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Oxford is at the forefront of teaching and research to help combat diseases affecting populations worldwide. Through its world-leading Centre for Tropical Medicine and Global Health (CTMGH), the University is working to find practical solutions to the problems these diseases cause. The centre conducts its research overseas in Africa and Asia, and across two sites in Oxford. The linked article shares three Oxford profiles.
Glucose-6-phosphate dehydrogenase activity in individuals with and without malaria: Analysis of clinical trial, cross-sectional and case–control data from Bangladesh
Background Glucose-6-phosphate dehydrogenase (G6PD) activity is dependent upon G6PD genotype and age of the red blood cell (RBC) population, with younger RBCs having higher activity. Peripheral parasitemia with Plasmodium spp. induces hemolysis, replacing older RBCs with younger cells with higher G6PD activity. This study aimed to assess whether G6PD activity varies between individuals with and without malaria or a history of malaria. Methods and findings Individuals living in the Chittagong Hill Tracts of Bangladesh were enrolled into 3 complementary studies: (i) a prospective, single-arm clinical efficacy trial of patients (n = 175) with uncomplicated malaria done between 2014 and 2015, (ii) a cross-sectional survey done between 2015 and 2016 (n = 999), and (iii) a matched case–control study of aparasitemic individuals with and without a history of malaria done in 2020 (n = 506). G6PD activity was compared between individuals with and without malaria diagnosed by microscopy, rapid diagnostic test (RDT), or polymerase chain reaction (PCR), and in aparasitemic participants with and without a history of malaria. In the cross-sectional survey and clinical trial, 15.5% (182/1,174) of participants had peripheral parasitemia detected by microscopy or RDT, 3.1% (36/1,174) were positive by PCR only, and 81.4% (956/1,174) were aparasitemic. Aparasitemic individuals had significantly lower G6PD activity (median 6.9 U/g Hb, IQR 5.2–8.6) than those with peripheral parasitemia detected by microscopy or RDT (7.9 U/g Hb, IQR 6.6–9.8, p < 0.001), but G6PD activity similar to those with parasitemia detected by PCR alone (submicroscopic parasitemia) (6.1 U/g Hb, IQR 4.8–8.6, p = 0.312). In total, 7.7% (14/182) of patients with malaria had G6PD activity < 70% compared to 25.0% (248/992) of participants with submicroscopic or no parasitemia (odds ratio [OR] 0.25, 95% CI 0.14–0.44, p < 0.001). In the case–control study, the median G6PD activity was 10.3 U/g Hb (IQR 8.8–12.2) in 253 patients with a history of malaria and 10.2 U/g Hb (IQR 8.7–11.8) in 253 individuals without a history of malaria (p = 0.323). The proportion of individuals with G6PD activity < 70% was 11.5% (29/253) in the cases and 15.4% (39/253) in the controls (OR 0.7, 95% CI 0.41–1.23, p = 0.192). Limitations of the study included the non-contemporaneous nature of the clinical trial and cross-sectional survey. Conclusions Patients with acute malaria had significantly higher G6PD activity than individuals without malaria, and this could not be accounted for by a protective effect of G6PD deficiency. G6PD-deficient patients with malaria may have higher than expected G6PD enzyme activity and an attenuated risk of primaquine-induced hemolysis compared to the risk when not infected.
Phylogenetic analysis of six SARS-CoV-2 genomes collected from the Comoros islands confirmed local circulation of the 501Y.V2 variant of concern during the country’s first major SARS-CoV-2 wave in January 2021. These findings demonstrate the importance of SARS-CoV-2 genomic surveillance and have implications for ongoing COVID-19 control strategies on the islands. Article summary line Circulation of SARS-CoV-2 501Y.V2 variant of concern in the Comoros Islands during a major COVID-19 infection wave in January 2021
We generated 274 SARS-CoV-2 genomes from samples collected during the early phase of the Kenyan pandemic. Phylogenetic analysis identified 8 global lineages and at least 76 independent SARS-CoV-2 introductions into Kenyan coast. The dominant B.1 lineage (European origin) accounted for 82.1% of the cases. Lineages A, B and B.4 were detected from screened individuals at the Kenya-Tanzania border or returning travellers but did not lead to established transmission. Though multiple lineages were introduced in coastal Kenya within three months following the initial confirmed case, none showed extensive local expansion other than cases characterised by lineage B.1, which accounted for 45 of the 76 introductions. We conclude that the international points of entry were important conduits of SARS-CoV-2 importations. We speculate that early public health responses prevented many introductions leading to established transmission, but nevertheless a few undetected introductions were sufficient to give rise to an established epidemic.
