Evolution of resistance to antimalarial drugs: The impact of vector factors

Resistance to antimalarial drugs is a significant burden on worldwide efforts to control malaria. The evolutionary forces that drive the emergence and spread of resistant Plasmodium strains result from complex interactions between scales, influenced by transmission dynamics between hosts and vectors as well as within-hosts competition among parasite strains (both within human hosts and mosquito vectors). We present a modeling framework that simulates in combination the dynamics of between-host transmission and within-hosts growth of multiple Plasmodium strains. The competition between sensitive and resistant strains across these modeling scales determines the fate of resistance in a given population. Here we focus on the effects of within-vector parasite dynamics. The establishment of oocysts within the mosquito midgut constitutes the strongest bottleneck in Plasmodium dynamics along its life cycle. We illustrate in our model the impact of this bottleneck on the selection for resistant strains. We demonstrate in particular how this effect depends on eco-epidemiological settings of the simulated population, most notably on the local transmission intensity and the level of resistance in the population. We also investigate how within-vector costs of resistance impact these selective dynamics. We study costs impacting the probability of oocyst establishment and/or the within-vector development rate, and illustrate the relative impacts of these different costs on the evolution of resistance in various transmission settings. We conclude by discussing how mechanisms of mosquito immunity are likely to impact within-vector costs of resistance, and emphasizing the need for a better empirical characterization of these costs.