The prevention and augmentation of tetravalent recombinant measles-vectored dengue vaccine in dengue-2 infected AG129 mice

Abstract

Abstract Dengue is an emerging mosquito-borne disease and the use of prophylactic vaccine is still limited. We have previously developed the tetravalent dengue vaccine (rMV-TDV) by a recombinant measles virus (MV) vector expressing envelope protein domain III (ED3). In this study, we used AG129 mice to evaluate the protective and/or pathogenic immune responses induced by rMV-TDV. Immunization of rMV-TDV has induced a significant neutralizing antibody response against all serotypes of DENV, as well as a significant CD4-dependent IFN-γ response biased to DENV-3, compared to the vector controls. After DENV-2 challenge, rMV-TDV-immunized mice showed a significant lower viremia and no increase of inflammatory cytokines comparing to the vector controls, which had a ~100 times higher viremia and a significant increase of IFN-γ and TNF-α 3 days after challenge. A robust DENV-2 specific IFN-γ response detected in rMV-TDV-immunized mice suggested that pre-existing DENV-3 biased T-cell responses didn’t cross-react to DENV-2 but an anamnestic DENV-2 specific T-cell response was recalled. Prior to the challenge, only DENV-3 specific IgG demonstrated a significant higher avidity than other serotypes, whose specific IgG avidity increased after DENV-2 challenge, particular in DENV-1 and -2. However, the passive transfer of rMV-TDV immunized sera plus splenocytes resulted in the higher viremia and the significant increase of inflammatory cytokines in AG129 recipient mice after DENV-2 challenge than the vector control donors did. It suggested that while the immunity by rMV-TDV waned, the potential risks for the severe disease increased. Our data shed the lights on the role of a balanced CD4 T-cell response in the prevention of severe dengue.