Magnitude and Functionality of the NS1-Specific Antibody Response Elicited by a Live-Attenuated Tetravalent Dengue Vaccine Candidate.

BACKGROUND: Dengue virus (DENV) can cause life-threatening disease characterized by endothelial dysfunction and vascular leakage. DENV nonstructural protein 1 (NS1) induces human endothelial hyperpermeability and vascular leak in mice, and NS1 vaccination confers antibody-mediated protective immunity. We evaluated the magnitude, cross-reactivity, and functionality of NS1-specific IgG antibody responses in sera from a phase II clinical trial of Takeda's live-attenuated tetravalent dengue vaccine candidate (TAK-003).

METHODS: We developed an ELISA to measure DENV NS1 IgG in sera from DENV-naive or pre-immune subjects pre- and post-vaccination with TAK-003 and evaluated the functionality of this response using in vitro models of endothelial permeability.

RESULTS: TAK-003 significantly increased DENV-2 NS1 IgG in naive individuals, which cross-reacted with DENV-1, -3, and -4 NS1 to varying extents. NS1-induced endothelial hyperpermeability was unaffected by pre-vaccination serum from naive subjects but was variably inhibited by serum from pre-immune subjects. Post-TAK-003 vaccination, all samples from naive and pre-immune vaccinees completely abrogated DENV-2 NS1-induced hyperpermeability and cross-inhibited hyperpermeability induced by DENV-1, -3, and -4 NS1. Inhibition of NS1-induced hyperpermeability correlated with NS1-specific IgG concentrations. Post-vaccination sera also prevented NS1-induced degradation of endothelial glycocalyx components.

CONCLUSION: We provide evidence for functional NS1-specific IgG responses elicited by a candidate dengue vaccine.