Spatial and Temporal Heterogeneity of Malaria Transmission in sub-Saharan Africa

The past decade has seen a marked decline in malaria transmission and substantial progress towards malaria control in parts of Africa. A key tool in malaria control is the insecticide treated net (ITN). However, malaria remains a public health emergency in sub-Saharan Africa with children under five years of age bearing the greatest burden of the disease. In this thesis, I examine three sets of questions that are relevant to the changing epidemiology of malaria. a) I investigated trends in malaria cases in Kilifi County on the Kenyan Coast over geographical area and over time, age, and the effectiveness of ITN use in the community. I observed a decline in the proportion of admitted children who had malaria parasites detected by microscopy from 1998 to 2009 as previously observed in some countries of sub-Saharan African. However, there was a steady and marked increase in the proportion of children with malaria parasites after 2009 accompanied by a shift in burden of disease from younger age groups to older age groups. Community ITN use was highly effective in reducing the risk of malaria. As transmission fell, geographical heterogeneity became more marked. b) I undertook an analysis of data shared from 19 studies conducted between 1996 and 2015 in 7 countries of sub-Saharan Africa to examine whether micro-geographical heterogeneity was generalizable. Hotspots were identified in all datasets, and were more marked at lower transmission intensity. Given the predictability with which hotspots occur as transmission intensity falls, malaria control programmes should have a low threshold for responding to apparent clustering of cases. c) I then considered whether rapid diagnostic tests (RDTs) or PCR would alter detection of hotspots. Using cross-sectional studies of asymptomatic parasitaemia, I describe hotspots of malaria transmission in three sites on the Kenyan Coast using data from 8581 study participants. Microscopy and RDT missed a larger proportion of infections in low transmission settings. PCR hotspots completely overlapped with microscopy hotspots at a moderate transmission, but not at two low transmission setting. From this work, I recommend that malaria control programmes consider PCR testing for targeted control when transmission intensity is low

Spatiotemporal analysis of insecticide-treated net use for children under 5 in relation to socioeconomic gradients in Central and East Africa

Background: Insecticide-treated net (ITN) use is the core intervention among the strategies against malaria in subSaharan Africa (SSA) and the percentage of ITN ownership has increased from 47% in 2010 to 72% in 2017 across countries in SSA. Regardless of this massive expansion of ITN distribution, considerable gap between ownership and use of ITNs has been reported. Using data from more than 100,000 households in Central and East Africa (CEA) countries, the main aim of this study was to identify barriers associated with low ITN use and conduct geospatial analyses to estimate numbers and locations of vulnerable children living in areas with high malaria and low ITN use. Methods: Main sources of data for this study were the Demographic and Health Surveys and Malaria Indicator Surveys conducted in 11 countries in CEA. Logistic regression models for each country were built to assess the association between ITN ownership or ITN use and several socioeconomic and demographic variables. A density map of children under 5 living in areas at high-risk of malaria and low ITN use was generated to estimate the number of children who are living in these high malaria burden areas. Results: Results obtained suggest that factors such as the number of members in the household, total number of children in the household, education and place of residence can be key factors linked to the use of ITN for protecting children against malaria in CEA. Results from the spatiotemporal analyses found that although total rates of ownership and use of ITNs across CEA have increased up to 70% and 48%, respectively, a large proportion of children under 5 (19,780,678; 23% of total number of children) still lives in high-risk malaria areas with low use of ITNs. Conclusion: The results indicate that despite substantial progress in the distribution of ITNs in CEA, with about 70% of the households having an ITN, several socioeconomic factors have compromised the effectiveness of this control intervention against malaria, and only about 48% of the households protect their children under 5 with ITNs. Increasing the effective ITN use by targeting these factors and the areas where vulnerable children reside can be a core strategy meant to reducing malaria transmission

A systematic review of changing malaria disease burden in sub-Saharan Africa since 2000: comparing model predictions and empirical observations.