The full diversity of the circulating human B cell compartment is unknown. Flow cytometry analysis suggests that in addition to naïve and memory B cells, there exists a population of CD11c + , CD27 − CD21 − “atypical” B cells, that are associated with chronic or recurrent infection and autoimmunity. We used single cell RNA-seq approaches to examine the diversity of both antigen-specific B cells and total B cells in healthy subjects and individuals naturally-exposed to recurrent malaria infections. This analysis revealed two B cell lineages: a classical lineage of activated and resting memory B cells, and an atypical-like lineage. Surprisingly, the atypical lineage was common in both malaria exposed individuals and non-exposed healthy controls. Using barcoded antibodies in conjunction with our transcriptomic data, we found that atypical lineage cells in healthy individuals lack many atypical B markers and thus represent an undercounted cryptic population. We further determined using antigen specific probes that atypical cells can be induced by primary vaccination in humans and can be recalled upon boosting. Collectively these data suggest that atypical cells are not necessarily pathogenic but can be a normal component of B responses to antigen.
Impact of Plasmodium falciparum small-sized extracellular vesicles on host peripheral blood mononuclear cells
Background: Exagerated immune activation has a key role in the pathogenesis of malaria. During blood-stage infection, Plasmodium falciparum can interact directly with host immune cells through infected red blood cells (PfiRBCs), or indirectly by the release of extracellular vesicles (EVs). Here, we compared the impact of PfiRBCs and P. falciparum small-sized EVs (PfsEVs, also known as exosomes) from a Kenyan clinical isolate (PfKE12) adapted to short-term laboratory culture conditions on host peripheral blood mononuclear cells (PBMC). Methods: PfsEVs were isolated from cell-free culture-conditioned media by ultracentrifugation while mature trophozoite PfiRBCs were purified by magnetic column separation. The PfsEVs and the PfiRBCs were co-cultured for 18 hours with PBMC. Cellular responses were quantified by cell surface expression of activation markers (CD25, CD69) and cytokine/chemokine levels in the supernatant. Results: Relative to negative control conditions, PfsEVs induced CD25 expression on CD4+, CD19+ and CD14+ cells, while PfiRBCs induced on CD19+ and CD14+ cells. Both PfsEVs and PfiRBCs induced CD69 on CD4+, CD8+ and CD19+ cells. In addition, PfiRBCs induced higher expression of CD69 on CD14+ cells. CD69 induced by PfiRBCs on CD4+ and CD19+ cells was significantly higher than that induced by PfsEVs. Secretion of MIP1α, MIP1β, GM-CSF, IL-6, IL-8, and TNFα were significantly induced by both PfsEVs and PfiRBCs whereas MCP-1, IL-10, IL-17α were preferentially induced by PfsEVs and IP-10 and IFN-γ by PfiRBCs. Prior exposure to malaria (judged by antibodies to schizont extract) was associated with lower monocyte responses to PfsEVs. Conclusions: PfsEVs and PfiRBCs showed differential abilities to induce secretion of IL-17α and IFN-γ, suggesting that the former are better at inducing Th17, whilst the latter induce Th1 immune responses respectively. Prior exposure to malaria significantly reduces the ability of PfsEVs to activate monocytes, suggesting immune tolerance to PfsEVs may play a role in naturally acquired anti-disease immunity.
10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity
Background: Studies of long-term malaria cohorts have provided essential insights into how Plasmodium falciparum interacts with humans, and influences the development of antimalarial immunity. Immunity to malaria is acquired gradually after multiple infections, some of which present with clinical symptoms. However, there is considerable variation in the number of clinical episodes experienced by children of the same age within the same cohort. Understanding this variation in clinical symptoms and how it relates to the development of naturally acquired immunity is crucial in identifying how and when some children stop experiencing further malaria episodes. Where variability in clinical episodes may result from different rates of acquisition of immunity, or from variable exposure to the parasite. Methods: Using data from a longitudinal cohort of children residing in an area of moderate P. falciparum transmission in Kilifi district, Kenya, we fitted cumulative episode curves as monotonic-increasing splines, to 56 children under surveillance for malaria from the age of 5 to 15. Results: There was large variability in the accumulation of numbers of clinical malaria episodes experienced by the children, despite being of similar age and living in the same general location. One group of children from a particular sub-region of the cohort stopped accumulating clinical malaria episodes earlier than other children in the study. Despite lack of further clinical episodes of malaria, these children had higher asymptomatic parasite densities and higher antibody titres to a panel of P. falciparum blood-stage antigens. Conclusions: This suggests development of clinical immunity rather than lack of exposure to the parasite, and supports the view that this immunity to malaria disease is maintained by a greater exposure to P. falciparum, and thus higher parasite burdens. Our study illustrates the complexity of anti-malaria immunity and underscores the need for analyses which can sufficiently reflect the heterogeneity within endemic populations.
