Association of Endothelial Protein C Receptor (EPCR) rs867186 Gene Polymorphism With Increased Levels of Soluble EPCR and High Risk of Severe Malaria and Fatality in Beninese Children.

The endothelial protein C receptor (EPCR)-rs867186 G allele has been linked to high plasma levels of soluble EPCR (sEPCR) and controversially associated with either susceptibility or resistance to severe and cerebral malaria. In this study, quantitative enzyme-linked immunosorbent assay and sequencing were used to assess sEPCR levels and EPCR-rs867186 polymorphism in blood samples from Beninese children with different clinical presentations of malaria. Our findings show that sEPCR levels were higher at hospital admission than during convalescence and that EPCR-rs867186 G allele was associated with increased sEPCR plasma levels, malaria severity, and mortality rate (P < .001, P = .03, and P = .04, respectively), suggesting a role of sEPCR in the pathogenesis of severe malaria.

Background malaria incidence and parasitemia during the three-dose RTS,S/AS01 vaccination series do not reduce magnitude of antibody response nor efficacy against the first case of malaria.

BACKGROUND: RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. METHODS: To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria (to exclude the effect of naturally acquired immunity) using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009-2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and background malaria incidence. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. RESULTS: We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by background incidence or parasitemia during the primary vaccination series. CONCLUSIONS: We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that control-group immunity is likely a major reason for lower efficacy in high transmission settings, not reduced immune responses to RTS,S/AS01. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Malaria Transmission Intensity Likely Modifies RTS, S/AS01 Efficacy Due to a Rebound Effect in Ghana, Malawi, and Gabon.

BACKGROUND: RTS,S/AS01 is the first malaria vaccine to be approved and recommended for widespread implementation by the World Health Organization (WHO). Trials reported lower vaccine efficacies in higher-incidence sites, potentially due to a "rebound" in malaria cases in vaccinated children. When naturally acquired protection in the control group rises and vaccine protection in the vaccinated wanes concurrently, malaria incidence can become greater in the vaccinated than in the control group, resulting in negative vaccine efficacies. METHODS: Using data from the 2009-2014 phase III trial (NCT00866619) in Lilongwe, Malawi; Kintampo, Ghana; and Lambaréné, Gabon, we evaluate this hypothesis by estimating malaria incidence in each vaccine group over time and in varying transmission settings. After estimating transmission intensities using ecological variables, we fit models with 3-way interactions between vaccination, time, and transmission intensity. RESULTS: Over time, incidence decreased in the control group and increased in the vaccine group. Three-dose efficacy in the lowest-transmission-intensity group (0.25 cases per person-year [CPPY]) decreased from 88.2% to 15.0% over 4.5 years, compared with 81.6% to -27.7% in the highest-transmission-intensity group (3 CPPY). CONCLUSIONS: These findings suggest that interventions, including the fourth RTS,S dose, that protect vaccinated individuals during the potential rebound period should be implemented for high-transmission settings.

Improved adherence to test, treat, and track (T3) malaria strategy among Over-the-Counter Medicine Sellers (OTCMS) through interventions implemented in selected rural communities of Fanteakwa North district, Ghana.

BACKGROUND: Prompt diagnosis and treatment of malaria prevents a mild case from developing into severe disease and death. Unfortunately, parasitological testing of febrile children is greater in the public and formal private sector than in the informal private sector where many patients with malaria-like symptoms first seek treatment. This study was aimed at improving implementation of the T3 policy among OTCMS using some interventions that could be scaled-up easily at the national level. METHODS: Interventions were evaluated using a two-arm, cluster randomized trial across 8 rural communities (4 clusters per arm), in two adjacent districts of Ghana. A total of 7 OTCMS in the intervention arm and 5 OTCMS in the control arm in the selected communities participated in the study. Five interventions were implemented in the intervention arm only. These were acquisition of subsidized malaria rapid diagnostic test (RDT) kits, training of OTCMS, supportive visits to OTCMS, community sensitization on malaria, and introduction of malaria surveillance tool. The primary outcome was the proportion of children under 10 years with fever or suspected to have malaria visiting OTCMS and getting tested (using RDT) before treatment. Secondary outcomes included OTCMS adherence to national malaria treatment guidelines and the recommended RDT retail price. Outcomes were measured using mystery client (an adult who pretends to be a real patient) surveys supplemented by a household survey. Proportions were compared using chi-square test or Fisher exact test. RESULTS: Following deployment of interventions, mystery client survey showed that OTCMS' adherence to malaria protocol in the intervention arm increased significantly (p < 0.05) compared to the control arm. Household surveys in the intervention arm showed that caregivers self-treating their children or visiting drug vendors significantly decreased in favour of visits to OTCMS shops for treatment (p < 0.001). End-line malaria testing rate was higher compared with the baseline rate, though not statistically significant (30.8% vs 10.5%; p = 0.1238). OTCMS in the intervention arm also adhered to the subsidized RDT retail price of GHc2.40. CONCLUSION: Interventions targeting OTCMS in rural communities have the potential of improving adherence to the T3 malaria policy and subsequently improving management of uncomplicated malaria in Ghana. TRIAL REGISTRATION: ISRCTN registry ISRCTN77836926. Registered on 4 November 2019.

