Immunodomination of Serotype-Specific CD4+ T-Cell Epitopes Contributed to the Biased Immune Responses Induced by a Tetravalent Measles-Vectored Dengue Vaccine

Abstract

Dengue is an emerging mosquito-borne disease, and the use of prophylactic vaccines is still limited. We previously developed a tetravalent dengue vaccine (rMV-TDV) by a recombinant measles virus (MV) vector expressing envelope protein domain III (ED3). In this study, we used dengue-susceptible AG129 mice to evaluate the protective and/or pathogenic immune responses induced by rMV-TDV. Consistent with the previous study, rMV-TDV-immunized mice developed a significant neutralizing antibody response against all serotypes of DENV, as well as a significant IFN-γ response biased to DENV-3, compared to the vector controls. We further demonstrated that this DENV-3-specific IFN-γ response was dominated by one CD4 + T-cell epitope located in E 349−363. After DENV-2 challenge, rMV-TDV-immunized mice showed a significantly lower viremia and no inflammatory cytokine increase compared to the vector controls, which had an ∼100 times higher viremia and a significant increase in IFN-γ and TNF-α. As a correlate of protection, a robust memory IFN-γ response specific to DENV-2 was boosted in rMV-TDV-immunized mice after challenge. This result suggested that pre-existing DENV-3-dominated T-cell responses did not cross-react, but a DENV-2-specific IFN-γ response, which was undetectable during immunization, was recalled. Interestingly, this recalled T-cell response recognized the epitope in the same position as the E 349−363 but in the DENV-2 serotype. This result suggested that immunodomination occurred in the CD4 + T-cell epitopes between dengue serotypes after rMV-TDV vaccination and resulted in a DENV-3-dominated CD4 + T-cell response. Although the significant increase in IgG against both DENV-2 and-3 suggested that cross-reactive antibody responses were boosted, the increased neutralizing antibodies and IgG avidity still remained DENV-2 Lin et al. Immunodomination by MV-Vectored Dengue Vaccine specific, consistent with the serotype-specific T cell response post challenge. Our data reveal that immunodomination caused a biased T-cell response to one of the dengue serotypes after tetravalent dengue vaccination and highlight the roles of cross-reactive T cells in dengue protection.

Mice immunized with trimethyl chitosan nanoparticles containing DENV-2 envelope domain III elicit neutralizing antibodies with undetectable antibody-dependent enhancement activity

“…Though many of the developed EDIII-based vaccines have been shown to elicit a potent neutralizing antibody response, a weak T cell response, especially in terms of CD8 + T cells, has been demonstrated [23][24][25]. A possible explanation for this failure could be that EDIII is not the dominant target for a T cell response [26].…”

Versatility of live-attenuated measles viruses as platform technology for recombinant vaccines

“…However, mouse data were confirmed in squirrel monkeys or other non-human primate models for the WNV 63 and the CHIKV vaccines 64 , respectively. For the DENV vaccine, A129 mice were additionally used to demonstrate efficacy 65 .…”