The impact of child health interventions and risk factors on child survival in Kenya, 1993–2014: a Bayesian spatio-temporal analysis with counterfactual scenarios
Abstract Background During the millennium development goals period, reduction in under-five mortality (U5M) and increases in child health intervention coverage were characterised by sub-national disparities and inequities across Kenya. The contribution of changing risk factors and intervention coverage on the sub-national changes in U5M remains poorly defined. Methods Sub-national county-level data on U5M and 43 factors known to be associated with U5M spanning 1993 and 2014 were assembled. Using a Bayesian ecological mixed-effects regression model, the relationships between U5M and significant intervention and infection risk ecological factors were quantified across 47 sub-national counties. The coefficients generated were used within a counterfactual framework to estimate U5M and under-five deaths averted (U5-DA) for every county and year (1993–2014) associated with changes in the coverage of interventions and disease infection prevalence relative to 1993. Results Nationally, the stagnation and increase in U5M in the 1990s were associated with rising human immunodeficiency virus (HIV) prevalence and reduced maternal autonomy while improvements after 2006 were associated with a decline in the prevalence of HIV and malaria, increase in access to better sanitation, fever treatment-seeking rates and maternal autonomy. Reduced stunting and increased coverage of early breastfeeding and institutional deliveries were associated with a smaller number of U5-DA compared to other factors while a reduction in high parity and fully immunised children were associated with under-five lives lost. Most of the U5-DA occurred after 2006 and varied spatially across counties. The highest number of U5-DA was recorded in western and coastal Kenya while northern Kenya recorded a lower number of U5-DA than western. Central Kenya had the lowest U5-DA. The deaths averted across the different regions were associated with a unique set of factors. Conclusion Contributions of interventions and risk factors to changing U5M vary sub-nationally. This has important implications for targeting future interventions within decentralised health systems such as those operated in Kenya. Targeting specific factors where U5M has been high and intervention coverage poor would lead to the highest likelihood of sub-national attainment of sustainable development goal (SDG) 3.2 on U5M in Kenya.
Subnational estimates of factors associated with under-five mortality in Kenya: a spatio-temporal analysis, 1993–2014
BackgroundTo improve child survival, it is necessary to describe and understand the spatial and temporal variation of factors associated with child survival beyond national aggregates, anchored at decentralised health planning units. Therefore, we aimed to provide subnational estimates of factors associated with child survival while elucidating areas of progress, stagnation and decline in Kenya.MethodsTwenty household surveys and three population censuses conducted since 1989 were assembled and spatially aligned to 47 subnational Kenyan county boundaries. Bayesian spatio-temporal Gaussian process regression models accounting for inadequate sample size and spatio-temporal relatedness were fitted for 43 factors at county level between 1993 and 2014.ResultsNationally, the coverage and prevalence were highly variable with 38 factors recording an improvement. The absolute percentage change (1993–2014) was heterogeneous ranging between 1% and 898%. At the county level, the estimates varied across space and over time with a majority showing improvements after 2008 which was preceded by a period of deterioration (late-1990 to early-2000). Counties in Northern Kenya were consistently observed to have lower coverage of interventions and remained disadvantaged in 2014 while areas around Central Kenya had and historically have had higher coverage across all intervention domains. Most factors in Western and South-East Kenya recorded moderate intervention coverage although having a high infection prevalence of both HIV and malaria.ConclusionThe heterogeneous estimates necessitates prioritisation of the marginalised counties to achieve health equity and improve child survival uniformly across the country. Efforts are required to narrow the gap between counties across all the drivers of child survival. The generated estimates will facilitate improved benchmarking and establish a baseline for monitoring child development goals at subnational level.