Global Analysis of Plasmodium falciparum Dihydropteroate Synthase Variants Associated with Sulfadoxine Resistance Reveals Variant Distribution and Mechanisms of Resistance: A Computational-Based Study.

The continual rise in sulfadoxine (SDX) resistance affects the therapeutic efficacy of sulfadoxine-pyrimethamine; therefore, careful monitoring will help guide its prolonged usage. Mutations in Plasmodium falciparum dihydropteroate synthase (Pfdhps) are being surveilled, based on their link with SDX resistance. However, there is a lack of continuous analyses and data on the potential effect of molecular markers on the Pfdhps structure and function. This study explored single-nucleotide polymorphisms (SNPs) in Pfdhps that were isolated in Africa and other countries, highlighting the regional distribution and its link with structure. In total, 6336 genomic sequences from 13 countries were subjected to SNPs, haplotypes, and structure-based analyses. The SNP analysis revealed that the key SDX resistance marker, A437G, was nearing fixation in all countries, peaking in Malawi. The mutation A613S was rare except in isolates from the Democratic Republic of Congo and Malawi. Molecular docking revealed a general loss of interactions when comparing mutant proteins to the wild-type protein. During MD simulations, SDX was released from the active site in mutants A581G and A613S before the end of run-time, whereas an unstable binding of SDX to mutant A613S and haplotype A437A/A581G/A613S was observed. Conformational changes in mutant A581G and the haplotypes A581G/A613S, A437G/A581G, and A437G/A581G/A613S were seen. The radius of gyration revealed an unfolding behavior for the A613S, K540E/A581G, and A437G/A581G systems. Overall, tracking such mutations by the continuous analysis of Pfdhps SNPs is encouraged. SNPs on the Pfdhps structure may cause protein-drug function loss, which could affect the applicability of SDX in preventing malaria in pregnant women and children.

Annual and intra-annual climate variability and change of the Volta Delta, Ghana.

Deltas are geographically and socio-ecologically distinct systems, with a unique climate and contextually high vulnerabilities to climate dynamics. Hence, they require specific climate change adaptation and policy responses, informed by delta-scale analysis. However, available climate knowledge on deltas is based mainly on broad-scale analysis that masks information unique to deltas. This applies to the Volta Delta system of Ghana. This study presents annual and intra-annual climate variability and trend analysis carried out across the Volta Delta, using the coefficient of variation (CV), anomaly, Mann-Kendall and Pettit statistics. There were time and space differences in climate change and variability. Statistically significant (P < 0.05) positive trends were observed for the major wet season and the mean annual rainfall for Ada and highly significant (P < 0.01) positive trends for Akatsi. These contrasted with the observations in Adidome, which experienced a statistically highly significant (P < 0.01) decreasing trend in rainfall. There were significant (P< 0.05) increases in annual minimum, maximum, and mean temperatures over time in both coastal and inland delta stations. The annual rate of change of mean temperature ranged from 0.03 to 0.05. Ada, the more coastal location, has experienced a narrow range of temperature change, most probably due to the buffering capacity of the ocean. Point changes were observed in the climate data series in four (4) localities. We recommend that adaption and policy actions should include, the provision of small-scale irrigation, encouraging adoption of drought-resistant crop varieties and crop diversification, and also be made responsive to the existing spatiotemporal climate variability and change within the Volta Delta.

Urbanizing with or without nature: pollution effects of human activities on water quality of major rivers that drain the Kumasi Metropolis of Ghana.

