Temporal and spatial analysis of Plasmodium falciparum genomics reveals patterns of connectivity in a low-transmission district in Southern Province, Zambia

Abstract

Understanding temporal and spatial dynamics of ongoing malaria transmission will be critical to inform effective interventions and elimination strategies in low transmission regions approaching elimination. Parasite genomics are being used as a tool to monitor epidemiologic trends, including assessing residual transmission across seasons or importation of malaria into these regions. Southern Province, Zambia is a low-transmission setting with seasonal malaria. We genotyped 441 Plasmodium falciparum samples using molecular inversion probes at 1,832 positions across the genome, using dried blood spots collected from 2012-2018 from 8 health centers in the catchment area of Macha Hospital in Choma District. We show that highly related parasites persist across multiple seasons, suggesting that the persistence of malaria is at least in part fueled by parasites seeding across the dry season. In addition, we identify clusters of clonal parasites that are dissimilar to the general population, suggesting that introduction of parasites from elsewhere may contribute to the continued malaria burden. We identified signals of population size fluctuation over the course of individual transmission seasons, suggesting a ramp-up of malaria transmission from a seasons beginning. Despite the small spatial scale of the study (2,000 sq km), we identified an inverse relationship between genetic relatedness of parasite pairs and distance between health centers, as well as increased relatedness between specific health centers. These results, leveraging both genomic and epidemiological data, provide a comprehensive picture of fluctuations in parasite populations in this pre-elimination setting of southern Zambia.

Scientific Findings of the Southern and Central Africa International Center of Excellence for Malaria Research: Ten Years of Malaria Control Impact Assessments in Hypo-, Meso-, and Holoendemic Transmission Zones in Zambia and Zimbabwe

“…1,800 sites along the parasite genome revealed a more comprehensive picture of malaria transmission within the district with four key findings. 27 First, highly related parasites were seen across multiple years-including during the dry season-corroborating the earlier studies and confirming that persistent low-level transmission in Choma District is sustained in part by locally persistent reservoirs that survive through the dry season. Long-term asymptomatic carriers, hidden intact parasites in the spleen, or even dormant P. falciparum stages have been proposed as the means by which malaria is sustained during ebbs of mosquito abundance.…”

Systematic bias in malaria parasite relatedness estimation

“…The error structure in sparse data HMM estimates is heteroskedastic: underestimation is most pronounced for parasite pairs with low relatedness. At the other end of the spectrum, genomic epidemiology applications typically focus on highly related parasite pairs, often using a threshold-based approach [9,14,16,48,49,50]. Since relatedness is systematically underestimated using sparse data, false positives (pairs with low levels of relatedness that appear highly related) are relatively rare.…”

Policy Implications of the Southern and Central Africa International Center of Excellence for Malaria Research: Ten Years of Malaria Control Impact Assessments in Hypo-, Meso-, and Holoendemic Transmission Zones in Zambia and Zimbabwe

“…Using cross-sectional and longitudinal cohort study designs, the Southern and Central Africa ICEMR has sought to understand the temporal and spatial dynamics of malaria transmission, the responsible vectors, and the characteristics of transmission foci (i.e., hot spots or hot populations) that should be targeted to reduce transmission and achieve elimination. 4 , 5 , 7 , 10 , 11 Such studies are critically important but inherently challenging because precise measurements in settings with low malaria incidence and low parasite prevalence require large sample sizes to capture sufficient outcomes, and low levels of parasitemia in infected individuals make high-resolution parasite genotyping challenging.…”

“…2 , 3 In low-burden settings, such as southern Zambia, residual reservoirs of infection in the human population that are difficult to identify and eliminate can lead to persistent, low-level transmission. 4 , 5 In some high-transmission settings, such as northern Zambia, malaria morbidity and mortality remain elevated despite intensive vector control (IRS, ITNs) and case management using rapid diagnostic tests (RDTs) and artemisinin-based combination therapy. 6 Important considerations for countries such as Zambia and Zimbabwe are how should malaria control and elimination programs balance the substantial investments needed to achieve and sustain malaria elimination in low-transmission settings, where the cost per case averted is high, with investments in reducing the burden of malaria in moderate or high transmission zones.…”