In this review for the Vivax malaria collection, Kamala Thriemer and colleagues explore efforts to eliminate P. vivax malaria.
Lorenz von Seidlein and Nicholas White introduce a Collection on Plasmodium vivax malaria.
After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.
The remaining unknowns: a mixed methods study of the current and global health research priorities for COVID-19.
IntroductionIn March 2020, the WHO released a Global Research Roadmap in an effort to coordinate and accelerate the global research response to combat COVID-19 based on deliberations of 400 experts across the world. Three months on, the disease and our understanding have both evolved significantly. As we now tackle a pandemic in very different contexts and with increased knowledge, we sought to build on the work of the WHO to gain a more current and global perspective on these initial priorities.MethodsWe undertook a mixed methods study seeking the views of the global research community to (1) assess which of the early WHO roadmap priorities are still most pressing; (2) understand whether they are still valid in different settings, regions or countries; and (3) identify any new emerging priorities.ResultsThematic analysis of the significant body of combined data shows the WHO roadmap is globally relevant; however, new important priorities have emerged, in particular, pertinent to low and lower middle-income countries (less resourced countries), where health systems are under significant competing pressures. We also found a shift from prioritising vaccine and therapeutic development towards a focus on assessing the effectiveness, risks, benefits and trust in the variety of public health interventions and measures. Our findings also provide insight into temporal nature of these research priorities, highlighting the urgency of research that can only be undertaken within the period of virus transmission, as well as other important research questions but which can be answered outside the transmission period. Both types of studies are key to help combat this pandemic but also importantly to ensure we are better prepared for the future.ConclusionWe hope these findings will help guide decision-making across the broad research system including the multilateral partners, research funders, public health practitioners, clinicians and civil society.
Introduction: The 4-aminoquinolines, chloroquine, and hydroxychloroquine have been used for over 70 years for malaria and rheumatological conditions, respectively. Their broad-spectrum antiviral activity, excellent safety profile, tolerability, low cost, and ready availability made them prime repurposing therapeutic candidates at the beginning of the COVID-19 pandemic.Areas covered: Here, the authors discuss the history of hydroxychloroquine and chloroquine, the in vitro data which led to their widespread repurposing and adoption in COVID-19 and their complex pharmacokinetics. The evidence for the use of these drugs is assessed through in vivo animal experiments and the wealth of conflicting data and interpretations published during COVID-19, including the more informative results from randomized controlled trials (RCTs). The safety aspects of these drugs, in particular cardiotoxicity, are then reviewed.Expert opinion: The evidence from clinical trials in COVID-19 supports the well-established safety record of the 4-aminoquinolines at currently recommended dosage. In hospitalized patients with severe COVID-19 RCTs show clearly that the 4-aminoquinolines are not beneficial. The only treatments with proven benefit at this stage of infection are immunomodulators (dexamethasone, IL-6 receptor antagonists). No antiviral drugs have proven life-saving in late-stage COVID-19.
New Hope for a "Cursed" Crop? Understanding Stakeholder Attitudes to Plant Molecular Farming With Modified Tobacco in Europe.
Plant molecular farming (PMF) with tobacco could provide a sustainable and cheap platform for the production of high-value proteins for medical use. It could also offer European tobacco farmers an alternative, healthful end use for their crop. New plant breeding techniques (NPBTs) offer a means of quickly and precisely optimizing molecular farming platforms for this purpose. However, there has been little empirical research focussing on the barriers and facilitators of these technologies in the agricultural sphere. Here, we explore key stakeholder perceptions toward this combination of technologies, exploring their understanding of risk and opportunity. We interviewed N = 24 key stakeholders - tobacco farmers, agronomists, policymakers, and researchers - in three tobacco-growing areas of Spain and Italy. Our findings demonstrate these stakeholders have a favorable attitude toward PMF with tobacco due to its beneficial medical purpose and the opportunity it provides farmers to continue growing tobacco in a declining European market. Tobacco producers also reported favorable views toward NPBTs, though for some this was contingent on their use for non-food crops like tobacco. Most stakeholders' concerns are economic in nature, such as potential profitability and demands for new agronomic practices or infrastructure. Tobacco producer associations were thought to be important facilitators for future PMF scale-up. The attitude toward these technologies by smoking tobacco companies is, however, unknown and constitutes a potential risk to the development of PMF.
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3·5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.
MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.