Dimerization of Dengue Virus E Subunits Impacts Antibody Function and Domain Focus

Area of Science:

• Virology and Immunology
• Vaccine Development
• Structural Biology

Background:

• Dengue virus (DENV) poses a significant global health challenge, with current live-attenuated vaccines struggling to induce balanced immunity against all four serotypes.
• DENV envelope (E) protein subunit vaccines offer a potential alternative, but historically underperformed due to the use of monomeric antigens lacking native quaternary structures.
• The immunogenicity of subunit vaccines is independent of viral replication, offering a theoretical advantage for balanced immune responses.

Purpose of the Study:

• To compare the immunogenicity of Dengue virus type 2 (DENV2) envelope (E) protein homodimers versus monomers as potential vaccine antigens.
• To investigate whether mimicking the quaternary structure of the DENV surface enhances neutralizing antibody responses.

Main Methods:

• Production and characterization of stabilized DENV2 E protein homodimers and monomers.
• Immunization of mice with DENV2 E homodimers or monomers.
• Assessment of virus-specific and cross-reactive neutralizing antibody responses, including epitope mapping.

Main Results:

• DENV2 E homodimers, but not monomers, were recognized by potent neutralizing antibodies targeting quaternary-structure epitopes.
• Dimer immunization induced 3-fold higher levels of virus-specific neutralizing IgG compared to monomers.
• Dimers elicited stronger responses against E domain I (EDI) and EDII, while monomers induced EDIII and fusion loop epitope antibodies, the latter associated with antibody-dependent enhancement (ADE).

Conclusions:

• Authentic presentation of DENV E protein subunits, mimicking the viral surface structure (dimers), significantly enhances immunogenicity and elicits more potent neutralizing antibodies.
• DENV E subunit antigens designed to replicate the viral envelope's structural organization are superior vaccine antigens compared to monomers.
• This structural mimicry is crucial for developing effective DENV subunit vaccines that induce balanced and protective immunity.