The effects of urbanization such as population upsurge, increased industrialization, urban agriculture, and rural-urban migration of persons exert pressure on the limited water resources in most cities. This study investigated the impact of human activities on the water and sediment quality of the three main rivers (Wiwi, Subin, and Suntre) in Kumasi, the second-largest city in Ghana. The physicochemical parameters and the concentrations of contaminants, including heavy metals, polycyclic aromatic hydrocarbons, pesticide residues, and microbial loads in the rivers, were linked to the specific human activities at the riverbanks. While all the 37 pesticide residues investigated in river sediments had concentrations below the detection limits (0.005 mg/kg for organochlorines, 0.010 mg/kg for organophosphates, and 0.010 mg/kg for synthetic pyrethroids), the study showed that the sediments are polluted with petrogenic and pyrogenic polycyclic aromatic hydrocarbons. River Subin, the most polluted among the three rivers, recorded benzo[e]pyrene concentrations up to 47,169 µg/kg. The geoaccumulation index and concentration factors show that the rivers are highly contaminated with metals such as cadmium, chromium, mercury, and arsenic and are related to human activities. The microbial quality of the rivers was poor, recording specific microbial loads of 6.8, 4.1, and 1.5 × 107 counts/100 mL respectively for Wiwi, Subin, and the Suntre Rivers. The three water bodies are therefore not suitable for recreational and irrigational purposes.

Antimalarial Drug Resistance Profiling of Plasmodium falciparum Infections in Ghana Using Molecular Inversion Probes and Next-Generation Sequencing.

A key drawback to monitoring the emergence and spread of antimalarial drug resistance in sub-Saharan Africa is early detection and containment. Next-generation sequencing methods offer the resolution, sensitivity, and scale required to fill this gap by surveilling for molecular markers of drug resistance. We performed targeted sequencing using molecular inversion probes to interrogate five Plasmodium falciparum genes (pfcrt, pfmdr1, pfdhps, pfdhfr, and pfk13) implicated in chloroquine, sulfadoxine-pyrimethamine (SP), and artemisinin resistance in two sites in Ghana. A total of 803 dried blood spots from children aged between 6 months and 14 years presenting with uncomplicated P. falciparum malaria at the Begoro District Hospital in Begoro and the Ewim Polyclinic in Cape Coast, Ghana, from 2014 to 2017 were prepared on filter paper. Thirteen years after the removal of drug pressure, chloroquine-sensitive parasite strains with pfcrt K76 have increased nearly to fixation in Begoro, in the forest area (prevalence = 95%), but at a lower rate in Cape Coast, in the coastal region (prevalence = 71%, Z = -3.5, P < 0.001). In addition, pfmdr1 184F-bearing parasites are under strong selection. The pfdhfr/pfdhps quadruple genotype ( IRNG K), associated with SP resistance, is near saturation. Our study identified at a 2 to 10% prevalence pfdhps 581G, which is a sulfadoxine resistance marker that correlates with the failure of SP prophylaxis in pregnancy and which has not been observed in Ghana. The differences in the reexpansion of chloroquine-sensitive strains observed at the two study sites, the stronger SP resistance, and the high prevalence of pfmdr1 184F should be further monitored to inform malaria control strategies in Ghana.

Prevalence of asymptomatic malaria parasitaemia following mass testing and treatment in Pakro sub-district of Ghana.

