Dengue genetic divergence generates within-serotype antigenic variation, but serotypes dominate evolutionary dynamics

Area of Science:

• Virology
• Evolutionary Biology
• Epidemiology

Background:

• Dengue virus (DENV) has four serotypes, previously thought antigenically uniform.
• Emerging evidence suggests antigenic heterogeneity within DENV serotypes, but its drivers and effects are not fully understood.

Purpose of the Study:

• To develop a model linking genetic changes to antigenic variation in DENV.
• To investigate the extent of antigenic diversity within DENV serotypes.
• To quantify the impact of antigenic variation on DENV population dynamics and evolution.

Main Methods:

• Construction of a sequence-based model to map genetic divergence to antigenic change.
• Identification of specific genetic substitutions and clusters predicting DENV antigenic relationships.
• Analysis of real-world DENV population data to assess antigenic variation's impact.

Main Results:

• Identified 49 specific substitutions and four substitution clusters predicting DENV antigenic relationships.
• Confirmed moderate antigenic diversity within each DENV serotype.
• Demonstrated genotype-specific heterotypic cross-neutralization patterns.
• Showed that serotype-level antigenic fitness is a key driver of DENV clade turnover.

Conclusions:

• DENV exhibits significant antigenic diversity within serotypes, influencing cross-neutralization.
• Antigenic fitness plays a critical role in DENV evolutionary dynamics and population structure.
• Provides a refined understanding of dengue virus genetic and antigenic evolution.