Abstract
Repeated homologous antigen immunization has been hypothesized to hinder antibody diversification, whereas sequential immunization with heterologous immunogens can educate B cell differentiations towards conserved residues thereby facilitating the generation of cross-reactive immunity. In this study, we developed a sequential vaccination strategy that utilized epitope-decreasing antigens to reinforce the cross-reactivity of T and B cell immune responses against all four serotypes dengue virus. The epitope-decreasing immunization was implemented by sequentially inoculating mice with antigens of decreasing domain complexity that first immunized with DENV1 live-attenuated virus, following by the Envelope protein (Env), and then Env domain III (EDIII) subunit protein. When compared to mice immunized with DENV1 live-attenuated virus three times, epitope-decreasing immunization induced higher TNF-α CD8+ T cell immune response against consensus epitopes. Epitope-decreasing immunization also significantly improved neutralizing antibody response to heterologous serotypes. Moreover, this sequential approach promoted somatic hypermutations in the immunoglobulin gene of antigen-specific memory B cells in comparison to repeated immunization. This proof-of-concept work on epitope-decreasing sequential vaccination sheds light on how successively exposing the immune system to decreasing-epitope antigens can better induce cross-reactive antibodies.
Highlights
A major challenge in dengue vaccine development is to induce robust and protective cross-reactive immunity against all four serotypes of dengue viruses (DENV)
We compared the T cell immune responses between mice that were immunized with three doses of live DENV1 virus and mice that were sequentially immunized with live DENV1 virus, DENV1 Envelope protein (Env) protein and DENV1 Env domain III (EDIII) subunit protein
Epitope-decreasing immunization significantly boosted anti-DENV2 Neutralizing antibody titer (nAb) response to near 2 times than the titer obtained from repeated immunization
Summary
A major challenge in dengue vaccine development is to induce robust and protective cross-reactive immunity against all four serotypes of dengue viruses (DENV). Optimization and vaccine types in vaccine development, the immunization regimen is critical. Vaccination regimens employ multiple inoculations of immunogens, such as inactivated virus and cocktails of antigens. In a monkey DENV vaccination model, interference between DENV serotypes and immunodominance of certain epitopes led to dominance of neutralizing antibody titers against DENV4 [12]. Sequential immunization with a series of directional immunogens with decreasing epitope modifications have been shown to elicit heterologous neutralizing responses against HIV-1 [13]. The successive boosting with epitopes of decreasing complexity forced B cells to rearrange the immunoglobin and promoted antibody avidity to recognize the conserved epitopes through somatic hypermutations
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