BACKGROUND: Global efforts to scale-up malaria control interventions are gaining steam. These include the use of Long-Lasting Insecticide Nets, Indoor Residual Spraying, Intermittent Preventive Treatment and Test, Treat and Track. Despite these, the drive for malaria elimination is far from being realistic in endemic communities in Africa. This is partly due to the fact that asymptomatic parasite carriage, not specifically targeted by most interventions, remains the bedrock that fuels transmission. This has led to mass testing, treatment and tracking (MTTT) as an alternative strategy to target asymptomatic individuals. We report the impact of MTTT on the prevalence of asymptomatic malaria parasitaemia over a one-year period in Ghana, hypothesizing that implementing MTTT could reduce the rate of asymptomatic parasitaemia. METHODS: A population of about 5000 individuals in seven communities in the Pakro sub-district of Ghana participated in this study. A register was developed for each community following a census. MTTT engaged trained community-based health volunteers who conducted house-to-house testing using RDTs every 4 months and treated positive cases with Artemisinin-based Combination Therapy. Between interventions, community-based management of malaria was implemented for symptomatic cases. RESULTS: MTTT Coverage was 98.8% in July 2017 and 79.3% in July 2018. Of those tested, asymptomatic infection with malaria parasites reduced from 36.3% (1795/4941) in July 2017 to 32.9% (1303/3966) in July 2018 (p = 0.001). Prevalence of asymptomatic parasitaemia among children under 15 years declined from 52.6% (1043/1984) in July 2017 to 47.5% (820/1728) in July 2018 (p = 0.002). Implementing MTTT significantly reduced asymptomatic parasitaemia by 24% from July 2017 to July 2018 after adjusting for age, ITN use and axillary temperature (OR = 0.76, CI = 0.67, 0.85 p ≤ 0.001). CONCLUSION: This study has demonstrated that implementing MTTT is feasible and could reduce the prevalence of asymptomatic malaria parasitaemia in children under 15 years of age. Furthermore, the use of community-based health volunteers could ensure high coverage at lower cost of implementation. TRIAL REGISTRATION: NCT04167566, Date 14/11/2019. Retrospective registration.

Efficient transplacental transfer of SARS-CoV-2 antibodies between naturally exposed mothers and infants in Accra, Ghana.

We aimed to determine SARS-CoV-2 antibody seropositivity among pregnant women and the transplacental transfer efficiency of SARS-CoV-2-specific antibodies relative to malaria antibodies among SARS-CoV-2 seropositive mother-cord pairs. This cross-sectional study was conducted in Accra, Ghana, from March to May 2022. Antigen- specific IgG antibodies against SARS-CoV-2 (nucleoprotein and spike-receptor binding domain) and malarial antigens (circumsporozoite protein and merozoite surface protein 3) in maternal and cord plasma were measured by ELISA. Plasma from both vaccinated and unvaccinated pregnant women were tested for neutralizing antibodies using commercial kit. Of the unvaccinated pregnant women tested, 58.12% at antenatal clinics and 55.56% at the delivery wards were seropositive for both SARS-CoV-2 nucleoprotein and RBD antibodies. Anti-SARS-CoV-2 antibodies in cord samples correlated with maternal antibody levels (N antigen rs = 0.7155, p < 0.001; RBD rs = 0.8693, p < 0.001). Transplacental transfer of SARS-CoV-2 nucleoprotein antibodies was comparable to circumsporozoite protein antibodies (p = 0.9999) but both were higher than transfer rates of merozoite surface protein 3 antibodies (p < 0.001). SARS-CoV-2 IgG seropositivity among pregnant women in Accra is high with a boost of SARS-CoV-2 RBD-specific IgG in vaccinated women. Transplacental transfer of anti-SARS-CoV-2 and malarial antibodies was efficient, supporting vaccination of mothers as a strategy to protect infants against SARS-CoV-2.

Diagnostic performance of an ultra-sensitive RDT and a conventional RDT in malaria mass testing, treatment and tracking interventions in southern Ghana.

BACKGROUND: Application of numerous malaria control interventions has led to reduction in clinical malaria cases and deaths but also the realisation that asymptomatic parasite carriers play a key role in sustaining transmission. This study assessed the effectiveness of using the Ultra-sensitive NxTek eliminate RDT (uRDT) and conventional SD Bioline HRP2 RDT (cRDT) in diagnosing asymptomatic parasitaemia while measuring the impact of mass testing, treatment and tracking (MTTT) on the prevalence of asymptomatic malaria over a 1-year period in Ghana. METHODS: A total of 4000 targeted participants from two towns, Obom and Kofi Kwei, with their surrounding villages, were tested for asymptomatic malaria four times over the study period using uRDT (intervention) and the cRDT (control) respectively. Participants carrying malaria parasites were followed by home visit and phone calls for compliance to treatment, and filter paper blood blots collected from participants were used to determine true parasite carriage by PET-PCR. A mathematical model of the study site was developed and used to test the impact of test sensitivity and mass migration on the effect of MTTT. RESULTS: The start and end point sensitivities of the cRDT were 48.8% and 41.7% and those for the uRDT were 52.9% and 59.9% respectively. After a year of MTTTs, asymptomatic parasite prevalence, as determined by PCR, did not differ statistically in the control site (40.6% to 40.1%, P = 0.730) but decreased at the intervention site (55.9% to 46.4%, P < 0.0001). Parasite prevalence by RDT, however, indicated statistical reduction in the control site (25.3% to 22.3%, P = 0.017) and no change in the intervention site (35.1% to 36.0%, P = 0.614). The model predicted a mild effect of both diagnostic sensitivity and human movement in diminishing the impact of MTTT in the study sites. CONCLUSIONS: Asymptomatic parasite prevalence at the molecular level reduced significantly in the site where the uRDT was used but not where the cRDT was used. Overall, the uRDT exhibited higher sensitivity relative to the cRDT. Highly sensitive molecular techniques such as PET-PCR should be included in parasite prevalence estimation during MTTT exercises.

