Abstract
Dengue is the leading cause of mosquito-borne viral infections and no vaccine is available now. Envelope protein domain III (ED3) is the major target for the binding of dengue virus neutralizing antibodies; however, the ED3-specifc T-cell response is less well understood. To investigate the T-cell responses to four serotypes of dengue virus (DENV-1 to 4), we immunized mice using either a tetravalent ED3-based DNA or protein vaccine, or combined both as a DNA prime-protein boost strategy (prime-boost). A significant serotype-dependent IFN-γ or IL-4 response was observed in mice immunized with either the DNA or protein vaccine. The IFN-γ response was dominant to DENV-1 to 3, whereas the IL-4 response was dominant to DENV-4. Although the similar IgG titers for the four serotypes were observed in mice immunized with the tetravalent vaccines, the neutralizing antibody titers varied and followed the order of 2 = 3>1>4. Interestingly, the lower IFN-γ response to DENV-4 is attributable to the immunodominance change between two CD4+ T-cell epitopes; one T-cell epitope located at E349-363 of DENV-1 to 3 was more immunogenic than the DENV-4 epitope E313-327. Despite DENV-4 specific IFN-γ responses were suppressed by immunodominance change, either DENV-4-specific IFN-γ or neutralizing antibody responses were still recalled after DENV-4 challenge and contributed to virus clearance. Immunization with the prime-boost elicited both IFN-γ and neutralizing antibody responses and provided better protection than either DNA or protein immunization. Our findings shed light on how ED3-based tetravalent dengue vaccines sharpen host CD4 T-cell responses and contribute to protection against dengue virus.
Highlights
Dengue is the most prevalent mosquito-borne infectious disease and has spread to over 100 countries due to global warming and an increase in international travel [1]
We used a tetravalent ED3-expressing DNA vaccine and a tetravalent recombinant ED3 subunit vaccine formulated with an alum adjuvant, as well as the combination of both as a DNA prime-protein boost vaccination, to investigate the ED3-specific CD4+ T-cell response; we evaluated the protection of this response against dengue virus challenge in a mouse model
Previous studies to identify CD4+ T-cell responses were performed on the subjects infected with dengue, mostly for DENV-2 and analyzed at a genome-wide scale. These results are valuable for understanding the virus infectioninduced T-cell responses but may not reflect the T-cell immunity elicited by vaccination, for tetravalent vaccines, which contain highly homologous antigens from viruses of four serotypes
Summary
Dengue is the most prevalent mosquito-borne infectious disease and has spread to over 100 countries due to global warming and an increase in international travel [1]. The complexity of interactions between the four serotypes of dengue virus (DENV-1 to 4) and the poorly understood mechanisms of immune protection impede the development of a dengue vaccine [3]. Both serotype-specific/ homotypic and cross-reactive/heterotypic immune responses are elicited. Due to the lack of long-lasting cross-protection, the heterotypic immune responses have been reported to be less protective and associated with severe dengue diseases, including dengue hemorrhagic fever and dengue shock syndrome [4]. Antibody-dependent enhancement (ADE) and the concept of original antigenic sin mediated by cross-reactive antibodies and T cells have been proposed in the pathogenesis of severe dengue [5, 6]. It is believed that an ideal dengue vaccine would be able to induce balanced immunity against all dengue serotypes
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