Sequential immunization induces strong and broad immunity against all four dengue virus serotypes

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Developing a dengue vaccine requires inducing immunity against all four dengue virus (DENV) serotypes.
• The current licensed dengue vaccine, Dengvaxia®, shows suboptimal protection and can exacerbate dengue in naive individuals.
• Existing tetravalent vaccines face challenges in achieving broad and effective immunity.

Purpose of the Study:

• To investigate if sequential immunization elicits superior immunity against DENV compared to simultaneous tetravalent immunization.
• To evaluate the impact of immunization strategy on T cell responses, antibody production, and B cell repertoire diversification.

Main Methods:

• Mice were immunized with DNA plasmids encoding DENV pre-membrane and envelope proteins.
• Immunization was performed either sequentially (one serotype at a time) or simultaneously (all four serotypes together).
• Immune responses were assessed by measuring T cell activation (IFNγ, TNFα), neutralizing antibody titers, and B cell repertoire diversity (CDR3 length, germinal center reactions).

Main Results:

• Sequential immunization significantly increased interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) expressing CD4+ and CD8+ T cells against conserved and serotype-specific epitopes.
• Higher levels of neutralizing antibodies against all four DENV serotypes were observed following sequential immunization.
• Sequential immunization led to a more diverse immunoglobulin repertoire, characterized by increased complementarity determining region 3 (CDR3) length and enhanced germinal center activity.

Conclusions:

• Sequential immunization is a promising strategy for enhancing dengue vaccine efficacy.
• This approach may offer a solution to the limitations of current tetravalent dengue vaccines.
• Sequential immunization elicits broader and more robust immune responses against multiple DENV serotypes.