Ligamentum arteriosum: Muscular and contractile.

Ductus arteriosus is a muscular artery in fetal circulation, spanning from the bifurcation of the pulmonary trunk to the aortic arch, shunting blood directly from pulmonary circulation into systemic circulation thus by-passing the fluid-filled lungs. Postnatally, it changes name to the ligamentum arteriosum (LA), when a cascade of anatomical and physiological processes leads to its closure. Though the LA has generally been considered as a fibrosed remnant of the ductus arteriosus, anecdotal and contradictory reports still describe the LA as a small muscular artery. We hypothesized the likelihood of contractile muscular elements retainment in this so-called ligament. To investigate this, mediastinum of wild-type mouse, pig, and human LA were subjected to routine and special histological staining, single-immunolabeling, electron microscopy (mouse and pig only), and tension recording of explanted pig LA in organ bath experiments. Contrary to a canonical ligament, the LA was mainly made up of α-smooth muscle actin-positive cells in all three species, confirmed by routine and special histological staining as well as transmission electron microscopy. Myocytes within the LA contracted in response to exogenous noradrenalin (NA). NA-induced precontracted LA relaxed upon administration of the α1-adrenergic blockers (prazosin and tamsulosin). Though the LA does not function in its original capacity as fetal shunt, it is clearly not a passive structure, and may be described as muscular and contractile. The contractile abilities of LA myocytes may act on the two great vessels to which it is attached causing a change in their distensibility.

Ligamentum arteriosum and its telocytes: An ultrastructure description.

Results from my study have shown in 2022 the existence of telocytes (TCs) in mice ligamentum arteriosum (LA). Telocytes (TCs) are unique interstitial or stromal cells of mesodermal origin, defined by long cellular extensions called telopodes (Tps) which form a network, connecting them to surrounding cells. These Tps have dilated portions named podoms (usually containing mitochondria, endoplasmic reticulum and caveolae) and very thin segments (below resolving power of light microscopy), called podomers. Generally, transmission electron microscope revealed the existence of Tps with various conformations: (a) long, flattened irregular veils (ribbon-like segments) with knobs, corresponding to podoms, and (b) tubular structures (podomers) with uneven caliber because of irregular dilations (knobs)-the podoms. Also shown were numerous extracellular vesicles and exosomes released by the TCs which sometimes made direct contact with telopodes. Telopodes were observed communicating with each other through adherens junctions. Telopodes sandwiched between myocytes or in close proximity (0.01 µm) from nerve terminals were also observed. These data might be useful for understanding the role(s) of TCs in intercellular signaling and communication, neuromodulation as well as comprehension of pathologies like structural remodeling within the LA.

Performance of SNP barcodes to determine genetic diversity and population structure of Plasmodium falciparum 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 Plasmodium falciparum 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 0.10, and iii) are independently segregating, to minimise bias in the analysis of genetic diversity and population structure. Further, to be standardised and used in many population genetic studies, these barcodes should maintain characteristics i) to iii) across various iv) geographies and v) time points. Using haplotypes generated from the MalariaGEN P. falciparum Community Project version six database, we investigated the ability of these two barcodes to fulfil these criteria in moderate-to-high transmission African populations in 25 sites across 10 countries. Predominantly clinical infections were analysed, with 52.3% found to be multiclonal, generating high proportions of mixed-allele calls (MACs) per isolate thereby impeding haplotype construction. Of the 24- and 96-SNPs, loci were removed if they were not biallelic and had low minor allele frequencies in all study populations, resulting in 20- and 75-SNP barcodes respectively for downstream population genetics analysis. Both SNP barcodes had low expected heterozygosity estimates in these African settings and consequently biased analyses of similarity. Both minor and major allele frequencies were temporally unstable. These SNP barcodes were also shown to identify weak genetic differentiation across large geographic distances based on Mantel Test and DAPC. These results demonstrate that these SNP barcodes are vulnerable to ascertainment bias and as such cannot be used as a standardised approach for malaria surveillance in moderate-to-high transmission areas in Africa, where the greatest genomic diversity of P. falciparum exists at local, regional and country levels.

