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This study employs landscape genetics to investigate the environmental drivers of a deadly vector-borne disease, malaria caused by Plasmodium falciparum, in a more spatially comprehensive manner than any previous work. With 1804 samples from 44 sites collected in western Kenya in 2012 and 2013, we performed resistance surface analysis to show that Lake Victoria acts as a barrier to transmission between areas north and south of the Winam Gulf. In addition, Mantel correlograms clearly showed significant correlations between genetic and geographic distance over short distances (less than 70 km). In both cases, we used an identity-by-state measure of relatedness tailored to find highly related individual parasites in order to focus on recent gene flow that is more relevant to disease transmission. To supplement these results, we performed conventional population genetics analyses, including Bayesian clustering methods and spatial ordination techniques. These analyses revealed some differentiation on the basis of geography and elevation and a cluster of genetic similarity in the lowlands north of the Winam Gulf of Lake Victoria. Taken as a whole, these results indicate low overall genetic differentiation in the Lake Victoria region, but with some separation of parasite populations north and south of the Winam Gulf that is explained by the presence of the lake as a geographic barrier to gene flow. We recommend similar landscape genetics analyses in future molecular epidemiology studies of vector-borne diseases to extend and contextualize the results of traditional population genetics.

In October 2021, the world's first malaria vaccine RTS,S was endorsed by WHO for broad use in children, despite its low efficacy. This study examined polyclonal infections and the associations of parasite genetic variations with binding affinity to human leukocyte antigen (HLA). Multiplicity of infection was determined by amplicon deep sequencing of PfMSP1. Genetic variations in PfCSP were examined across 88 samples from Ghana and analyzed together with 1655 PfCSP sequences from other African and non-African isolates. Binding interactions of PfCSP peptide variants and HLA were predicted using NetChop and HADDOCK. High polyclonality was detected among infections, with each infection harboring multiple non-3D7 PfCSP variants. Twenty-seven PfCSP haplotypes were detected in the Ghanaian samples, and they broadly represented PfCSP diversity across Africa. The number of genetic differences between 3D7 and non-3D7 PfCSP variants does not influence binding to HLA. However, CSP peptide length after proteolytic degradation significantly affects its molecular weight and binding affinity to HLA. Despite the high diversity of HLA, the majority of the HLAI and II alleles interacted/bound with all Ghana CSP peptides. Multiple non-3D7 strains among P. falciparum infections could impact the effectiveness of RTS,S. Longer peptides of the Th2R/Th3R CSP regions should be considered in future versions of RTS,S. • The world's first malaria vaccine RTS,S has low efficacy against P. falciparum. • Infections were highly polyclonal each with multiple non-3D7 PfCSP variants. • Genetic differences between 3D7 and non-3D7 PfCSP do not affect binding to HLA. • CSP peptide length significantly affects its binding affinity to the HLA. [ABSTRACT FROM AUTHOR]