Characterization of the type-specific and cross-reactive B cell responses elicited by a live-attenuated tetravalent dengue vaccine.

BACKGROUND Dengue is caused by four antigenically distinct serotypes of dengue virus (DENV1-4). Takeda's live attenuated tetravalent dengue vaccine (TAK-003) candidate is composed of an attenuated DENV2 and chimeric viruses containing prM/E of DENV1, 3 and 4 on the DENV2 backbone. The Multi-Color FluoroSpot (MCF) assay enables quantitation of serotype-specific and cross-reactive individual memory B cells (MBCs) secreting DENV-specific antibodies in a polyclonal mixture. METHODS Using the MCF assay, we determined the type-specific and cross-reactive MBC response in peripheral blood mononuclear cells collected pre- and post-vaccination from 7 macaques and 15 randomly selected individuals who received TAK-003 (8 DENV-seronegative and 7 DENV-seropositive) in a Phase 2 clinical trial in Singapore (DEN-205 study). RESULTS Pre-existing DENV-specific MBC responses were detected only in seropositive vaccine recipients at day 0. Following vaccination, both type-specific and cross-reactive MBCs to all four DENV serotypes were observed in all macaques and clinical trial participants. The proportion of type-specific MBCs was higher than cross-reactive MBCs and remained stable between day 30 and 360 post-vaccination. CONCLUSIONS These results demonstrate that, unlike primary or secondary natural DENV infection, tetravalent vaccination elicits tetravalent type-specific MBCs, and thus all four components of TAK-003 contribute to the DENV-specific MBC response following vaccination.