High Plasma Levels of Neopterin Are Associated with Increased Mortality among Children with Severe Malaria in Benin.

Among the barriers to accessing adequate treatment and high-level monitoring for malaria febrile patients is the lack of effective prognostic markers. Neopterin, which is a marker of monocyte/macrophage activation, was found have increased during severe malaria. In this study, we used quantitative ELISA in order to assess the levels of plasma soluble neopterin in 151 patients from a cohort of Beninese children with severe malaria. We evaluated the prognostic accuracy of this molecule in order to predict the outcome of the disease. Our results show that neopterin levels were not significantly different between patients with different forms of severe malaria, including severe non-cerebral malaria (SNCM) and cerebral malaria (CM). However, the levels of this molecule were found to be higher in patients with severe malarial anemia (SMA) among both CM and SNCM cases (p-value = 0.02). Additionally, the levels of this molecule were found to be higher in patients who died from these pathologies compared to those who survived among the two clinical groups (p-value < 0.0001) and within the same group (p-value < 0.0001 for the CM group, p-value = 0.0046 for the SNCM group). The AUC-ROC for fatality among all the severe cases was 0.77 with a 95%CI of (0.69-0.85). These results suggest that plasma neopterin levels constitute a potential biomarker for predicting fatality among severe falciparum malaria patients.

Malaria Transmission Intensity and Parasitemia during the Three-Dose RTS,S/AS01 Vaccination Series do not Reduce Magnitude of Antibody Response nor Efficacy Against the First Case of Malaria.

Background: RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. Methods: To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria to exclude the delayed malaria effect using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009-2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and malaria transmission intensity. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. Results: We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by transmission intensity or parasitemia during the primary vaccination series. Conclusions: We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that delayed malaria is likely the main reason for lower efficacy in high transmission settings, not reduced immune responses. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Genomic approaches for monitoring transmission dynamics of malaria: A case for malaria molecular surveillance in Sub-Saharan Africa.

Transmission dynamics is an important indicator for malaria control and elimination. As we move closer to eliminating malaria in Sub-Saharan Africa (sSA), transmission indices with higher resolution (genomic approaches) will complement our current measurements of transmission. Most of the present programmatic knowledge of malaria transmission patterns are derived from assessments of epidemiologic and clinical data, such as case counts, parasitological estimates of parasite prevalence, and Entomological Inoculation Rates (EIR). However, to eliminate malaria from endemic areas, we need to track changes in the parasite population and how they will impact transmission. This is made possible through the evolving field of genomics and genetics, as well as the development of tools for more in-depth studies on the diversity of parasites and the complexity of infections, among other topics. If malaria elimination is to be achieved globally, country-specific elimination activities should be supported by parasite genomic data from regularly collected blood samples for diagnosis, surveillance and possibly from other programmatic interventions. This presents a unique opportunity to track the spread of malaria parasites and shed additional light on intervention efficacy. In this review, various genetic techniques are highlighted along with their significance for an enhanced understanding of transmission patterns in distinct topological settings throughout Sub-Saharan Africa. The importance of these methods and their limitations in malaria surveillance to guide control and elimination strategies, are explored.

The Effect of Mass Testing, Treatment and Tracking on the Prevalence of Febrile Illness in Children under 15 in Ghana.

