Medical Biology - Theses
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ItemThe molecular epidemiology of Plasmodium spp. in Solomon Islands( 2018)Malaria is a major global disease burden with significant mortality rates amongst young children. The renewed commitment to eradicate malaria along with intensified control efforts has drastically reduced malaria transmission worldwide. In Solomon Islands, the malaria burden had steadily reduced over the last 20 years, achieving 90% reduction in malaria cases, and now the country is aiming to eliminate malaria by 2030. The journey towards malaria elimination requires knowledge of the local malaria epidemiology to identify the population at risk, as well as to understand the underlying risk of infection. In 2013, a longitudinal cohort study was conducted in Ngella. This study was a follow up from the 2012 cross-sectional survey of all ages in Ngella, which previously identified with a relatively higher prevalence of P. vivax infections (13.4% or 468 P. vivax infections) compared to only five P. falciparum infections, with majority of infections asymptomatic and submicroscopic (Waltmann et al., 2015). However, the underlying Plasmodium spp. infection dynamics in Ngella is unclear and it is unknown if P. falciparum infections has disappeared. This follow up study therefore aimed to investigate the local epidemiology of asymptomatic and submicroscopic Plasmodium spp. infections among a cohort of children aged between six months to twelve years old, which will be presented in this thesis. During the 2013 paediatric cohort study, monthly active case detection (ACD) and passive case detection (PCD) were conducted from May 2013 until April 2014. Plasmodium spp. infections were detected by light microscopy, rapid diagnostics test (RDT) and quantitative polymerase chain reaction (qPCR). The qPCR-detectable infection prevalence for P. vivax infections among the 860 children that attended at least six ACD visits was 11.9% (989 episodes), while P. falciparum infections was 0.3% (27 episodes). Most infections detected were submicroscopic (68%) and/or asymptomatic (92.8%). Of children who had at least one P. vivax infection, two thirds had subsequent infections. Genotyping of these P. vivax infections revealed that the subsequent infections have similar genotypes as the initial infections. Since the recorded primaquine (PQ) treatment among the cohort children was uncommon, this indicated that relapses from hypnozoites contributed a majority of P. vivax infections and anti-relapse treatment is important. Heterogeneous transmission and strong individual variation in risk were observed, suggesting that future malaria control program should tailor made accordingly to the varying risk of infections within Ngella and individuals. Drug treatment with PQ among P. vivax infected individuals is nonetheless challenging. It requires the individual to be glucose-6-phosphate dehydrogenase (G6PD) normal to avoid haemolysis during treatment and have a normal cytochrome P450 2D6 (CYP2D6) phenotype for an efficient treatment. All cohort children were screened for G6PD deficiency prior to the start of the study using the BinaxNOW G6PD Test (Alere Inc., USA), a qualitative rapid diagnosis test for G6PD enzyme activity in human whole blood. If any children were identified with P. vivax infections during the study, only G6PD normal children were administered with treatment for both liver (PQ) and blood (artemether-lumefantrine) stages. Meanwhile, P. vivax infected G6PD deficient children were treated with blood stage drug only. Without PQ treatment, these G6PD deficient children were observed to have significantly higher risk of P. vivax infection. This highlights G6PD deficiency is an obstacle for hypnozoite treatment. As such, it is important to screen individuals for G6PD and CYP2D6 prior to PQ drug treatment. This leads to one of the main aims of this thesis, which is to develop a high throughput population genetic screening assay with long read sequencing capability of both G6PD and CYP2D6 genes. A G6PD and CYP2D6 population based genotyping assay can serve to identify populations at risk of unsafe or ineffective treatment with PQ, thus improving the safety and efficacy of PQ treatment among P. vivax infected individuals in future. The occurrence of P. falciparum infections in Ngella was observed to be sporadic yet persisting throughout the year. By employing ten microsatellite markers and 192 SNP barcodes, the genetic diversity, structure and connectivity of the P. falciparum population in Ngella was studied. Comparative examination of the 27 P. falciparum infections from the cohort along with the five P. falciparum infections from previous cross-sectional survey in Ngella, against other villages (Auki and Tetere) of neighbouring islands of P. falciparum infections revealed that the P. falciparum population in Ngella is genetically related and inbred. Evidence of bottleneck event among the Ngella’s P. falciparum population was observed as well. The data presented in this thesis highlighted the risk factors associating with P. vivax infections, as well as the genetic structure of residual P. falciparum in Ngella. The development of large-scale genotyping assay for G6PD and CYP2D6 with long read sequencing allows population level genetic risk assessment for future radical cure of P. vivax infections. Collectively, these findings may support follow up elimination strategies in Solomon Islands or in other low malaria transmission setting with both P. falciparum and P. vivax coexist. For instance, a safe and efficient PQ mass drug administration can be organised among residents after genetic risk evaluation and high P. vivax transmission pockets identification. Evidence from population genetic approaches such as the identified population bottleneck event and low genetic diversity among the P. falciparum population can be useful knowledge that malaria control program has work effectively and further strengthening of the local control program could possibly eliminate P. falciparum.
