Abstract
There is substantial variation in the relapse frequency of Plasmodium vivax malaria, with fast-relapsing strains in tropical areas, and slow-relapsing strains in temperate areas with seasonal transmission. We hypothesize that much of the phenotypic diversity in P. vivax relapses arises from selection of relapse frequency to optimize transmission potential in a given environment, in a process similar to the virulence trade-off hypothesis. We develop mathematical models of P. vivax transmission and calculate the basic reproduction number R0 to investigate how transmission potential varies with relapse frequency and seasonality. In tropical zones with year-round transmission, transmission potential is optimized at intermediate relapse frequencies of two to three months: slower-relapsing strains increase the opportunity for onward transmission to mosquitoes, but also increase the risk of being outcompeted by faster-relapsing strains. Seasonality is an important driver of relapse frequency for temperate strains, with the time to first relapse predicted to be six to nine months, coinciding with the duration between seasonal transmission peaks. We predict that there is a threshold degree of seasonality, below which fast-relapsing tropical strains are selected for, and above which slow-relapsing temperate strains dominate, providing an explanation for the observed global distribution of relapse phenotypes.
Highlights
Plasmodium vivax malaria is endemically transmitted or has been historically endemic across the globe in regions with extremely diverse climates [1,2], from temperate locations such as Finland [3] to Papua New Guinea in the tropics [4]
We develop mathematical models of malaria transmission accounting for the patterns of relapses arising from hypnozoites, but with the simplifying assumption that variations in blood-stage density are ignored, and test the hypothesis that optimal relapse frequencies depend on the duration of P. vivax blood-stage infection and the seasonality and intensity of transmission
Relapses are a key driver of P. vivax transmission [15], with the fitness of P. vivax strongly influenced by relapse frequency
Summary
Plasmodium vivax malaria is endemically transmitted or has been historically endemic across the globe in regions with extremely diverse climates [1,2], from temperate locations such as Finland [3] to Papua New Guinea in the tropics [4]. Following primary infection with a tropical strain of P. vivax, hypnozoites enter a latent stage in the liver where they either activate to cause relapses, or die within liver hepatocytes. Following primary infection with a temperate strain, hypnozoites enter a long-latent stage where activation to cause relapses does not immediately occur [7]. The mathematical model for P. falciparum transmission outlined in figure 1 can be extended to incorporate relapses of tropical strains of P. vivax through the addition of states for latent hypnozoites. Following an infectious mosquito bite, an individual will develop blood-stage infection and dormant liver-stage infection (from sporozoites that transform into hypnozoites) These hypnozoites will remain in the dormant stage for an expected duration of d days, during which time relapse is not possible.
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