BACKGROUND: The most widely used measures of declining burden of malaria across sub-Saharan Africa are predictions from geospatial models. These models apply spatiotemporal autocorrelations and covariates to parasite prevalence data and then use a function of parasite prevalence to predict clinical malaria incidence. We attempted to assess whether trends in malaria cases, based on local surveillance, were similar to those captured by Malaria Atlas Project (MAP) incidence surfaces. METHODS: We undertook a systematic review (PROSPERO International Prospective Register of Systematic Reviews; ID = CRD42019116834) to identify empirical data on clinical malaria in Africa since 2000, where reports covered at least 5 continuous years. The trends in empirical data were then compared with the trends of time-space matched clinical malaria incidence from MAP using the Spearman rank correlation. The correlations (rho) between changes in empirically observed and modelled estimates of clinical malaria were displayed by forest plots and examined by meta-regression. RESULTS: Sixty-seven articles met our inclusion criteria representing 124 sites from 24 African countries. The single most important factor explaining the correlation between empirical observations and modelled predictions was the slope of empirically observed data over time (rho = - 0.989; 95% CI - 0.998, - 0.939; p < 0.001), i.e. steeper declines were associated with a stronger correlation between empirical observations and modelled predictions. Factors such as quality of study, reported measure of malaria and endemicity were only slightly predictive of such correlations. CONCLUSIONS: In many locations, both local surveillance data and modelled estimates showed declines in malaria burden and hence similar trends. However, there was a weak association between individual surveillance datasets and the modelled predictions where stalling in progress or resurgence of malaria burden was empirically observed. Surveillance data were patchy, indicating a need for improved surveillance to strengthen both empiric reporting and modelled predictions

Effect of transmission intensity on hotspots and micro-epidemiology of malaria in sub-Saharan Africa.

BACKGROUND: Malaria transmission intensity is heterogeneous, complicating the implementation of malaria control interventions. We provide a description of the spatial micro-epidemiology of symptomatic malaria and asymptomatic parasitaemia in multiple sites. METHODS: We assembled data from 19 studies conducted between 1996 and 2015 in seven countries of sub-Saharan Africa with homestead-level geospatial data. Data from each site were used to quantify spatial autocorrelation and examine the temporal stability of hotspots. Parameters from these analyses were examined to identify trends over varying transmission intensity. RESULTS: Significant hotspots of malaria transmission were observed in most years and sites. The risk ratios of malaria within hotspots were highest at low malaria positive fractions (MPFs) and decreased with increasing MPF (p < 0.001). However, statistical significance of hotspots was lowest at extremely low and extremely high MPFs, with a peak in statistical significance at an MPF of ~0.3. In four sites with longitudinal data we noted temporal instability and variable negative correlations between MPF and average age of symptomatic malaria across all sites, suggesting varying degrees of temporal stability. CONCLUSIONS: We observed geographical micro-variation in malaria transmission at sites with a variety of transmission intensities across sub-Saharan Africa. Hotspots are marked at lower transmission intensity, but it becomes difficult to show statistical significance when cases are sparse at very low transmission intensity. Given the predictability with which hotspots occur as transmission intensity falls, malaria control programmes should have a low threshold for responding to apparent clustering of cases

Variation in the effectiveness of insecticide treated nets against malaria and outdoor biting by vectors in Kilifi, Kenya

Background: Insecticide treated nets (ITNs) protect humans against bites from the Anopheles mosquito vectors that transmit malaria, thereby reducing malaria morbidity and mortality. It has been noted that ITN use leads to a switch from indoor to outdoor feeding among these vectors. It might be expected that outdoor feeding would undermine the effectiveness of ITNs that target indoors vectors, but data are limited. Methods: We linked homestead level geospatial data to clinical surveillance data at a primary healthcare facility in Kilifi County in order to map geographical heterogeneity in ITN effectiveness and observed vector feeding behaviour using landing catches and CDC light traps in six selected areas of varying ITN effectiveness. We quantified the interaction between mosquitoes and humans to evaluate whether outdoor vector biting is a potential explanation for the variation in ITN effectiveness. Results: We observed 37% and 46% visits associated with positive malaria slides among ITN users and non-ITN-users, respectively; ITN use was associated with 32% protection from malaria (crude OR = 0.68, 95% CI: 0.64, 0.73). We obtained modification of ITN effectiveness by geographical area (p=0.016), and identified 6 hotspots using the spatial scan statistic. Majority of mosquitoes were caught outdoor (60%) and were of the An. funestus group (75%). The overall propensity to feed at times when most people were asleep was high; the vast majority of the Anopheles mosquitoes were caught at times when most people are indoors asleep. Estimates for the proportion of human-mosquito contact between the first and last hour when most humans were asleep was consistently high across all locations, ranging from 0.83 to 1.00. Conclusion: Our data do not provide evidence of an epidemiological association between microgeographical variations in ITN effectiveness and variations in the microgeographical distribution of outdoor biting.</ns4:p

