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

Sidney M. Bell^1,2, Leah Katzelnick^3,4, Trevor Bedford¹

¹Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, ²Molecular and Cell Biology Program, University of Washington, Seattle, WA, USA, ³Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA, ⁴Department of Biology, University of Florida, Gainesville, FL, USA

Abstract

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.

Install

Everything is Python 2.7 based. Python packages that are required can be installed via:

cd dengue-antigenic-dynamics/
pip install -r requirements

Analysis outline

1. Run the titer model via augur (repackaged portion of the Nextstrain pipeline) to build a viral phylogeny, assign antigenic change to specific mutations, and infer clade frequencies.
2. Run the fitness model to quantify population immunity over time, predict clade frequencies, and assess performance.
3. Use the visualization notebooks to explore results and recreate all the figures from the paper.

Citation

Bell SM, Katzelnick L, Bedford T. 2019. Dengue genetic divergence generates within-serotype antigenic variation, but serotypes dominate evolutionary dynamics. eLife 8: e42496.

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All contents including manuscript text and source code are copyright 2016-2019 Sidney Bell, Leah Katzelnick and Trevor Bedford. All manuscript text (files ending in .tex) are licensed under Creative Commons Attribution 4.0 and all code (files ending in .py and .ipynb) is licensed under an MIT License.