four DENV serotypes in mice and limited viremia in a DENV2 challenge model. These results provide insights into the design of broadly acting vaccines against DENV serotypes.