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ItemThe molecular epidemiology of malaria in Solomon Islands( 2016)Historically, Solomon Islands in the Southwest Pacific has endured considerable P. falciparum and P. vivax burden. In the last 20 years, it has achieved 90% reduction in malaria cases through sustained, intensified malaria interventions (long lasting insecticide nets, indoor residual sprays and artemisinin-combination therapy) and is aiming for elimination by 2030. In 2012 and 2013, we conducted two cross-sectional surveys (study 1, all age, n=3501; study 2, age 0.5-12 years, n=1078) in Ngella, an area of low to moderate transmission. We aimed to investigate the natural reservoir and local epidemiology of P. vivax and P. falciparum. The contrast was striking. In the 2012 survey, only five clonal P. falciparum infections were identified from a single village and had the same msp2 genotpye. P. vivax prevalence was found to be moderately high (PCR, 13.4%), with predominantly afebrile, submicroscopic infections. The P. vivax infections displayed high genetic complexity (by genotyping with msp1F3 and MS16) and considerable spatial heterogeneity among and within different Ngella regions, and even at sub-village level with some households disproportionately harboring more infected co-inhabitants than others. In the 2013 study, a further seven P. falciparum infections were found in multiple locations, indicating that transmission of this species is continuing but at very low levels and infections are predominantly asymptomatic. To investigate the transmission scenario of the two species in more detail, we undertook population genetics analyses. We typed the five 2012 P. falciparum infections at 10 polymorphic microsatellite loci and 323 P. vivax infections at nine microsatellite loci. The five P. falciparum infections also clonal by this panel of 10 markers. Subsequent analyses of diversity (FST, GST, Jost’s D) and structure (Bayesian clustering) for P. vivax, revealed a genetically diverse population, but spatially fragmented, even among villages 6-15km apart. This indicates that whilst P. vivax may be more difficult to eliminate than P. falciparum, local parasite populations of both species have been affected by control interventions. A noteworthy epidemiological result from the 2012 survey was that living in a household with at least one other P. vivax carrier increased the risk of P. vivax infection, suggesting possible intra-household transmission. Subsequent analysis of genetic relatedness of P. vivax infections within households vs. among households indicated supported this hypothesis. Isolates from the same household were more genetically related than isolates from different households, and a high level of genetic kinship was retained among households located up to 100 meters of each other. Associations of P. vivax infection with human genetic factors known to confer protection against infection (α-thalassemia and Southeast Asian ovalocytosis, SAO) have been investigated in a second cross-sectional study conducted in 2013 in children aged 6 months to 12 years of age. SAO was not found in Ngella, whereas approximately a third of 1078 subjects were found to harbor the α-thalassemia alleles. The findings presented in this thesis will be discussed in the context of factors which may impact on follow-up elimination strategies in Solomon Islands, the Southwest Pacific and elsewhere in the endemic world where both P. falciparum and P. vivax are co-endemic.