Hyper-diverse antigenic variation and resilience to transmission-reducing intervention in falciparum malaria.

Intervention efforts against falciparum malaria in high-transmission regions remain challenging, with rapid resurgence typically following their relaxation. Such resilience co-occurs with incomplete immunity and a large transmission reservoir from high asymptomatic prevalence. Incomplete immunity relates to the large antigenic variation of the parasite, with the major surface antigen of the blood stage of infection encoded by the multigene and recombinant family known as var.

Mathematical Assessment of the Role of Intervention Programs for Malaria Control.

Malaria remains a global health problem despite the many attempts to control and eradicate it. There is an urgent need to understand the current transmission dynamics of malaria and to determine the interventions necessary to control malaria. In this paper, we seek to develop a fit-for-purpose mathematical model to assess the interventions needed to control malaria in an endemic setting.

From multiplicity of infection to force of infection for sparsely sampled populations at high transmission.

High multiplicity of infection or MOI, the number of genetically distinct parasite strains co-infecting a single human host, characterizes infectious diseases including falciparum malaria at high transmission. It accompanies high asymptomatic prevalence despite high exposure, creating a large transmission reservoir challenging intervention. High MOI and asymptomatic prevalence are enabled by immune evasion of the parasite achieved via vast antigenic diversity.

Hyper-diverse antigenic variation and resilience to transmission-reducing intervention in falciparum malaria.

Intervention against falciparum malaria in high transmission regions remains challenging, with relaxation of control efforts typically followed by rapid resurgence. Resilience to intervention co-occurs with incomplete immunity, whereby children eventually become protected from severe disease but not infection and a large transmission reservoir results from high asymptomatic prevalence across all ages. Incomplete immunity relates to the vast antigenic variation of the parasite, with the major surface antigen of the blood stage of infection encoded by the multigene family known as .

Mathematical assessment of the role of intervention programs for malaria control.

Malaria remains a global health problem despite the many attempts to control and eradicate it. There is an urgent need to understand the current transmission dynamics of malaria and to determine the interventions necessary to control malaria. In this paper, we seek to develop a fit-for-purpose mathematical model to assess the interventions needed to control malaria in an endemic setting.

Comparison of molecular surveillance methods to assess changes in the population genetics of in high transmission.

A major motivation for developing molecular methods for malaria surveillance is to measure the impact of control interventions on the population genetics of as a potential marker of progress towards elimination. Here we assess three established methods (i) single nucleotide polymorphism (SNP) barcoding (panel of 24-biallelic loci), (ii) microsatellite genotyping (panel of 12-multiallelic loci), and (iii) coding (fingerprinting gene diversity, akin to microhaplotyping) to identify changes in parasite population genetics in response to a short-term indoor residual spraying (IRS) intervention. Typical of high seasonal transmission in Africa, multiclonal infections were found in 82.

A paradoxical population structure of DBLα types in Africa.

The multigene family encodes the erythrocyte membrane protein 1 (PfEMP1), which is important in host-parasite interaction as a virulence factor and major surface antigen of the blood stages of the parasite, responsible for maintaining chronic infection. Whilst important in the biology of , these genes (50 to 60 genes per parasite genome) are routinely excluded from whole genome analyses due to their hyper-diversity, achieved primarily through recombination. The PfEMP1 head structure almost always consists of a DBLα-CIDR tandem.

Performance of SNP barcodes to determine genetic diversity and population structure of in Africa.

Panels of informative biallelic single nucleotide polymorphisms (SNPs) have been proposed to be an economical method to fast-track the population genetic analysis of in malaria-endemic areas. Whilst used successfully in low-transmission areas where infections are monoclonal and highly related, we present the first study to evaluate the performance of these 24- and 96-SNP molecular barcodes in African countries, characterised by moderate-to-high transmission, where multiclonal infections are prevalent. For SNP barcodes it is generally recommended that the SNPs chosen i) are biallelic, ii) have a minor allele frequency greater than 0.

Neutral vs. non-neutral genetic footprints of Plasmodium falciparum multiclonal infections.

At a time when effective tools for monitoring malaria control and eradication efforts are crucial, the increasing availability of molecular data motivates their application to epidemiology. The multiplicity of infection (MOI), defined as the number of genetically distinct parasite strains co-infecting a host, is one key epidemiological parameter for evaluating malaria interventions. Estimating MOI remains a challenge for high-transmission settings where individuals typically carry multiple co-occurring infections.

Molecular epidemiology of continued disease transmission after an outbreak in Ecuador.

To better understand the factors underlying the continued incidence of clinical episodes of falciparum malaria in E-2025 countries targeting elimination, we characterized the molecular epidemiology of disease transmission after a clonal outbreak in Ecuador. Here we study disease transmission by documenting the diversity and population structure of the major variant surface antigen of the blood stages of encoded by the multigene family. We used a high-resolution genotyping method, "coding", involving targeted amplicon sequencing to fingerprint the DBLα encoding region of genes to describe both antigenic diversity and repertoire similarity or relatedness in parasite isolates from clinical cases.

Age-specific patterns of DBLα var diversity can explain why residents of high malaria transmission areas remain susceptible to Plasmodium falciparum blood stage infection throughout life.

Immunity to Plasmodium falciparum is non-sterilising, thus individuals residing in malaria-endemic areas are at risk of infection throughout their lifetime. Here we seek to find a genomic epidemiological explanation for why residents of all ages harbour blood stage infections despite lifelong exposure to P. falciparum in areas of high transmission.

The impact of indoor residual spraying on Plasmodium falciparum microsatellite variation in an area of high seasonal malaria transmission in Ghana, West Africa.

Here, we report the first population genetic study to examine the impact of indoor residual spraying (IRS) on Plasmodium falciparum in humans. This study was conducted in an area of high seasonal malaria transmission in Bongo District, Ghana. IRS was implemented during the dry season (November-May) in three consecutive years between 2013 and 2015 to reduce transmission and attempt to bottleneck the parasite population in humans towards lower diversity with greater linkage disequilibrium.

Evolutionary analyses of the major variant surface antigen-encoding genes reveal population structure of Plasmodium falciparum within and between continents.

Malaria remains a major public health problem in many countries. Unlike influenza and HIV, where diversity in immunodominant surface antigens is understood geographically to inform disease surveillance, relatively little is known about the global population structure of PfEMP1, the major variant surface antigen of the malaria parasite Plasmodium falciparum. The complexity of the var multigene family that encodes PfEMP1 and that diversifies by recombination, has so far precluded its use in malaria surveillance.