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trvrb committed Aug 7, 2019
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# Dengue antigenic relationships predict evolutionary dynamics
# Dengue genetic divergence generates within-serotype antigenic variation, but serotypes dominate evolutionary dynamics

Sidney M. Bell<sup>1,2</sup>, Leah Katzelnick<sup>3,4</sup>, Trevor Bedford<sup>1</sup>

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<img align="right" width="450" src="figures/png/genotype_dTiter_heatmap.png">

Dengue virus (DENV) exists as four genetically distinct serotypes, each of which is also antigenically distinct: the immune response to primary infection can be either cross-protective or associated with severe disease upon heterotypic secondary infection.
Each serotype is historically assumed to be antigenically uniform.
Recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear.
Here, we construct a substitution-based model to directly map antigenic change to underlying genetic divergence.
We identify 49 specific mutations and four colinear mutation clusters that contribute to dengue antigenic variation.
We report moderate antigenic diversity within each serotype, resulting in genotype-specific heterotypic cross-neutralization.
We also quantify the impact of this antigenic heterogeneity on real-world DENV population dynamics.
We find that antigenic fitness mediates fluctuations in DENV clade frequencies, although this appears to be driven by coarser serotype-level antigenic differences.
These results provide a more nuanced understanding of dengue antigenic evolution, with important ramifications for vaccine design and epidemic preparedness.
Dengue virus (DENV) exists as four genetically distinct serotypes, each of which is historically assumed to be antigenically uniform. However, recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear. Here, we construct a sequence-based model to directly map antigenic change to underlying genetic divergence. We identify 49 specific substitutions and four colinear substitution clusters that robustly predict dengue antigenic relationships. We report moderate antigenic diversity within each serotype, resulting in variation in genotype-specific patterns of heterotypic cross-neutralization. We also quantify the impact of antigenic variation on real-world DENV population dynamics, and find that serotype-level antigenic fitness is a dominant driver of dengue clade turnover. These results provide a more nuanced understanding of the relationship between dengue genetic and antigenic evolution, and quantify the effect of antigenic fitness on dengue evolutionary dynamics.

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