Background: Malaria remains a serious threat to children under 15 years of age in sub-Sahara Africa. Mass testing, treatment and tracking (MTTT) of malaria has been reported to reduce parasite load significantly. However, the impact of MTTT on the prevalence of febrile illnesses in children under 15 is not yet clear. This study explores the impact of MTTT complemented by prompt home-based management of malaria on febrile illnesses and their treatment in children under 15 years old. Methods: A cohort of 460 children under 15 years were recruited from the Pakro subdistrict in Ghana during a community-wide implementation of a quarterly MTTT intervention. The MTTT implementation involved testing all household members for malaria using RDTs, and positive cases were treated with Artemisinin-based combination therapy (ACT). Febrile illnesses among this cohort in the two weeks prior to the prevalence survey at baseline and endline were recorded to constitute date for analysis. Results: The prevalence of febrile illnesses, such chills, convulsion, fever, diarrhoea, headache, vomit, cough/rashes or stomachache, etc., were recorded). Asymptomatic parasitaemia prevalence at baseline was 53.3%, which dropped to 44.1% at evaluation. An overall decrease in the parasitaemia prevalence of 33.0% (OR = 0.67, CI = 0.50, 0.89) was observed at evaluation compared to baseline after adjusting for age, ITN use and temperature. A 67% decrease in severe anaemia cases (Hb < 7) was observed at evaluation. Conclusion: Our findings suggest that implementing MTTT complemented by home-based timely management of malaria does not only reduce febrile illnesses and for that matter malaria prevalence, but could also reduce severe anaemia in children under 15 years old.

The impact of COVID-19 on implementation of mass testing, treatment and tracking of malaria in rural communities in Ghana: A qualitative study.

BACKGROUND: Mass test, treat and track (MTTT) of malaria is ongoing in the Pakro sub district of Ghana. In the delivery of MTTT of malaria, community health volunteers are trained to routinely provide this service through a door-to-door strategy. Following the report of the first cases of COVID-19 in Ghana, we conducted this study to explore the effects of the pandemic on the implementation of the MTTT of malaria intervention. METHODS: Using qualitative methodology, we conducted ten focus groups discussions (FGDs) in eight communities: eight with community members (N = 49); one with health workers (N = 6), and one with MTTT of malaria volunteers. In addition, two in-depth interviews (IDI) were conducted, one with health worker and another with a health manager. All interviews were recorded, translated into English during transcription and analysed using QSR NVivo 12. Thematic content analysis was used in this study. RESULTS: The findings of the study showed an increase in the number of people reporting with complications of malaria in health facilities in the study communities during the COVID-19 period. Some participants were of the view that COVID-19 rumours and misinformation could largely be responsible for the low coverage and uptake of the MTTT of malaria intervention. To sustain the uptake of the MTTT intervention, community engagement strategies were employed to identify and respond to these rumours. Also, incentive schemes were introduced to encourage parents and children to participate in the MTTT intervention during this period of COVID-19. CONCLUSION: Findings suggest that the COVID-19 pandemic has adversely affected the provision and uptake of malaria prevention and treatment services, especially the MTTT of malaria being implemented at the community level. These observations underscore the need to find innovative ways to address the challenges encountered in providing essential services during public health emergencies.

Specific Combinations of Inflammatory, Angiogenesis and Vascular Integrity Biomarkers Are Associated with Clinical Severity, Coma and Mortality in Beninese Children with Plasmodium Falciparum Malaria.

Malaria-related deaths could be prevented if powerful diagnostic and reliable prognostic biomarkers were available to allow rapid prediction of the clinical severity allowing adequate treatment. Using quantitative ELISA, we assessed the plasma concentrations of Procalcitonin, Pentraxine-3, Ang-2, sTie-2, suPAR, sEPCR and sICAM-1 in a cohort of Beninese children with malaria to investigate their potential association with clinical manifestations of malaria. We found that all molecules showed higher levels in children with severe or cerebral malaria compared to those with uncomplicated malaria (p-value < 0.005). Plasma concentrations of Pentraxine-3, Procalcitonin, Ang-2 and the soluble receptors were significantly higher in children with coma as defined by a Blantyre Coma Score < 3 (p < 0.001 for Pentraxine-3, suPAR, and sTie-2, p = 0.004 for PCT, p = 0.005 for sICAM-1, p = 0.04 for Ang-2). Moreover, except for the PCT level, the concentrations of Pentraxine-3, suPAR, sEPCR, sICAM-1, sTie-2 and Ang-2 were higher among children who died from severe malaria compared to those who survived (p = 0.037, p = 0.035, p < 0.0001, p= 0.0008, p = 0.01 and p = 0.02, respectively). These findings indicate the ability of these molecules to accurately discriminate among clinical manifestations of malaria, thus, they might be potentially useful for the early prognostic of severe and fatal malaria, and to improve management of severe cases.