Skip to content
Permalink
Browse files

First pass at minor revision text changes

  • Loading branch information...
sidneymbell
sidneymbell committed Jul 7, 2019
1 parent 69f3c96 commit e08f57333558998265e62409fc45bef29722c016
Showing with 12 additions and 7 deletions.
  1. +12 −7 manuscript/dengue-antigenic-dynamics.tex
@@ -42,11 +42,10 @@
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 contribute to dengue antigenic diversity.
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 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 primarily explained 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.
We also quantify the impact of this antigenic heterogeneity 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.
\end{abstract}

\pagebreak
@@ -64,8 +63,8 @@ \section*{Author Summary}
We find that DENV antigenic divergence is tightly coupled to DENV genetic divergence, and is likely a gradual, ongoing process.
We report modest but significant antigenic diversity within each serotype of DENV, which may have important ramifications for vaccine design.
To understand the impact of this antigenic heterogeneity on real-world DENV population dynamics, we also quantify the extent to which population immunity---accumulated through recent circulation of antigenically similar genotypes---determines the success and decline of DENV clades in a hyperendemic population.
We find that antigenic fitness is a key determinant of DENV population turnover, although this appears to be driven by coarser serotype-level antigenic differences.
By leveraging both molecular data and real-world population dynamics, these results provide a more nuanced understanding of dengue antigenic evolution, with important ramifications for improving vaccine design and epidemic preparedness.
We find that serotype-level antigenic fitness is a key determinant of DENV population turnover.
By leveraging both molecular data and real-world population dynamics, 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.

\pagebreak

@@ -519,7 +518,13 @@ \subsection*{Viral clade dynamics}
This lack of signal could be explained by either (A) genotype-level frequency trajectories estimated from public data are overly noisy for this application or (B) our model of antigenic fitness based on PRNT assay data does not match reality, due to either PRNT assay data not well reflecting human immunity or due to our particular model formulation that parameterizes immunity from titer distances (Eq.~\ref{eq_population_immunity}--\ref{eq_fitness}).
In the present analysis, we are not able to firmly resolve these disparate possibilities.

This observation is also subject to caveats imposed by the available data and model assumptions.
% EDIT THIS PARAGRAPH
Alternatively, it is possible that within-serotype antigenic heterogeneity mediates individual disease severity but not infection or onward transmission.
Consistent with this hypothesis, recent work by \citet{quirine2018contributions} \textit{et al.} demonstrates that dengue transmissibility is largely independent of disease severity.
This is also consistent with \citet{nagao2008decreases}'s findings that epidemiological incidence data is consistent with a model of clinical protection, wherein immunity confers protection against symptomatic infection, but asymptomatic infection is largey unaffected.
ached
% FIX THIS TRANSITION
These observations are also subject to caveats imposed by the available data and model assumptions.
Our estimates of antigenic fitness are informed by the antigenic distances inferred by the substitution model; thus, as above, we are unable to account for nuanced antigenic differences between sub-genotype clades of DENV due to limited titer data.
We estimate DENV population composition over time based on available sequence data, pooled across all of Southeast Asia (Methods, Eq.~\ref{eq_estimate_frequency}).
As the vast majority of cases of DENV are asymptomatic, sequenced viruses likely represent a biased sample of more severe cases from urban centers where patients are more likely to seek and access care.

0 comments on commit e08f573

Please sign in to comment.
You can’t perform that action at this time.