Low Immune Activation in Early Pregnancy Is Associated With Preterm But Not Small-for-gestational-age Delivery in Women Infected With Human Immunodeficiency Virus Initiating Antiretroviral Therapy in Pregnancy: A Prematurity Immunology in HIV-infected Mothers and their Infants Study (PIMS) Case-control Study in Cape Town, South Africa.

BACKGROUND: Mechanisms underlying an association between human immunodeficiency virus (HIV) or antiretroviral therapy (ART) during pregnancy with risk of preterm delivery (PTD) and small-for-gestational-age (SGA) remain unclear. We explored the association between cellular immune activation and PTD or SGA in women with HIV initiating ART during or before pregnancy. METHODS: Women with HIV enrolled at median 15 weeks' gestation, were analyzed for immune markers, and matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery 25th percentile) as outcomes. Lymphocytes, monocytes, and dendritic cell populations and their activation status or functionality were enumerated by flow cytometry. RESULTS: PTD cases initiating ART in pregnancy showed decreased CD8+ T cell, monocyte, and dendritic cell activation; increased classical (CD14+CD16-) and intermediate (CD14+CD16+) monocyte frequencies; and decreased inflammatory monocytes (CD14dimCD16+) compared with SGA cases and term controls (all P < .05). Allowing for baseline viral load, the immune markers remained significantly associated with PTD but only in women initiating ART in pregnancy. Lower monocyte activation was predictive of PTD. TLR ligand-induced interferon-α and macrophage inflammatory protein-1β levels in monocytes were significantly lower in PTD women initiating ART in pregnancy. CONCLUSION: Low immune activation, skewing toward anti-inflammatory monocytes, and lower monocyte cytokine production in response to TLR ligand stimulation were associated with PTD but not SGA among women initiating ART in, but not before, pregnancy, suggesting immune anergy to microbial stimulation as a possible underlying mechanism for PTD in women initiating ART in pregnancy

Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study

Background Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children, which has implications for ongoing control strategies. Methods and findings We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked to data on residence and Insecticide Treated Net (ITN) ownership. This included data from 69,104 children admitted to Kilifi County Hospital aged from 3 months to 13 years between 1st January 1990 and 31st December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the predictors; location of residence, calendar time, child’s age, ITN use and Enhanced Vegetation Index (a proxy for soil moisture). The proportion of malaria slide positive admissions declined from 0.56 with 95% confidence interval (95%CI) 0.54 to 0.58 in 1998 to 0.07 95%CI 0.06 to 0.08 in 2009, but then increased again through to 0.24 95%CI 0.22 to 0.25 in 2014. Older children accounted for most of the increase after 2009 (0.035 95%CI (0.030 to 0.040) among young children compared to 0.22 95%CI 0.21 to 0.23 in older children). There was a non-linear relationship between malaria risk and prevalence of ITN use within a 2km radius of an admitted child’s residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. Conclusion Following a period of reduced transmission a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate against the increasing burden among older children and universal ITN coverage is a promising strategy to achieve this

Geographic-genetic analysis of Plasmodium falciparum parasite populations from surveys of primary school children in Western Kenya.

