In meaningfully antigenically diverse viral populations, antigenic novelty (relative to standing population immunity) contributes to viral fitness: as a given virus i circulates in a population, the proportion of the population that is susceptible to infection with i--and other viruses antigenically similar to i--decreases over time as more people acquire immunity. Antigenically novel viruses that are able to escape this population immunity are better able to infect hosts and sustain transmission chains, making them fitter than the previously circulating viruses. Thus, if antigenic novelty constitutes a fitness advantage for DENV, then we would expect greater antigenic distance from recently circulating viruses to correlate with higher growth rates. We use a simple model, adapted from Luksza and Lassig (Nature, 2014) and illustrated below, to estimate population immunity and viral fitness. We then use viral fitness to predict clade frequencies and growth rates.
1 - Estimate empirical clade frequencies over time by running augur.
2 - Parse clade frequencies to identify which clades correspond to serotypes and genotypes of interest.
3 - Parse the titer model output (also output from augur) to estimate the antigenic distance between each pair of clades.
N.B.: For this dataset, steps 1-3 have already been completed; prepared input files for the fitness model can be found here
4 - Explore parameter space
We fit parameters to minimize the root mean squared error between predicted and actual clade frequencies using the Nelder-Mead algorithm as implemented in SciPy. To run parameter fitting:
python2 antigenic_fitness.py --mode fit
beta Slope of linear relationship between population immunity and viral fitness
gamma Slope of linear relationship between titers and probability of protection
sigma Proportion of titers waning each year since primary infection
f_{s0} Relative intrinsic fitness of each serotype (f_0 = 0 for DENV4)
N Number of years of previous immunity that contribute to antigenic fitness
dt Number of years in the future to predict clade frequencies
6 - Run antigenic_fitness.py -h to see all available options. Simply running with the default options will run the serotype model with parameters fit to optimize RMSE.
7 - Explore model output and visualize results with this notebook