BACKGROUND: Malaria control, and finally malaria elimination, requires the identification and targeting of residual foci or hotspots of transmission. However, the level of parasite mixing within and between geographical locations is likely to impact the effectiveness and durability of control interventions and thus should be taken into consideration when developing control programs. METHODS: In order to determine the geographic-genetic patterns of Plasmodium falciparum parasite populations at a sub-national level in Kenya, we used the Sequenom platform to genotype 111 genome-wide distributed single nucleotide polymorphic (SNP) positions in 2486 isolates collected from children in 95 primary schools in western Kenya. We analysed these parasite genotypes for genetic structure using principal component analysis and assessed local and global clustering using statistical measures of spatial autocorrelation. We further examined the region for spatial barriers to parasite movement as well as directionality in the patterns of parasite movement. RESULTS: We found no evidence of population structure and little evidence of spatial autocorrelation of parasite genotypes (correlation coefficients <0.03 among parasite pairs in distance classes of 1km, 2km and 5km; p value<0.01). An analysis of the geographical distribution of allele frequencies showed weak evidence of variation in distribution of alleles, with clusters representing a higher than expected number of samples with the major allele being identified for 5 SNPs. Furthermore, we found no evidence of the existence of spatial barriers to parasite movement within the region, but observed directional movement of parasites among schools in two separate sections of the region studied. CONCLUSIONS: Our findings illustrate a pattern of high parasite mixing within the study region. If this mixing is due to rapid gene flow, then "one-off" targeted interventions may not be currently effective at the sub-national scale in Western Kenya, due to the high parasite movement that is likely to lead to re-introduction of infection from surrounding regions. However repeated targeted interventions may reduce transmission in the surrounding regions

Observational study: 27 years of severe malaria surveillance in Kilifi, Kenya.

BACKGROUND: Many parts of Africa have witnessed reductions in Plasmodium falciparum transmission over the last 15 years. Since immunity to malaria is acquired more rapidly at higher transmission, the slower acquisition of immunity at lower transmission may partially offset the benefits of reductions in transmission. We examined the clinical spectrum of disease and predictors of mortality after sustained changes in transmission intensity, using data collected from 1989 to 2016. METHODS: We conducted a temporal observational analysis of 18,000 children, aged 14 days to 14 years old, who were admitted to Kilifi County Hospital, Kenya, from 1989 to 2016 with malaria. We describe the trends over time of the clinical and laboratory criteria for severe malaria and associated risk of mortality. RESULTS: During the time periods 1989-2003, 2004-2008, and 2009-2016, Kilifi County Hospital admitted averages of 657, 310, and 174 cases of severe malaria per year including averages of 48, 14, and 12 malaria-associated deaths per year, respectively. The median ages in years of children admitted with cerebral malaria, severe anaemia, and malaria-associated mortality were 3.0 (95% confidence interval (CI) 2.2-3.9), 1.1 (95% CI 0.9-1.4), and 1.1 (95% CI 0.3-2.2) in the year 1989, rising to 4.9 (95% CI 3.9-5.9), 3.8 (95% CI 2.5-7.1), and 5 (95% CI 3.3-6.3) in the year 2016. The ratio of children with cerebral malaria to severe anaemia rose from 1:2 before 2004 to 3:2 after 2009. Hyperparasitaemia was a risk factor for death after 2009 but not in earlier time periods. CONCLUSION: Despite the evidence of slower acquisition of immunity, continued reductions in the numbers of cases of severe malaria resulted in lower overall mortality. Our temporal data are limited to a single site, albeit potentially applicable to a secular trend present in many parts of Africa

Dataset 1: Genotyping results for 111 single nucleotide polymorphisms (SNPs) typed in 2486 Plasmodium falciparum samples collected from primary school children during a parasitological survey in western Kenya in 2009 and 2010.

The columns contain the following information: sample_id, unique sample identifier; admin1, provincial location of school; district_name, district location of school; date_visit, date of sample collection; assay_code, name of assay; allele1 and allele2, alternative alleles at a specific SNP position; result, genotype call after processing; allele_ratio1, proportion of allele 1; allele_ratio2, proportion of allele 2; pass_fail, coding of SNP based on availability of valid genotype (pass=1) or lack of a valid genotype (fail=0). Geospatial data for individual school locations is considered sensitive data and therefore cannot be made open access. However, it can be accessed through a request to our data governance committee at [email protected]. The criteria for such access is specified in detail in the data sharing guidelines under which the DGC operates, and relates to a) addressing health research, b)operating within the bounds of informed consent, c)complying with confidentiality procedures, d) mitigating potential harm to participants in research